Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities

Abstract

Background

Among breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities.

Methods

We quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects.

Results

TNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases.

Conclusions

Similar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients.

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Systemic inflammatory response after hernia repair: a systematic review

Abstract

Purpose

All surgical procedures elicit a complex systemic inflammatory response effectuated and modulated by cytokines. The purpose of this systematic review was to present an overview of the inflammatory response and the serum markers associated with hernia repair and to compare the response between patients treated with and without mesh.

Methods

The review was conducted in line with PRISMA guidelines. The outcomes of interest were serum concentration of leukocytes, cytokines, and acute phase proteins before and after hernia repair with or without mesh reinforcement. The risk of bias was assessed using the Cochrane ROBINS-I tool for non-randomized studies of intervention.

Results

A total of 31 studies were included in the systematic review including 1326 patients with a mean age ranging from 33 to 67 years. The studies predominantly included males (95.0% males, 5.0% female) with inguinal hernias (98.5% inguinal hernias, 1.5% incisional hernias). The inflammatory response after hernia repair was characterized by an increase in CRP, IL-6, leukocytes, neutrophils, IL-1, IL-10, fibrinogen, and α1-antitrypsin and a decrease in lymphocytes and albumin within the first 24 postoperative hours. The systemic inflammatory response was normalized before or on the seventh postoperative day. A higher CRP and IL-6 serum concentration was found in patients treated with mesh compared with sutured repairs.

Conclusions

Hernia repair elicits a systemic inflammatory response characterized by an increase in CRP, IL-6, leukocytes, neutrophils, IL-1, IL-10, fibrinogen, and α1-antitrypsin and a decrease in lymphocytes and albumin. A higher inflammatory response was found after mesh repair compared with non-mesh repair and after open mesh repair compared with laparoscopic mesh repair.

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S198 Different region-specific networks sustain focal seizures with a fast-activity onset: Evidence from patients and animal models

Focal seizure patterns generated by different cortical networks are not well characterized. I will provide evidence that different seizure patterns are generated by specific brain regions explored with stereo-EEG in patients with drug-resistant focal epilepsy candidate for surgery. Two main patterns typical of temporo-mesial involvement and neocortical involvement are identified. These two patterns were reproduced in an in vitro isolated brain preparation to characterize the network and cellular determinants.

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S200 Paroxyzmal depolarization shift – Is it an interictal phenomenon is humans?

Paroxysmal depolarization shift (PDS) was extensively studied in animal models of acute and subacut epilepsy. Based on the observation that PDS occurred between behavioral seizures it had been complemented by interictal discharges, that can be recorded in humans in the seizure onset zone (SOZ) and around. PDS is characterized by excessive discharge of large number of neurons within a certain area of the cortex. Studying human SOZ with microelectrodes revealed that selective or no neuronal firing increase happen during IIDs.

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P382 Neural mechanisms of attentional switching during distraction analgesia: A single-trial laser evoked potential study

Noxious stimuli capture attention and at the same time, pain is attenuated by a concurrent cognitive task. The present study aimed to elucidate the cortical mechanisms underlying diminution of pain during attentional distraction using single-trial electrocortical and subjective responses.

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P381 Event-related potentials and personality type in patients with multiple sclerosis

The clinical course of multiple sclerosis (MS) can vary significantly among patients and is affected by many factors. Among these, psychoaffective aspects, including the type of personality, have been recently gaining attention. The aim of our study was to investigate the parameters of event-related potentials (ERP) with regards to personality type in MS patients.

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AYA-Myeloma: Real-World, Single-Center Experience Over Last 5 Years

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Dynamics of regulatory T cells (Tregs) in patients with oral squamous cell carcinoma

Background and Objectives

The immune dysfunction in oral squamous cell carcinoma (OSCC) patients is one of the major factors for growth and dissemination of tumor affecting disease-free survival.

Methods

The phenotypic and functional characteristics of Regulatory T (T_reg) CD4⁺CD25⁺FoxP3⁺ subsets in OSCC patients were assessed by multicolor flow cytometry and its effector component (TGF-β) by Western blot and qRT-PCR.

Results

An increased (P < 0.05) prevalence of T_reg phenotypes (CD4⁺CD25⁺, CD4⁺FoxP3⁺, CD8⁺FoxP3⁺, CD4⁺CD25⁺FoxP3⁺) was observed in the peripheral circulation of OSCC patients that positively correlated with clinicopathological features. The increased frequency of CD4⁺CD8⁺CD25⁺FoxP3⁺, a unique T cell subset, CTLA-4⁺, GITR⁺, NrP1⁺, HLA-DR⁺, CD127⁺, Tbet⁺, TGF-β⁺, and granzyme B⁺ (GzmB) T_regs also showed a significantly higher prevalence in OSCC patients. Functionally, CD4⁺FoxP3⁺ T_regs showed skewed expression of IL-2, IL-10, and IL-35 in patients as compared with the normal controls. Further, enhanced expression of CCR5 and CCR7 on T_regs with up regulation of their ligands (CCL5, CCL19, and CCL21) in tumor cells indicates efficient recruitment and trafficking of T_regs to the tumor site.

Conclusion

It seems reasonable to assume that modulation of functional dynamics of selective T_reg subsets may be useful in developing immunotherapeutic strategy for OSCC patients.

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Best practices for multidisciplinary integration of a DCIS genomic assay into clinical practice

Most newly diagnosed ductal carcinoma in situ (DCIS) is treated with breast-conserving surgery (BCS) ± radiation therapy (RT). A key challenge is deciding whether or not to include RT with BCS. This decision is often determined by the degree of risk associated with disease recurrence. However, methods for risk assessment have not kept pace with diagnostic advances. The DCIS Score is an independent predictor and quantifier of individualized recurrence risk in patients with DCIS. Although the test is the only available genomic classifier for DCIS, the degree of adoption is varied, and it has not yet been fully accepted as standard practice. Recognizing the importance of individualizing recurrence assessment in patients with DCIS, the authors convened to review relevant clinical data, share best practices, and establish recommendations regarding how the assay should be incorporated into the decision-making process. Based on their clinical experiences, the authors concluded that effective integration of the DCIS Score should involve shared decision-making between surgeons and other specialties (radiation oncologists, pathologists, patient navigators, and physician assistants), with the patient's preference being a primary consideration. This manuscript aims to provide easy-to-use, clear-cut, and practical guidance to help physicians utilize the DCIS Score to improve risk assessment and inform treatment decisions for their patients with DCIS, including how to understand, run, interpret, and communicate the actionable results to patients.

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Changes in shoulder muscle activity pattern on surface electromyography after breast cancer surgery

Background and Objectives

Alterations in muscle activation and restricted shoulder mobility, which are common in breast cancer patients, have been found to affect upper limb function. The purpose of this study was to determine muscle activity patterns, and to compare the prevalence of abnormal patterns among the type of breast surgery.

Methods

In total, 274 breast cancer patients were recruited after surgery. Type of breast surgery was divided into mastectomy without reconstruction (Mastectomy), reconstruction with tissue expander/implant (TEI), latissimus dorsi (LD) flap, or transverse rectus abdominis flap (TRAM). Activities of shoulder muscles were measured using surface electromyography. Experimental analysis was conducted using a Gaussian filter smoothing method with regression.

Results

Patients demonstrated different patterns of muscle activation, such as normal, lower muscle electrical activity, and tightness. After adjusting for BMI and breast surgery, the odds of lower muscle electrical activity and tightness in the TRAM are 40.2% and 38.4% less than in the Mastectomy only group. The prevalence of abnormal patterns was significantly greater in the ALND than SLNB in all except TRAM.

Conclusions

Alterations in muscle activity patterns differed by breast surgery and reconstruction type. For breast cancer patients with ALND, TRAM may be the best choice for maintaining upper limb function.

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Recurrence patterns and associated factors of locoregional failure following neoadjuvant chemoradiation and surgery for esophageal cancer

Background

Despite neoadjuvant chemoradiation (nCRT) followed by esophagectomy for locally advanced esophageal cancer, locoregional recurrence (LRR) is common and factors associated with LRR have not been clearly identified.

Methods

Patients were identified from a single institution, prospectively maintained database (1996-2013). Patterns of recurrence were described and associated factors of LRR were analyzed using competing risks regression models.

Results

Of the 456 patients treated with nCRT and surgery, 167 patients developed recurrence. Locoregional and distant recurrences were observed in 69 (15.1%) and 140 (30.9%) patients, respectively. Time to recurrence (13.6 vs 10.4 months, P = 0.20) and median overall survival (29.3 vs 19.1 months, P = 0.12) were no different among the 27 patients (6%) who developed a solitary LRR compared to patients who developed distant recurrence. Univariable analysis identified lymphovascular invasion (HR 1.46, P = 0.07), lymph node ratio >0.5 (HR 2.16, P = 0.02), positive margin (HR 1.95, P = 0.05), lack of response to neoadjuvant therapy (HR 1.99, P < 0.01), clinical T stage (HR 2.62, P < 0.01) and final T3/4 stage (HR 2.06, P < 0.01) as factors significantly associated with LRR. Clinical T stage and response to neoadjuvant treatment were independently associated with LRR on multivariable analysis.

Conclusions

Although aggressive tumor biology plays a significant role in LRR, optimizing neoadjuvant treatments to obtain a complete pathologic response may lead to improved locoregional control.

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Trismus surgical release and free flap reconstruction after radiation therapy in oral and oropharyngeal squamous cell carcinoma

Background and Objectives

This study aims to review our experience in trismus release followed by free flap reconstruction after radiotherapy in oral and oropharyngeal cancer, describe the results obtained in long-term follow-up and identify possible predictors of outcome.

Methods

Patients' demographics, tumor characteristics and treatment where retrieved. Surgical release and reconstructive procedures were detailed. Interincisor distances (IIDs) where measured preoperatively (PO-IID), intraoperatively after release (IO-IID) and in the last follow-up (FU-IID). Potential predictors of outcome in terms of interincisor long-term gain (LT-gain) and postoperative loss (PO-loss) were analyzed.

Results

Twenty-eight patients were included in our study. The mean LT-gain was 8.9 ± 7.0 mm, and the PO-loss was 22.14 ± 7.27 mm. Patients with a PO-IID of 10 mm or less had a significant higher LT-gain (P = 0.038). Predictors of worse outcome included having received a previous maxillectomy during tumor ablation (lower LT-gain, P = 0.035), and previous buccal mucosa resection (higher PO-loss, P = 0.044).

Conclusions

Trismus release and free flap reconstruction after radiotherapy in oral and oropharyngeal cancer patients seems to be associated with modest long term results and a high incidence of trismus recurrence, particularly in cases of prior buccal resections or maxillectomy. Patients should be adequately informed and carefully selected before indicating the procedure.

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A study of 853 high grade osteosarcomas from a single institution—Are outcomes in Indian patients different?

Aims

To review outcomes of 853 patients of primary high grade osteosarcoma operated with curative intent between January 2006 to December 2013.

Methods

All patients underwent appropriate surgical resection after preoperative chemotherapy (non methotrexate based). Excised specimen was analyzed for margins and response to chemotherapy. We analysed various factors (sex, age, size, site, type of surgery, pathologic fractures, margin status, and chemotherapy induced necrosis) for their impact on outcomes.

Results

Five year overall survival (OS) for entire cohort was 49% and event free survival (EFS) was 42%. Seventy hundred thirty-eight non metastatic patients had OS of 53% and EFS of 47% at 5 years. The 3 year OS and EFS of the metastatic patients was 22% and 9%, respectively. Analysis of 738 non metastatic patients demonstrated that chemotherapy induced necrosis, size of tumor (< / >8 cms), type of surgery (limb salvage vs amputation) significantly affected overall survival. Local recurrence was 9%. Site of tumor (long bone vs pelvis), type of surgery and chemotherapy induced necrosis influenced local recurrence.

Conclusions

Our patients appeared to have poorer survival compared to most Western data, possibly attributable to large tumors. In contrast to existing data, males (71%) were predominantly affected and only patients with 100% necrosis qualified as good responders regarding OS.

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Comparison of risk factors and complications in patients by stratified mastectomy weight: An institutional review of 1041 consecutive cases

Background and Objectives

This study aims to investigate the specific complication rates, reconstructive differences, and delineate the pertinent independent risk factors in patients with different mastectomy weights.

Methods

A retrospective chart review of consecutive patients undergoing mastectomy between 2010 and 2015 was performed. Patient demographics, comorbidities, and intraoperative and postoperative outcomes were collected. Patients were divided into three groups: those with mastectomy weight <500, 500-1000, and >1000 g.

Results

During the study period, a total of 704 consecutive patients and 1041 total mastectomy surgeries had complete mastectomy specimen weight data. Of these, 437 breasts were in the <500 g specimen group, 425 were included in the 500-1000 g group and 179 in the >1000g group. The rate of overall complications between the three mastectomy weight groups (<500, 500-1000, and >1000 g) was statistically significant (14.0%, 17.6%, and 25.7%; P = 0.002, respectively) and were higher with increased mastectomy weights. Notably, in patients with breast mastectomy weight >1000 g, autologous reconstruction had significantly reduced rates of overall complications (AOR = 0.512, P = 0.048).

Conclusion

Complication rates were lower in women with larger breast weights undergoing autologous reconstruction, warranting potential use of autologous free flap breast reconstruction in women with large mastectomy specimen weights when possible.

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Endoscopically-assisted transmastoid approach to the geniculate ganglion and labyrinthine facial nerve

Endoscopic transcanal approaches to the facial nerve allow excellent exposure of the tympanic facial nerve. This approach becomes limited when access is required to the more proximal geniculate ganglion and la...

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Welcome MA Speech-Language Pathology class of 2019!

See our incoming Master of Arts students (class of 2019) at the first day of orientation taking a break to watch the solar eclipse on August 21, 2017:

 

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Können 12- statt 4‑wöchentliche Zoledronsäuregaben skelettale Ereignisse bei Patienten mit Knochenmetastasen reduzieren?

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New chemotherapies in breast cancer

Summary

In the era of targeted therapies and immunotherapy for cancer, the focus in breast cancer (BC) research has shifted away from classical chemotherapy. Many BC patients, however, still need chemotherapy and thus benefit from the development of new chemotherapeutic agents or regimens. In the past decade, the approval of eribulin and trastuzumab emtansine (T-DM1) have been important advances in this regard. Improved ways of delivery of paclitaxel, anthracyclines, and vinorelbine have also had a considerable clinical impact. Finally, optimizing the use of well-known drugs, such as carboplatin, capecitabine, or adjuvant chemoimmunotherapy in low-risk early BC, has brought about progress in the field of chemo(immuno)therapy.

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Survival outcomes of hepatectomy for stage B Hepatocellular carcinoma in the BCLC classification

Abstract

Background

Because hepatectomy is not recommended in patients with stage B hepatocellular carcinoma (HCC) of the Barcelona Clinic Liver Cancer (BCLC) staging, we evaluated the survival outcomes of hepatectomy for stage B in the BCLC system.

Methods

Data were collected from 297 consecutive adult stage B patients who underwent curative hepatectomy for HCC between 1996 and 2014 in Hokkaido University Hospital. Overall survival (OS), disease-free survival (DFS), and risk factors were analyzed using the Kaplan–Meier method. Independent prognostic factors were evaluated using a Cox proportional hazards regression model. AP-factor (alpha-fetoprotein [AFP] × protein induced by vitamin K absence or antagonism factor II [PIVKA-II]) was categorized according to the serum concentrations of AFP and PIVKA-II: AP1 (AFP < 200 ng/ml and PIVKA-II < 100 mAU/ml), AP2 (AFP × PIVKA-II < 10⁵), and AP3 (AFP × PIVKA-II ≥ 10⁵).

Results

There were 130 deaths among our 297 stage B patients (43.8%). The causes of death in these cases were HCC recurrence (n = 106; 81.5%), liver failure (n = 7; 5.4%), and other causes (n = 17; 16.1%). The operative mortality rate was 0.34% (1/297). The 5-year OS and DFS rates for the stage B cases were 54.3 and 21.9%, respectively. By multivariate analysis, tumor number and AP-factor were risk factors for both survival and recurrence that were tumor related and could be evaluated preoperatively. The study patients with stage B HCC were classified into three groups by tumor number (B1, 1; B23, 2 or 3; B4over: ≥4) and into three groups stratified by AP-factor (AP1, AP2, and AP3). The 5-year OS rates of B1, B23, and B4over were 63.6, 52.3, and 29.0%. The 5-year OS rates of AP1, AP2, and AP3 were 67.6, 65.2, and 39.1%. Stratified by the 5-year OS rate, stage B HCC patients were classified into three subgroups (A-C).The 5-year OS rates of groups A (B1 or B23 and AP-1 or AP-2), B (B1 or B23 and AP-3, or B4over and AP-1 or AP-2), and C (B4over and AP-3) were 69.5, 43.7, and 21.3%.

Conclusion

Stage B HCC patients with a tumor number ≤ 3 and/or AP-factor < 1 × 10⁵ show acceptable 5-year OS rates and could be treated by hepatectomy.

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Encouraging option of multi-staged gross total resection for a C11orf - RelA fusion-positive supratentorial anaplastic ependymoma

Abstract

Ependymomas are primary neuroepithelial malignancies that mainly occur during childhood, and arise from ependymal cells along the ventricular systems of the CNS. Recently, it was elucidated that two-thirds of supratentorial (ST) ependymomas harbor oncogenic fusions of RELA, whose protein product is the principal effector of canonical NF-κB signaling. RELA fusion proteins activate signaling for tumor proliferation and malignant progression, resulting in poorer prognoses in these patients compared to those in patients with other ST ependymomas. In this study, we encountered a case of C11orf–RelA fusion-positive ST anaplastic ependymoma that was diagnosed in first tumor resection surgery of multi-staged gross total resection with molecular evidence. In ependymomas, regardless of tumor location or pathological grade, subtotal resection is associated with higher rates of mortality compared with GTR. Molecular analysis based on the application of recent molecular knowledge for ST ependymomas performs a role in appropriate and individualized treatment strategies.

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