Bendamustine plus Rituximab Versus R‐CHOP as First‐Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study

AbstractBackground.Rituximab plus bendamustine (R‐B) has been demonstrated to improve outcomes and reduce toxicity compared with rituximab, cyclophosphamide, doxorubicin, and prednisone (R‐CHOP) in follicular lymphoma (FL). Nevertheless, in clinical practice, many centers still prefer R‐CHOP to R‐B in patients with FL grade 3A (FL3A). Therefore, we retrospectively assessed patients with FL3A treated with either R‐CHOP or R‐B in five European cancer centers and compared their outcomes.Materials and Methods.We retrospectively assessed 132 patients affected by FL grade 3A treated with either R‐B or R‐CHOP in the first line and evaluated outcome and toxicity according to the type of treatment. This study included 101 patients who were a subgroup of a previously published cohort.Results.R‐B was less toxic and achieved a similar percentage of complete remissions compared with R‐CHOP (97% vs. 96%, p = .3). During follow‐up, 10 (16%) patients relapsed after R‐B and 29 (41%) after R‐CHOP (p = .001), leading to a median progression‐free survival (PFS) of 15 versus 11.7 years, respectively (p = .03). Furthermore, R‐B overcame the negative prognostic impact of BCL2 expression (15 vs. 4.8 years; p = .001). However, median overall survival was similar between both groups (not reached for both; p = .8).Conclusion.R‐B as a first‐line treatment of FL3A is better tolerated than R‐CHOP and seems to induce more profound responses, leading to a significantly lower relapse rate and prolonged PFS. Therefore, R‐B is a valid treatment option for FL grade 3A.Implications for Practice.Rituximab plus bendamustine (R‐B) has shown to be less toxic and more effective than rituximab, cyclophosphamide, doxorubicin, and prednisone (R‐CHOP) in follicular lymphoma grade 3A. Although both regimens can induce a complete remission in >95% of patients, relapses occur more frequently after R‐CHOP than R‐B, leading to a significantly longer progression‐free survival in the latter. R‐B is also able to overcome the impact of negative prognosticators, such as BCL2 expression. However, because of the indolent course of this disease and efficient salvage treatments, overall survival was similar in both treatment groups. Therefore, R‐B is a valid treatment option in this patient setting.

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Perception of Curability Among Advanced Cancer Patients: An International Collaborative Study

AbstractBackground.There are limited data on illness understanding and perception of cure among advanced cancer patients around the world. The aim of the study was to determine the frequency and factors associated with inaccurate perception of curability among advanced cancer patients receiving palliative care across the globe.Materials and Methods.Secondary analysis of a study to understand the core concepts in end‐of‐life care among advanced cancer patients receiving palliative care from 11 countries across the world. Advanced cancer patients were surveyed using a Patient Illness Understanding survey and Control Preference Scale. Descriptive statistics and multicovariate logistic regression analysis were performed.Results.Fifty‐five percent (763/1,390) of patients receiving palliative care inaccurately reported that their cancer is curable. The median age was 58, 55% were female, 59% were married or had a partner, 48% were Catholic, and 35% were college educated. Sixty‐eight percent perceived that the goal of therapy was "to get rid of their cancer," and 47% perceived themselves as "seriously ill." Multicovariate logistic regression analysis shows that accurate perception of curability was associated with female gender (odds ratio [OR] 0.73, p = .027), higher education (OR 0.37, p < .0001), unemployment status (OR 0.69, p = .02), and being from France (OR 0.26, p < .0001) and South Africa (OR 0.52, p = .034); inaccurate perception of curability was associated with better Karnofsky performance status (OR 1.02 per point, p = .0005), and being from Philippines (OR 15.49, p < .0001), Jordan (OR 8.43, p < .0001), Brazil (OR 2.17, p = .0037), and India (OR 2.47, p = .039).Conclusion.Inaccurate perception of curability in advanced cancer patients is 55% and significantly differs by gender, education, performance status, employment status, and country of origin. Further studies are needed to develop strategies to reduce this misperception of curability in advanced cancer patients.Implications for Practice.The findings of this study indicate that inaccurate perception of curability among advanced cancer patients is 55%. Inaccurate perception of curability significantly differs by gender, education, performance status, employment status, and country of origin. There is great need to facilitate improved patient–physician communication so as to improve health care outcomes and patient satisfaction.

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Therapeutic Anticoagulation in Patients with Primary Brain Tumors or Secondary Brain Metastasis

AbstractPatients with primary or metastatic brain tumors are at increased risk of developing venous thromboses. However, the potential benefit of therapeutic anticoagulation in these patients must be weighed against the deadly complication of intracranial hemorrhage. In this review, we summarize available evidence and recent studies of intracranial bleeding risks in primary and metastatic tumors and the impact of therapeutic anticoagulation. We find that for the majority of primary and treated metastatic brain tumors, the risk of spontaneous bleeding is acceptable and not further increased by careful therapeutic anticoagulation with low molecular weight heparin or direct oral anticoagulants, although thrombocytopenia (platelet count less than 50,000/μL) and other coagulopathies are relative contraindications. Patients with brain metastasis from melanoma, renal cell carcinoma, choriocarcinoma, thyroid carcinoma, and hepatocellular carcinoma have a higher tendency to bleed spontaneously than noted in patients with other malignancies, and thus warrant routine brain imaging and alternative strategies such as inferior vena cava filter placement in the acute setting of venous thromboembolism before consideration of therapeutic anticoagulation.Implications for Practice.Malignant gliomas are associated with increased risks of both venous thromboses and intracranial hemorrhage, but the additional bleeding risk associated with therapeutic anticoagulation appears acceptable, especially after treatment of primary tumors. Most patients with treated brain metastasis have a low risk of intracranial hemorrhage associated with therapeutic anticoagulation, and low molecular weight heparin is currently the preferred agent of choice. Patients with untreated brain metastasis from melanoma, renal cell carcinoma, thyroid cancer, choriocarcinoma, and hepatocellular carcinoma have a higher propensity for spontaneous intracranial bleeding, and systemic anticoagulation may be contraindicated in the acute setting of venous thromboembolism.

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Chemoprevention in Patients with Peutz‐Jeghers Syndrome: Lessons Learned

AbstractLessons Learned. Motivating patients to enroll in chemopreventive studies is challenging.Chemoprevention with toxic drugs is not feasible.Background.LKB1 mutations are the underlying genetic abnormality causing Peutz‐Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated.Methods.Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high‐risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts.Results.Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49‐year‐old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52‐year‐old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized.Conclusion.Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

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Decision‐Making Capacity for Chemotherapy and Associated Factors in Newly Diagnosed Patients with Lung Cancer

AbstractBackground.The objective of this study was to assess decision‐making capacity in patients newly diagnosed with lung cancer, clinical factors associated with impaired capacity, and physicians' perceptions of patients' decision‐making capacity.Materials and Methods.We recruited 122 patients newly diagnosed with lung cancer. One hundred fourteen completed the assessment. All patients were receiving a combination of treatments (e.g., chemotherapy, chemo‐radiotherapy, or targeted therapy). Decision‐making capacity was assessed using the MacArthur Competence Tool for Treatment. Cognitive impairment, depressive symptoms, and frailty were also evaluated. Physicians' perceptions were compared with the ascertainments.Results.Twenty‐seven (24%, 95% confidence interval [CI], 16–31) patients were judged to have incapacity. Clinical teams had difficulty in judging six (22.2%) patients for incapacity. Logistic regression identified frailty (odds ratio, 3.51; 95% CI, 1.13–10.8) and cognitive impairment (odds ratio, 5.45; 95% CI, 1.26–23.6) as the factors associated with decision‐making incapacity. Brain metastasis, emphysema, and depression were not associated with decision‐making incapacity.Conclusion.A substantial proportion of patients diagnosed with lung cancer show impairments in their capacity to make a medical decision. Assessment of cognitive impairment and frailty may provide appropriate decision‐making frameworks to act in the best interest of patients.Implications for Practice.Decision‐making capacity is the cornerstone of clinical practice. A substantial proportion of patients with cancer show impairments in their capacity to make a medical decision. Assessment of cognitive impairment and frailty may provide appropriate decision‐making frameworks to act in the best interest of patients.

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Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan‐Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

AbstractLessons Learned. A phase I study of the pan‐class I phosphoinositide 3‐kinase inhibitor pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.Based on pharmacokinetic data, the recommended phase II dose of pilaralisib tablets was established as 400 mg once daily.Background.A phase I trial of pilaralisib, an oral pan‐class I phosphoinositide 3‐kinase (PI3K) inhibitor, established the maximum tolerated dose (MTD) of the capsule formulation in patients with advanced solid tumors as 600 mg once daily. This phase I study investigated pilaralisib in tablet formulation.Materials and Methods.Patients with advanced solid tumors received pilaralisib tablets (100–600 mg once daily). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics, and efficacy.Results.Twenty‐two patients were enrolled. No dose‐limiting toxicities (DLTs) were reported. The most common treatment‐related adverse events were diarrhea (40.9%), fatigue (40.9%), decreased appetite (22.7%), and hyperglycemia (22.7%). Pilaralisib plasma exposure did not appear to increase dose‐proportionally. Steady‐state exposure was higher with pilaralisib tablet formulation at 400 mg than with pilaralisib capsule formulation at 400 or 600 mg (mean area under the curve [AUC0–24] 2,820,000 ng × h/mL vs. 2,653,000 and 1,930,000 ng × h/mL, respectively). Of 18 evaluable patients, 2 (11.1%) had a partial response (PR).Conclusion.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity. MTD was not determined. The recommended phase II dose for pilaralisib tablets, based on PK data, was 400 mg once daily.

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Early Steps in the Value of Cancer Care—Many Paths Remain Unexplored

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Safety Profile of Biosimilar Filgrastim (Zarzio/Zarxio): A Combined Analysis of Phase III Studies

AbstractBackground.Evaluation of adverse events (AEs) in pivotal registration trials and ongoing postmarketing surveillance is important for all biologics, including biosimilars. A combined analysis of two pivotal registration studies was performed to strengthen evidence on safety for biosimilar filgrastim EP2006 in patients with breast cancer receiving myelosuppressive chemotherapy, a sensitive clinical setting to confirm biosimilarity of filgrastim.Materials and Methods.Data were combined from two phase III studies of biosimilar filgrastim EP2006. The U.S. registration study was a randomized, double‐blind comparison of biosimilar and reference filgrastim in women aged ≥18 years with breast cancer, receiving (neo)adjuvant treatment with TAC (docetaxel + doxorubicin + cyclophosphamide). The European Union registration study was a single‐arm, open‐label study of biosimilar filgrastim in women aged ≥18 years with breast cancer receiving doxorubicin + docetaxel. Patients received filgrastim as a subcutaneous injection on day 2 of each cycle for <14 days or until the absolute neutrophil count reached 10 × 109/L after the expected nadir. Results were combined for cycles 1–4.Results.A total of 277 patients received biosimilar filgrastim EP2006. Patients had a mean (± standard deviation) age of 51.1 (± 10.8) years, and 78.7% of patients had stage II or III breast cancer. A total of 46 (20.6%) patients receiving biosimilar filgrastim had AEs considered filgrastim‐related. The most frequently reported filgrastim‐related AEs were musculoskeletal or connective tissue disorders (15.2%), including bone pain (7.2%). One death (due to pulmonary embolism) occurred of a patient receiving biosimilar filgrastim (not considered filgrastim‐related). No patient developed antidrug antibodies during the study.Conclusion.Biosimilar filgrastim has a safety profile consistent with previous filgrastim studies and is effective in preventing febrile neutropenia in patients with breast cancer.Implications for Practice.The biosimilar filgrastim EP2006 (Zarzio, Zarxio, biosimilar filgrastim‐sndz) has been approved in Europe since 2009 and in the U.S. since 2015. This combined analysis of two phase III studies provides additional clinical evidence that the biosimilar filgrastim EP2006 has a safety profile consistent with previous studies of reference filgrastim and supports large postmarketing studies of EP2006 in Europe. Strengthening the evidence for biosimilar filgrastim can help improve acceptance of biosimilars and increase patient access to biologics.

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Pre‐ and Postoperative Chemotherapy in Localized Extremity Soft Tissue Sarcoma: A European Organization for Research and Treatment of Cancer Expert Survey

AbstractBackground.The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre‐ and postoperative chemotherapy is unclear and debated among experts.Materials and Methods.Medical oncology experts of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group were asked to participate in this survey on the use of pre‐ and postoperative chemotherapy in STS. Experts from 12 centers in Belgium, France, Germany, Great Britain, Italy, Switzerland, and The Netherlands agreed to participate and provided their treatment algorithm. Answers were converted into decision trees based on the objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies.Results.Several criteria used for decision‐making in extremity STS were identified: chemosensitivity, fitness, grading, location, and size. In addition, resectability and resection status were relevant in the pre‐ and postoperative setting, respectively. Preoperative chemotherapy is considered in most centers for marginally resectable tumors only. Yet, in some centers, neoadjuvant chemotherapy is used routinely and partially combined with hyperthermia. Although most centers do not recommend postoperative chemotherapy, some offer this treatment on a regular basis. Radiotherapy is an undisputed treatment modality in extremity STS.Conclusion.Due to lacking evidence on the utility of pre‐ and postoperative chemotherapy in localized extremity STS, treatment strategies vary considerably among European experts. The majority recommended neoadjuvant chemotherapy for marginally resectable grade 2–3 tumors; the majority did not recommend postoperative chemotherapy in any setting.Implications for Practice.The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre‐ and postoperative chemotherapy is unclear and debated among experts. This study analyzed the decision‐making process among 12 European experts on systemic therapy for STS. A wide range of recommendations among experts regarding the use of perioperative chemotherapy was discovered. Discrepancies in the use of decision criteria were also uncovered, including the definition of what constitutes high‐risk cancer, which is a basis for many to recommend chemotherapy. Before any standardization is possible, a common use of decision criteria is necessary.

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Molecular Biomarkers of Primary and Acquired Resistance to T‐Cell‐Mediated Immunotherapy in Cancer: Landscape, Clinical Implications, and Future Directions

AbstractThe emergence of immunotherapy has revolutionized cancer treatment in recent years. Inhibitors of immune checkpoints, including antibodies against cytotoxic T‐lymphocyte‐associated protein 4, programmed cell death protein 1, and programmed death ligand 1, have demonstrated notable efficacy in certain advanced cancers. Unfortunately, many patients do not benefit from these therapies and either exhibit primary resistance to treatment or develop acquired mechanisms of resistance after initially responding to therapy. Here, we review the genomic and immune traits that may promote resistance to T‐cell‐mediated immunotherapy, with a focus on identifying potential biomarkers that could eventually be used in the clinical setting to guide treatment selection. We summarize the clinical evidence for these markers and discuss how current understanding of resistance mechanisms can inform future studies and aid clinical decision‐making in order to derive maximum benefit from immunotherapy.Implications for Practice.Immunotherapy has rapidly progressed as a treatment modality for multiple cancers, but it is still unclear which patients are likely to benefit from these therapies. Studies of resistance mechanisms have only recently started to identify biomarkers that can help predict patient outcomes. This review summarizes the available clinical data in regard to immunotherapy resistance, with a focus on molecular biomarkers that may be useful in guiding clinical decision‐making. It discusses possible applications of these biomarkers and highlights opportunities for further clinical discovery.

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Trastuzumab Plus Pertuzumab Resistance Does Not Preclude Response to Lapatinib Plus Trastuzumab in HER2‐Amplified Colorectal Cancer

AbstractHuman epidermal growth factor 2 (HER2) amplification represents a distinct molecular subgroup of colorectal cancers that is associated with anti‐epidermal growth factor receptor resistance and sensitivity to dual HER2 targeting. Although clinical trials have reported activity for trastuzumab/pertuzumab and trastuzumab/lapatinib combinations, there are no reports on lapatinib plus trastuzumab activity after resistance to trastuzumab plus pertuzumab. Presented are three cases of HER2 amplified colorectal cancer that developed acquired refractoriness to trastuzumab pertuzumab with subsequent clinical benefit to lapatinib plus trastuzumab, highlighting the potential for HER2 tyrosine kinase inhibition plus trastuzumab in overcoming trastuzumab/pertuzumab resistance.

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Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real‐World Data from the Spanish Tumor Registry (R‐GETNE)

AbstractBackground.Gastroenteropancreatic neuroendocrine neoplasms (GEP‐NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki‐67 cutoff values in GEP‐NENs.Subjects, Materials, and Methods.A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki‐67 index as G1 (Ki‐67 <2%), G2 (Ki‐67 3%–20%), or G3 (Ki‐67 >20%). Patients were stratified into five cohorts: NET‐G1, NET‐G2, NET‐G3, NEC‐G2, and NEC‐G3.Results.Five‐year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5‐year survival: 81% [Ki‐67 3%–5%], 72% [Ki‐67 6%–10%], 52% [Ki‐67 11%–20%]) and G3 NENs (5‐year survival: 35% [Ki‐67 21%–50%], 22% [Ki‐67 51%–100%]). Five‐year survival was significantly greater for NET‐G2 versus NEC‐G2 (75.5% vs. 58.2%) and NET‐G3 versus NEC‐G3 (43.7% vs. 25.4%).Conclusion.Substantial clinical heterogeneity is observed within G2 and G3 GEP‐NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index.Implications for Practice.Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real‐world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.

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Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010–2014

AbstractBackground.Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC.Materials and Methods.Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010–2014 with MBC or invasive ductal carcinoma (IDC). Kaplan‐Meier curves estimated overall survival (OS) and multivariate Cox models were fitted. For survival analyses, only first cancers were included, and 2014 diagnoses were excluded to allow for sufficient follow‐up.Results.Our MBC sample included 1,516 women. Relative to women with IDC, women with MBC were more likely to be older (63 vs. 61 years), black (16.0% vs. 11.1%), and present with stage III disease (15.6% vs. 10.8%). HER2 positive and HER2 negative/HR positive MBC tumors represented 5.2% and 23.0% of cases. For MBC overall, 3‐year OS was greatest for women with HER2 positive MBC (91.8%), relative to women with TN (75.4%) and HER2 negative/HR positive MBC (77.1%). This difference was more pronounced for stage III MBC, for which 3‐year OS was 92.9%, 47.1%, and 42.2% for women with HER2 positive, TN, and HER2 negative/HR positive MBC, respectively. A multivariate Cox model of MBC demonstrated that HER2 positive tumors (relative to TN) were associated with improved survival (hazard ratio = 0.32, 95% confidence interval [CI] 0.13–0.79). In a second Cox model of exclusively HER2 positive tumors, OS did not differ between MBC and IDC disease subtypes (hazard ratio = 1.16, 95% CI 0.48–2.81).Conclusion.In this contemporary, population‐based study of women with MBC, HER2 but not HR status was associated with improved survival. Survival was similar between HER2 positive MBC and HER2 positive IDC. This suggests HER2 positive MBC is responsive to HER2‐directed therapy, a finding that may offer insights for additional therapeutic approaches to MBC.Implications for Practice.This population‐based study reports recent outcomes, by receptor status, for women with metaplastic breast cancer. Survival in metaplastic breast cancer is not impacted by hormone receptor status. To the authors' knowledge, this is the first report indicating that women with human epidermal growth receptor 2 (HER2) positive metaplastic breast cancer have survival superior to women with HER2 negative metaplastic breast cancer and survival similar to women with HER2 positive invasive ductal carcinoma. This information can be used for counseling patients diagnosed with metaplastic breast cancer. Further understanding of HER2 positive metaplastic breast cancer could offer insights for the development of therapeutic approaches to metaplastic breast cancer more broadly.

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Patient‐Reported Comorbidity and Survival in Older Adults with Cancer

AbstractBackground.Our ability to optimize the care of older adults with cancer and comorbid illnesses is insufficient because most clinical trials lack systematic measurement. The primary purpose of this study was to evaluate the association between patient‐reported comorbidity and all‐cause mortality using various comorbidity scoring algorithms.Materials and Methods.The Carolina Senior Registry was linked with the North Carolina Central Cancer Registry to obtain mortality data. Comorbidity was assessed using the patient‐reported Older Americans Resources and Services Questionnaire subscale that assesses 13 specific conditions and the degree to which each impairs activities. Multivariable Cox proportional hazard regression models were used to evaluate the association between comorbidities and all‐cause mortality.Results.The study sample included 539 patients; the median age was 72 years, 72% were female, and 47% had breast cancer. Overall, 92% reported ≥1 comorbid condition, with a mean of 2.7 conditions (range 0–10), with arthritis and hypertension the most common (52% and 50%, respectively). Approximately 60% reported a functional limitation related to comorbidity. After adjusting for time from diagnosis to geriatric assessment, age, cancer type, and stage, the risk of death increased by 5% for each unit increase in comorbidity burden score (adjusted hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.01–1.10) and 12% for each comorbid condition impacting function (HR = 1.12, 95% CI: 1.02–1.23).Conclusion.Comorbid conditions in older adults with cancer are highly prevalent and associated with all‐cause mortality, particularly those conditions that impair function. Routine comorbidity assessment should be included in clinical trials and can be measured via a simple one‐page patient‐reported questionnaire.Implications for Practice.In order to optimize and personalize the care of older adults with cancer, systematic measurement of comorbidities is necessary in both clinical trials and routine practice. Patient‐reported comorbid conditions in older adults with cancer are highly prevalent and are associated with increased risk of all‐cause mortality, particularly for those conditions that impair function. Comorbidity can be systematically measured via a one‐page patient‐reported questionnaire and should be incorporated into future clinical trials and considered for use in oncology clinics to aid in assessing older adults with cancer.

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Benefit‐Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib

AbstractOn April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo‐controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28‐day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50–0.79, p < .0001) with an estimated median OS of 10.6 months in the regorafenib arm and 7.8 months in the placebo arm. A statistically significant improvement in progression‐free survival (PFS) based on modified RECIST for HCC [Semin Liver Dis 2010;30:52–60] (HR = 0.46; 95% CI, 0.37–0.56, p < .0001) was also demonstrated; the estimated median PFS was 3.1 and 1.5 months in the regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST for HCC, was 11% in the regorafenib arm and 4% in the placebo arm. The toxicity profile was consistent with that observed in other indications; the most clinically significant adverse reactions were palmar‐plantar erythrodysesthesia, diarrhea, and hypertension. Based on the improvement in survival and acceptable toxicity, a favorable benefit‐to‐risk evaluation led to approval for treatment of patients with advanced HCC.Implications for Practice.Regorafenib is the first drug approved by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients.

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Barriers and Explanatory Mechanisms of Delays in the Patient and Diagnosis Intervals of Care for Breast Cancer in Mexico

AbstractBackground.Most breast cancer patients in low‐ and middle‐income settings are diagnosed at advanced stages due to lengthy intervals of care. This study aimed to understand the mechanisms through which delays occur in the patient interval and diagnosis interval of care.Materials and Methods.We conducted a cross‐sectional survey including 886 patients referred to four major public cancer hospitals in Mexico City. Based in a conceptual model of help‐seeking behavior, a path analysis strategy was used to identify the relationships between explanatory factors of patient delay and diagnosis delay.Results.The patient and the diagnosis intervals were greater than 3 months in 20% and 65% of participants, respectively. We present explanatory models for each interval and the interrelationship between the associated factors. The patient interval was longer among women who were single, interpreted their symptoms as not worrisome, concealed symptoms, and perceived a lack of financial resources and the difficulty of missing a day of work as barriers to seek care. These barriers were more commonly perceived among patients who were younger, had lower socioeconomic status, and lived outside of Mexico City. The diagnosis interval was longer among those who used several different health services prior to the cancer hospital and perceived medical errors in these services. More health services were used among those who perceived errors and long waiting times for appointments, and who first consulted private services.Conclusion.Our findings support the relevance of strengthening early cancer diagnosis strategies, especially the improvement of quality of primary care and expedited referral routes to cancer services.Implications for Practice.This study's findings suggest that policy in low‐ and middle‐income countries (LMICs) should be directed toward reducing delays in diagnosis, before the implementation of mammography screening programs. The results suggest several factors susceptible to early diagnosis interventions. To reduce patient delays, the usually proposed intervention of awareness promotion could better work in LMIC contexts if the message goes beyond the advertising of screening mammography to encourage the recognition of potential cancer symptoms and sharing of symptoms with significant others. To reduce diagnosis delay, efforts should focus on strengthening the quality of public primary care services and improving referral routes to cancer care centers.

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Two Doctors, One Patient, and a Common Goal

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Multiplanar realignment for unstable Hangman’s fracture with Posterior C2-3 fusion: A prospective series

Publication date: June 2018
Source:Clinical Neurology and Neurosurgery, Volume 169
Author(s): Pravin Salunke, Madhivanan Karthigeyan, Sushanta K. Sahoo, Prashant K. Prasad
ObjectiveThere is lack of consensus on the preferred approach for unstable Hangman's fracture. The associated soft tissue injuries apart from apparent bony injury add to the complexity of dislocation and needs to be addressed. Here, we evaluated the clinico-radiological characteristics and outcome of patients managed by posterior C2-3 fusion.Patients & methodsNine patients with unstable Hangman's fracture (type II and IIA) were prospectively studied. The displacement of fractured fragments and C2-3 dislocation was studied in multiple planes. C2 pars-pedicle screw was placed to bring fractured fragments together (lag effect), which was then fused with C3 lateral masses to achieve multiplanar realignment. Clinical outcome was assessed in terms of pain (VAS score) and neurological status after surgery. Patient's clinico-radiological status was followed up at regular intervals.ResultsPain was the predominant symptom (VAS: 8.1 ± 1.1). Only one had neurological deficit (ASIA- D). Mean VAS score improved significantly in postoperative period (1.2 ± 1.6). About two-third (66.7%) had atypical Hangman's. In six, fractured segments were malaligned in multiple planes. Axial rotation, lateral translation and superior translation (over-riding) of fragments were seen in 4, 4 and 3 patients respectively. Two had adjacent level injuries. Reduction and realignment of fractured fragments as well as C2-3 in multiple planes could be achieved in all. Follow-up varied from 6 to 22 months (mean, 12.8 ± 5.7). Bony fusion was evident in 9 to 12 months. Three patients showed mild curvature change in subaxial spine.ConclusionThe fractures fragments may be dislocated in axial (rotation and lateral translation) apart from antero-posterior plane. It is important to study the radiology in various planes. Posterior C2-3 fusion is an effective way to achieve good realignment of bony fragments in all planes. It also addresses the instability resulting from soft tissue injury.



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Subjective Evaluation of Voice Characteristics of School Aged Children in a Basket Ball Team

Abstract

Voice disorders have been estimated to be present in between 3 and 9% of general population. Sports children have vocal abusive behavior i.e. the extra effort which they put on their voice while playing, leading to voice disorders. It is imperative to find out the voice characteristics of children involved in sports activity. To assess voice characteristics of school aged children, who are active participants in a basket ball team. A group of twenty children (13 males and 7 females) were included in the study. He or she was member of school basket ball team and had participated in many events. The perceptual voice assessment was conducted using GRBAS scale, Buffalo III Voice Profile and Voice Handicap Index (VHI). Findings on GRBAS voice rating scale—In the first parameter i.e. grade 46.7% of the subjects reported slight hoarse component. In the second parameter i.e. Roughness 46.7% of the subjects showed slight roughness component. In another parameter i.e. the asthenia 20% % of the subjects reported slight asthenia component in their voice. In the next parameter i.e. strain in the voice, 26.7% of the subjects showed slight strain component in their voice. Finding on BUFFALO III voice screening profile—In the laryngeal tone, 46.7% of the subjects showed mild hoarse component. Findings on voice handicap index (VHI)—28% of the subjects had functional symptoms of voice problems. 43% of the subjects had some physical symptoms while 28% had affected emotional component. Present study is first of its kind to focus on voice disorders among school going children who are members of a basket ball team. During sport events players tend to scream in order to communicate among their team mates, to show their aggressiveness to their opponents and to show excitement of win or frustration of the lost match leading to various voice problems. There is a high probability of occurrence of voice disorders among children who are active participants of basket ball. Proper counselling of these children is required for preventive measures and to seek voice therapy when required.

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Genetically Diversity of Pseudomonas aeruginosa Isolated from Chronic Suppurative Otitis Media with Respect to Their Antibiotic Sensitivity Pattern

Abstract

Pseudomonas aeruginosa is an important chronic suppurative otitis media (CSOM) pathogen that exhibits multiple resistances to antibiotics with increasing frequency, making patient treatment more difficult. The aim of the study is to ascertain the genetically diversity of this clinically isolated P. aeruginosa with inter simple sequence repeat (ISSR) markers. All 25 P. aeruginosa were isolated from CSOM patients by taking their ear swabs and culturing on blood agar and MacConkey agar. All strains were identified with morphological characters and biochemical testing. The antimicrobial susceptibility testing was carried out according to National Committee for Clinical Laboratory Standards. ISSR was used to study the genetic diversity of P. aeruginosa. Clinically CSOM isolated 25 P. aeruginosa were 88% Ciprofloxacin resistant and similarly resistant to other antibiotics were documented. The study has been made using ISSR marker to find out the genomic relation among the strains/populations of P. aeruginosa. The result was shown that maximum similarity (80%) was between S-11 and S-13 and minimum (28.2%) was between S-4 and S-16 with an average similarity of 53.2%. The dendogram showed a distinct separation in between all the strains/populations of P. aeruginosa. The strains/populations were broken up into two main clusters in which small one bear two strains/populations (S-4 and S-9) and another cluster have another 23 strains/populations. These 23 strains were also separated to form subcluster by having different range of small clades. The genetically diversity of pathogenic P. aeruginosa present in CSOM at our hospital indicates the coexistence different strains due to different antibiotic sensitivity patterns. The conventional culture and sensitivity methods are time consuming whereas in PCR, it will detect within 4–6 h for effective antibiotic. Basing upon the banding pattern with ISSR primers, clinicians can prescribe the effective antibiotics accordingly for CSOM patients in the same day.

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ER{alpha}-Mediated Nuclear Sequestration of RSK2 Is Required for ER+ Breast Cancer Tumorigenesis

Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of estrogen receptor–positive (ER+) breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N terminus to activate a proneoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies.Significance: Nuclear accumulation of active RSK drives a protumorigenic transcriptional program and renders ER+ breast cancer susceptible to endocrine-based therapies. Cancer Res; 78(8); 2014–25. ©2018 AACR.

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Cancer Research: Embracing the Complexity of Cancer and Emergence of Truth

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Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies

Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells. Therefore, evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we applied antiproliferative drug treatments to varying ratios of sensitive and resistant cells. We compared a continuous maximum-tolerated dose schedule with an adaptive schedule aimed at tumor control via competition between sensitive and resistant cells. Continuous treatment cured mostly sensitive tumors, but with any resistant cells, recurrence was inevitable. We identified two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors. These findings offer potential modifications to treatment regimens that may improve outcomes and reduce resistance and recurrence.Significance: By using drug dose modulation or treatment vacations, adaptive therapy strategies control the emergence of tumor drug resistance by spatially suppressing less fit resistant populations in favor of treatment sensitive ones. Cancer Res; 78(8); 2127–39. ©2018 AACR.

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Lessons from the Crypt: HMGA1—Amping up Wnt for Stem Cells and Tumor Progression

High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1890–7. ©2018 AACR.

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The Plausibility of Obesity Paradox in Cancer—Point

In contrast to the convincing evidence that obesity (measured by body mass index, BMI) increases the risk of many different types of cancer, there is an ambiguity in the role of obesity in survival among cancer patients. Some studies suggested that higher BMI decreased mortality risk in cancer patients, a phenomenon called the obesity paradox. The spurious positive association between BMI and cancer survival is likely to be explained by several methodologic limitations including confounding, reverse causation, and collider stratification bias. Also, the inadequacy of BMI as a measure of body fatness in cancer patients commonly experiencing changes in body weight and body composition may have resulted in the paradox. Other factors contributing to the divergent results in literature are significant heterogeneity in study design and method (e.g., study population, follow-up length); time of BMI assessment (pre-, peri-, or post-diagnosis); and lack of consideration for variability in the strength and directions of associations by age, sex, race/ethnicity, and cancer subtype. Robust but practical methods to accurately assess body fatness and body compositions and weight trajectories in cancer survivors are needed to advance this emerging field and to develop weight guidelines to improve both the length and the quality of cancer survival. Cancer Res; 78(8); 1898–903. ©2018 AACR.

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The Plausibility of the Obesity Paradox in Cancer—Response—Reply to Point

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HER2 Overexpression Triggers an IL1{alpha} Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance

Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem–like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1α and IL6 that stimulated NFκB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2–induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1α/IL6 expression and CSC-positive phenotype. Pharmacologic blockade of IL1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.Significance: IL1α signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers. Cancer Res; 78(8); 2040–51. ©2018 AACR.

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The Importance of Body Composition in Explaining the Overweight Paradox in Cancer—Counterpoint

Despite a greater risk of cancer associated with higher BMI, overweight (BMI 25–<30 kg/m2) and class I obese (BMI 30–<35 kg/m2) patients often have a paradoxically lower risk of overall mortality after a cancer diagnosis, a phenomenon called the "obesity paradox." Only when patients exceed a BMI ≥35 kg/m2 are elevations in mortality risk consistently noted. This paradox has been dismissed as the result of methodologic bias, which we will describe and debate here. However, even if such bias influences associations, there is growing evidence that body composition may in part explain the paradox. This phenomenon may more accurately be described as a BMI paradox. That is, BMI is a poor proxy for adiposity and does not distinguish muscle from adipose tissue, nor describe adipose tissue distribution. Low muscle mass is associated with higher risk of recurrence, overall and cancer-specific mortality, surgical complications, and treatment-related toxicities. Patients with who are overweight or obese have on average higher levels of muscle than their normal-weight counterparts. Also, there is some evidence that patients with moderate levels of subcutaneous adipose tissue may have lower mortality. More research utilizing body composition is needed to clarify the effects of adiposity on cancer mortality. Cancer Res; 78(8); 1906–12. ©2018 AACR.

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Discovery of Potent and Selective MRCK Inhibitors with Therapeutic Effect on Skin Cancer

The myotonic dystrophy–related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin–myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here, we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphologic changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent antiproliferative effects with greatest activity in hematologic cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.Significance: The development of selective small-molecule inhibitors of the Cdc42-binding MRCK kinases reveals their essential roles in cancer cell viability, migration, and invasive character. Cancer Res; 78(8); 2096–114. ©2018 AACR.

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Evidence for an Overweight Paradox in Cancer: Insights from Body Composition—Reply to Counterpoint

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Highlights from Recent Cancer Literature

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Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas

Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an SDHx-like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx- and FH-related tumors were observed both in tumors with mutated SLC25A11 and in Slc25a11Δ/Δ immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that SLC25A11 is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation.Significance: A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. Cancer Res; 78(8); 1914–22. ©2018 AACR.

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NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3K{alpha}

Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here, we report that coinhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS- or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo. We identified BCL-2–modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased. BMF silencing ablated MEK162/BYL719-induced apoptosis. Mechanistic investigations implicated a proapoptotic rebalancing of BCL-2 family members and suppression of cap-dependent translation in apoptotic sensitivity upon MEK162/BYL719 cotreatment. Our results offer a rationale for combining MEK- and PI3Kα-specific inhibitors in clinical treatment of RAS-mutated RMS.Significance: These findings offer a mechanistic rationale for combining MEK- and PI3Kα-specific inhibitors in the clinical treatment of RAS-mutated forms of often untreatable rhabdomyosarcomas. Cancer Res; 78(8); 2000–13. ©2018 AACR.

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LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response

Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein α-subunit Gαi2 disrupted LPA-stimulated aerobic glycolysis. LPA stimulated a pseudohypoxic response via Rac-mediated activation of NADPH oxidase and generation of reactive oxygen species, resulting in activation of HIF1α. HIF1α in turn induced expression of glucose transporter-1 and the glycolytic enzyme hexokinase-2 (HKII). Treatment of mice bearing ovarian cancer xenografts with an HKII inhibitor, 3-bromopyruvate, attenuated tumor growth and conferred a concomitant survival advantage. These studies reveal a critical role for LPA in metabolic reprogramming of ovarian cancer cells and identify this node as a promising therapeutic target in ovarian cancer.Significance: These findings establish LPA as a potential therapeutic target in ovarian cancer, revealing its role in the activation of HIF1α-mediated metabolic reprogramming in this disease. Cancer Res; 78(8); 1923–34. ©2018 AACR.

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Hybrid Capture-Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative.

Experimental Design: Hybrid capture–based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with gastrointestinal carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples.

Results: Evidence of ctDNA was detected in 344 of 417 samples (82%), and of these, ≥1 reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented.

Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with gastrointestinal carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced gastrointestinal cancers as a complementary approach to tissue testing, and further investigation is warranted. Clin Cancer Res; 24(8); 1881–90. ©2018 AACR.

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Introducing a New Series: Immunotherapy Facts and Hopes

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PBX3 Is Part of an EMT Regulatory Network and Indicates Poor Outcome in Colorectal Cancer

Purpose: Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression of the TALE transcription factor PBX3 in tumor cells undergoing epithelial–mesenchymal transition (EMT), analyze PBX3 regulation, and determine clinical associations in colorectal cancer.

Experimental design: We used transcriptomic and in situ analyses to identify PBX3 expression in colorectal cancer and cell biology approaches to determine its regulation and function. Clinical associations were analyzed in independent tissue collections and gene expression datasets of colorectal cancers with recorded follow-up data.

Results: PBX3 was expressed in tumor cells with high WNT activity undergoing EMT at the leading tumor edge of colorectal cancers, whereas stromal cells were PBX3 negative. PBX3 expression was induced by WNT activation and by the EMT transcription factors SNAIL and ZEB1, whereas these effects were mediated indirectly through microRNA miR-200. PBX3 was required for a full EMT phenotype in colon cancer cells. On the protein level, PBX3 expression indicated poor cancer-specific and disease-free survival in a cohort of 244 UICC stage II colorectal cancers, and was associated with metastasis in a case–control collection consisting of 90 cases with or without distant metastasis. On the mRNA level, high PBX3 expression was strongly linked to poor disease-free survival.

Conclusions: PBX3 is a novel indicator of EMT in colorectal cancer, part of an EMT regulatory network, and a promising prognostic predictor that may aid in therapeutic decision making for patients with colorectal cancer. Clin Cancer Res; 24(8); 1974–86. ©2018 AACR.

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Small-Cell Neuroendocrine Tumors: Cell State Trumps the Oncogenic Driver

Small-cell neuroendocrine cancers often originate in the lung but can also arise in the bladder or prostate. Phenotypically, small-cell carcinoma of the bladder (SCCB) shares many similarities with small-cell lung cancer (SCLC). It is unknown whether SCCB and SCLC share common genetic driver mutations. Clin Cancer Res; 24(8); 1775–6. ©2018 AACR.

See related article by Chang et al., p. 1965

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Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition

Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT.

Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT.

Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%.

Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932–43. ©2018 AACR.

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Harnessing the Power of Patient-Reported Outcomes in Oncology

Patient-reported outcomes (PRO) represent an increasingly important mechanism for incorporating patients' experiences and perspectives into their care to enhance cancer care delivery and outcomes. In this article, we discuss the importance of integrating PROs into both the clinical and research settings in oncology and highlight potential challenges. Clin Cancer Res; 24(8); 1777–9. ©2018 AACR.

See related article by Kim et al., p. 1780

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Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections

Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780–4. ©2017 AACR.

See related commentary by Nipp and Temel, p. 1777

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A Combination of SAHA and Quinacrine Is Effective in Inducing Cancer Cell Death in Upper Gastrointestinal Cancers

Purpose: We aimed to investigate the therapeutic efficacy of single agent and the combination of quinacrine and suberoylanilide hydroxamic acid (SAHA) in wt- and mut-p53 upper gastrointestinal cancer (UGC) cell models.

Experimental Design: ATP-Glo, clonogenic cell survival, Annexin V, comet, DNA double-strand breaks (DSBs), qPCR, and Western blot analysis assays were utilized.

Results: Using clonogenic cell survival, ATP-Glo cell viability, Annexin V, and sub-G₀ population analysis, we demonstrated that a combination of quinacrine and SAHA significantly decreased colony formation and increased cancer cell death (range, 4–20 fold) in six UGC cell models, as compared with single-agent treatments, irrespective of the p53 status (P < 0.01). The combination of quinacrine and SAHA induced high levels of DSB DNA damage (>20-fold, P < 0.01). Western blot analysis showed activation of caspases-3, 9, and -H2AX in all cell models. Of note, although quinacrine treatment induced expression of wt-p53 protein, the combination of quinacrine and SAHA substantially decreased the levels of both wt-P53 and mut-P53. Furthermore, cell models that were resistant to cisplatin (CDDP) or gefitinib treatments were sensitive to this combination. Tumor xenograft data confirmed that a combination of quinacrine and SAHA is more effective than a single-agent treatment in abrogating tumor growth in vivo (P < 0.01).

Conclusions: Our novel findings show that the combination of quinacrine and SAHA promotes DNA damage and is effective in inducing cancer cell death, irrespective of p53 status and resistance to CDDP or gefitinib in UGC models. Clin Cancer Res; 24(8); 1905–16. ©2018 AACR.

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Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785–94. ©2017 AACR.

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Wide Expression and Significance of Alternative Immune Checkpoint Molecules, B7x and HHLA2, in PD-L1-Negative Human Lung Cancers

Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non–small cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2.

Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x, and HHLA2 on human T-cell proliferation and cytokine production were investigated.

Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status, and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, whereas HHLA2 was positive in 61% and 64% of tumors in the two sets. The coexpression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1–negative cases expressed B7x, HHLA2, or both. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells.

Conclusions: The majority of PD-L1–negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1–negative tumors deserve to be explored to provide the rationale for an effective immunotherapy strategy in these tumors. Clin Cancer Res; 24(8); 1954–64. ©2018 AACR.

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Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain?

The brain is the most common site of first metastasis for patients with HER2-positive breast cancer treated with HER2-targeting drugs. However, the development of effective therapies for breast cancer brain metastases (BCBM) is limited by an incomplete understanding of the mechanisms governing drug sensitivity in the central nervous system. Pharmacodynamic data from patients and in vivo models suggest that inadequate drug penetration across the "blood–tumor" barrier is not the whole story. Using HER2-positive BCBMs as a case study, we highlight recent data from orthotopic brain metastasis models that implicate brain-specific drug resistance mechanisms in BCBMs and suggest a translational research paradigm to guide drug development for treatment of BCBMs. Clin Cancer Res; 24(8); 1795–804. ©2018 AACR.

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Long Noncoding RNA LINC01234 Functions as a Competing Endogenous RNA to Regulate CBFB Expression by Sponging miR-204-5p in Gastric Cancer

Purpose: Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases, including cancers. However, the overall biological roles and clinical significance of most lncRNAs in gastric carcinogenesis are not fully understood. We investigated the clinical significance, biological function, and mechanism of LINC01234 in gastric cancer.

Experimental Design: First, we analyzed LINC01234 alterations in gastric cancerous and noncancerous tissues through an analysis of sequencing data obtained from The Cancer Genome Atlas. Next, we evaluated the effect of LINC01234 on the gastric cancer cell proliferation and apoptosis, and its regulation of miR-204-5p by acting as a competing endogenous RNA (ceRNA). The animal model was used to support the in vitro experimental findings.

Results: We found that LINC01234 expression was significantly upregulated in gastric cancer tissues and was associated with larger tumor size, advanced TNM stage, lymph node metastasis, and shorter survival time. Furthermore, knockdown of LINC01234-induced apoptosis and growth arrest in vitro and inhibited tumorigenesis in mouse xenografts. Mechanistic investigations indicated that LINC01234 functioned as a ceRNA for miR-204-5p, thereby leading to the derepression of its endogenous target core-binding factor β (CBFB).

Conclusions: LINC01234 is significantly overexpressed in gastric cancer, and LINC01234–miR-204-5p–CBFB axis plays a critical role in gastric cancer tumorigenesis. Our findings may provide a potential new target for gastric cancer diagnosis and therapy. Clin Cancer Res; 24(8); 2002–14. ©2018 AACR.

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Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.

Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.

Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.

Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.

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Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA

Purpose: Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.

Experimental Design: We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non–small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement.

Results: Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days; P < 0.001). A ctDNA response was associated with superior progression-free survival [hazard ratio (HR), 0.29; 95% CI, 0.09–0.89; P = 0.03], and superior overall survival (HR, 0.17; 95% CI, 0.05–0.62; P = 0.007).

Conclusions: A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC. Clin Cancer Res; 24(8); 1872–80. ©2018 AACR.

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Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer

Purpose: Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies.

Experimental Design: Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0.6 to 10 mg/kg every 4 weeks. The primary study endpoint was dose-limiting toxicity (DLT) in the first two cycles.

Results: Utomilumab demonstrated a well-tolerated safety profile (N = 55). None of the patients experienced a DLT at the dose levels evaluated. The most common treatment-related adverse events were fatigue, pyrexia, decreased appetite, dizziness, and rash (<10% of patients). Only one (1.8%) patient experienced a grade 3–4 treatment-related adverse event (fatigue), and no clinically relevant elevations in transaminases were noted. Utomilumab demonstrated linear pharmacokinetics at doses ranging from 0.006 to 10 mg/kg, with similar safety and pharmacokinetics in anti-drug antibody (ADA)-negative and ADA-positive patients. The overall objective response rate was 3.8% (95% CI, 0.5%–13.0%) in patients with solid tumors and 13.3% in patients with Merkel cell carcinoma, including a complete response and a partial response. Circulating biomarkers support 4-1BB/CD137 engagement by utomilumab and suggest that circulating lymphocyte levels may influence probability of clinical benefit.

Conclusions: The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies. Clin Cancer Res; 24(8); 1816–23. ©2018 AACR.

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Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor-Mediated Natural Killer Cell Function

Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.

Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent.

Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer.

Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR.

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Induction Chemotherapy plus Concurrent Chemoradiotherapy in Endemic Nasopharyngeal Carcinoma: Individual Patient Data Pooled Analysis of Four Randomized Trials

Purpose: Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC.

Experimental Design: Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.

Results: Median follow-up was 5.0 years. The HR for PFS was 0.70 [95% confidence interval (CI), 0.56–0.86; P = 0.0009; 9.3% absolute benefit at 5 years] in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57–0.99; P = 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51–0.90; P = 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48–1.01; P = 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected.

Conclusions: This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control. Clin Cancer Res; 24(8); 1824–33. ©2018 AACR.

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STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair

Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.

Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.

Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.

Conclusions: This work introduces a novel concept of a pivotal role of Jak2–Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2–Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917–31. ©2018 AACR.

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Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML

Purpose: To evaluate the safety, efficacy, and immunobiological correlates of allogeneic NK-cell–based therapy in primary chemotherapy-refractory or relapsed high-risk myelodysplastic syndrome (MDS), secondary AML (MDS/AML), and de novo AML patients.

Experimental Design: Sixteen patients received fludarabine/cyclophosphamide conditioning combined with total lymphoid irradiation followed by adoptive immunotherapy with IL2–activated haploidentical NK cells.

Results: NK-cell infusions were well-tolerated, with only transient adverse events observed in the 16 patients. Six patients achieved objective responses with complete remission (CR), marrow CR, or partial remission (PR). Five patients proceeded to allogeneic hematopoietic stem cell transplantation (HSCT). Three patients are still free from disease >3 years after treatment. All evaluable patients with objective responses (5/5 evaluable) had detectable donor NK cells at days 7/14 following infusion and displayed reduction of tumor cell clones, some of which carried poor prognosis mutations. Residual lin^–CD34⁺CD123⁺CD45RA⁺ blast cells in responders had increased total HLA class I and HLA-E expression. Responding patients displayed less pronounced activation of CD8⁺ T cells and lower levels of inflammatory cytokines following NK-cell infusion. Intriguingly, despite omission of systemic IL2, all patients displayed increased frequencies of activated Ki-67⁺CD127^–FoxP3⁺CD25^hiCD4⁺ Treg cells of recipient origin following NK-cell therapy.

Conclusions: Overall, this study suggests that high-risk MDS is responsive to NK-cell therapy and supports the use of haploidentical NK-cell infusions as a bridge to HSCT in refractory patients. Objective clinical responses and reduction of high-risk clones were associated with detectable donor-derived NK cells, immunoediting of residual blast cells, and less pronounced host immune activation. Clin Cancer Res; 24(8); 1834–44. ©2018 AACR.

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Radiation and QoL During the Breast Reconstruction Process

In what ways might post-mastectomy radiotherapy impact patient reported outcomes and quality of life?
Plastic and Reconstructive Surgery

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Circular RNA Expression Profiles Alter Significantly after Traumatic Brain Injury in Rats

Journal of Neurotrauma, Ahead of Print.


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Intraosseous venous malformation of the zygomatico-orbital complex. Case report and literature review with focus on confusions in vascular lesion terms

Abstract

Intraosseous vascular malformations (VascM) of the facial skeleton are rare entities, raising difficulties even today in their treatment. We present a case for zygomatic intraosseous venous malformation of traumatic etiology with growth dynamics presentation and a multidisciplinary treatment approach, with intravascular embolization surgical ablation and primary reconstructruction using a titanium patient-specific implant (PSI), and a review of the literature for intraosseous vascular lesions of the facial skeleton focusing on the diagnostic syntagms used by the involved medical personnel, to shed light on the confusions over these terms.

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PM2.5 forecasting using SVR with PSOGSA algorithm based on CEEMD, GRNN and GCA considering meteorological factors

Publication date: June 2018
Source:Atmospheric Environment, Volume 183
Author(s): Suling Zhu, Xiuyuan Lian, Lin Wei, Jinxing Che, Xiping Shen, Ling Yang, Xuanlin Qiu, Xiaoning Liu, Wenlong Gao, Xiaowei Ren, Juansheng Li
The PM2.5 is the culprit of air pollution, and it leads to respiratory system disease when the fine particles are inhaled. Therefore, it is increasingly significant to develop an effective model for PM2.5 forecasting and warnings that informs people to foresee the air quality. People can reduce outdoor activities and take preventive measures if they know the air quality is bad ahead of time. In addition, reliable forecasting results can remind the relevant departments to control and reduce pollutants discharge. According to our knowledge, the current hybrid forecasting techniques of PM2.5 do not take the meteorological factors into consideration. Actually, meteorological factors affect the concentrations of air pollution, but it is unclear whether meteorological factors are helpful for improving the PM2.5 forecasting results or not. This paper proposes a hybrid model called CEEMD-PSOGSA-SVR-GRNN, based on complementary ensemble empirical mode decomposition (CEEMD), particle swarm optimization and gravitational search algorithm (PSOGSA), support vector regression (SVR), generalized regression neural network (GRNN) and grey correlation analysis (GCA), for the daily PM2.5 concentrations forecasting. The main steps of proposed model are described as follows: the original PM2.5 data decomposition with CEEMD, optimal SVR selection with PSOGCA, meteorological factors selection with GCA, residual revision by GRNN and forecasting results analysis. Three cities (Chongqing, Harbin and Jinan) in China with different characteristics of climate, terrain and pollution sources are selected to verify the effectiveness of proposed model, and CEEMD-PSOGSA-SVR*, EEMD-PSOGSA-SVR, PSOGSA-SVR, CEEMD-PSO-SVR, CEEMD-GSA-SVR, CEEMD-GWO-SVR are considered to be compared models. The experimental results show that the hybrid CEEMD-PSOGSA-SVR-GRNN model outperforms other six compared models. Therefore, the proposed CEEMD-PSOGSA-SVR-GRNN model can be used to develop air quality forecasting and warnings.

Graphical abstract

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Deliquescence behavior of photo-irradiated single NaNO3 droplets

Publication date: June 2018
Source:Atmospheric Environment, Volume 183
Author(s): Samantha Seng, Fangqin Guo, Yeny A. Tobon, Tomoki Ishikawa, Myriam Moreau, Shoji Ishizaka, Sophie Sobanska
Nitrate-containing particles are ubiquitous in the troposphere because of their secondary production due to anthropogenic emissions of NOx from the combustion of fossil fuels. Nitrate ions are recognized as photoactive species that may contribute to the formation of oxidants in the atmosphere through heterogeneous photochemical reactions. The chemical transformation of aerosol particles in the atmosphere often leads to modification of the particles' hygroscopic properties. Although the photo-transformation of nitrate ions into nitrite within aerosol particles has been investigated, the influence of the photoproducts formation on the hygroscopic behavior of particles has not been reported. In this study, we examined the hygroscopic properties of single, ultraviolet-irradiated NaNO3 droplets using Raman microspectrometry. We are the first demonstrated that irradiating NaNO3 particles affects their hygroscopic behavior. For short-term exposures, regarding hygroscopic behavior, the irradiated particles exhibited two-stage transitions that were clearly reproduced in the experimental NaNO3-NaNO2 phase diagram. The production of NO2⁻ decreased the deliquescence relative humidity values. For long irradiation times (>5 h), these values are even more affected by the additional production of peroxynitrite and carbonate ions in individual droplets. The NaNO3-NaNO2 deliquescence phase diagram cannot explain the hygroscopic behavior of long-term irradiated particles. Finally, we demonstrated the influence that CO2 has on the photo-transformation process in NaNO3 droplets.

Graphical abstract

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Animal models of acute otitis media – A review with practical implications for laboratory research

Publication date: Available online 12 April 2018
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): N.H. Davidoss, Y.K. Varsak, P.L. Santa Maria
Considerable animal research has focused on developing new strategies for the prevention and treatment of acute otitis media (AOM). Several experimental models of AOM have thus been developed. A PubMed search of the English literature was conducted from 1975 to July 2016 using the search terms "animal model" and "otitis media" from which 91 published studies were included for analysis, yielding 123 animal models. The rat, mouse and chinchilla are the preferred animals for experimental AOM models with their individual advantages and disadvantages. The most common pathogens used to create AOM are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Streptococcus pneumoniae (types 3, 23 and 6A) and non-typeable Haemophilus influenzae (NTHi) are best options for inoculation into rat and mouse models. Adding viral pathogens such as RSV and Influenza A virus, along with creating ET dysfunction, are useful adjuncts in animal models of AOM. Antibiotic prophylaxis may interfere with the inflammatory response without a significant reduction in animal mortality.



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Clinical Use of Navigation in Lateral Skull Base Surgery: Results of a Multispecialty National Survey among Skull Base Surgeons in Germany

J Neurol Surg B
DOI: 10.1055/s-0038-1635258

Objective To analyze the current clinical use of navigation at the lateral skull base among skull base surgeons in Germany. Methods A web-based questionnaire was provided to surgeons being head of the department and member of one of the following scientific societies: German Society of Head and Neck Surgery, Maxillo-Facial Surgery, Neurosurgery, and German Skull Base Society. Replies were recorded anonymously. The questionnaire included the estimated case load per year and percent of surgery performed with navigation (middle and posterior fossa), type of navigation, estimates of intraoperative inaccuracy, and reasons for not using navigation. Results Eighty nine out of 99 replies met requirements for final analysis. Overall, 37% of skull base surgeons use navigation on a regular basis (15% use no navigation). Optical tracking is more frequently used than magnetic tracking (71 vs 19). At the middle fossa, ENT surgeons split into routine users (n = 10/36) and rare users (n = 16/36), the latter stating navigation inaccuracy as a major reason for neglecting navigation. Neurosurgeons use navigation at the middle fossa significantly more often and criticize navigation inaccuracy less. At the posterior fossa, navigation is used less frequently by both ENT and neurosurgeons with similar rates of estimated inaccuracy. Conclusions A moderate use of navigation at the lateral skull base was demonstrated. Insufficient accuracy causes ENT surgeons to frequently omit navigation at the middle fossa (not neurosurgeons) and posterior fossa (also neurosurgeons). Higher intraoperative navigation accuracy is needed to enhance the use of navigation at the lateral skull base.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Volumetry in the Assessment of Pituitary Adenoma Resection: Endoscopy versus Microscopy

J Neurol Surg B
DOI: 10.1055/s-0038-1639618

Background Assessment of the extent of resection after surgical resection of pituitary adenomas is most commonly reported in terms of the presence or absence of residual tumor. A quantitative comparison of volumetric resection between endonasal endoscopy (EE) and microsurgery (MS) has rarely been done. Methods A retrospective analysis was performed on a consecutive series of 154 patients with pituitary adenomas treated by the same surgeon at a single institution. We employed volumetric analysis pre- and postoperatively on two cohorts of pituitary adenoma patients treated through MS (n = 37) versus EE approach (n = 117). Results Volumetric analysis revealed a higher incidence of complete resection (64.4 vs. 56.8%) and mean volume reduction in the EE cohort (92.7 vs. 88.4%), although not significant. Recurrence rates were significantly lower in the EE group (7.7% vs 24.3%, p = 0.015). Subgroup analysis identified that patients with preoperative tumor volumes >1 mL were less likely to recur through EE (7.8 vs. MS: 29.6%; p = 0.0063). A higher incidence of complete resection was also noted in patients with favorable Knosp grades (0–1) (EE: 87.8 vs. MS: 63.2%; p = 0.036). Postoperative complication rates were not significantly different between both techniques. Conclusion Both microscopy and endoscopy are well-tolerated, effective approaches in the treatment of pituitary adenomas. Our series demonstrated that EE may be superior to MS in preventing tumor recurrence and achieving a complete resection in certain subsets of patients. EE provides a slight advantage in tumor control outcomes that may justify the paradigm shift to pure endoscopy at our center.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

Publication date: Available online 12 April 2018
Source:Cancer Cell
Author(s): Matthew D. Hellmann, Tavi Nathanson, Hira Rizvi, Benjamin C. Creelan, Francisco Sanchez-Vega, Arun Ahuja, Ai Ni, Jacki B. Novik, Levi M.B. Mangarin, Mohsen Abu-Akeel, Cailian Liu, Jennifer L. Sauter, Natasha Rekhtman, Eliza Chang, Margaret K. Callahan, Jamie E. Chaft, Martin H. Voss, Megan Tenet, Xue-Mei Li, Kelly Covello, Andrea Renninger, Patrik Vitazka, William J. Geese, Hossein Borghaei, Charles M. Rudin, Scott J. Antonia, Charles Swanton, Jeff Hammerbacher, Taha Merghoub, Nicholas McGranahan, Alexandra Snyder, Jedd D. Wolchok
Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.

Teaser

Hellmann et al. examine non-small-cell lung cancers treated with combined PD-1 and CTLA-4 blockade using whole-exome sequencing and find that high tumor mutation burden is the strongest feature associated with improved objective response, durable benefit, and progression-free survival in multivariable analysis.


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