Concurrent presentation of an intraductal tubulopapillary neoplasm and intraductal papillary mucinous neoplasm in the branch duct of the pancreas, with a superior mesenteric artery aneurysm: a case report

Abstract

Background

Since the concept of intraductal tubulopapillary neoplasm (ITPN) was introduced in the current World Health Organization classification of tumors, the number of reports of ITPN occurrence has increased gradually. However, ITPN is usually located in the main pancreatic duct, with few reports of a branch duct ITPN. As a result, imaging protocols for the diagnosis of a branch duct ITPN have not been established.

Case presentation

We report a case of a concurrent presentation of a branch duct ITPN and intraductal papillary mucinous neoplasm (IPMN) in the head of the pancreas, with a superior mesenteric artery (SMA) aneurysm. Initially, the cystic masses in the pancreatic head were diagnosed as branch duct IPMNs, with treatment consisting of a pylorus-preserving pancreaticoduodenectomy, in combination with an aneurysmectomy performed for treatment of the SMA aneurysm. Pathological examination confirmed these cysts were a combination of branch-type ITPN and IPMN. The patient recovered from the treatment without complication, with no evidence of recurrence over a period of 34 months post-surgery.

Conclusion

This case report of a synchronous presentation of an ITPN and IPMN indicates the difficulty in differentiating these two types of neoplasms in the branch duct of the pancreatic head.

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3D-printed model improves clinical assessment of surgeons on anatomy

Abstract

Performing surgical procedures often requires a surgeon to develop a skill to create 3-dimensional (3D) mental model on patient's anatomy. Question remains whether the touching on the 3D printed model can facilitate learning of patient anatomy than viewing the rendered virtual on-screen model. The printed and the virtual 3D model were developed from CT films taken from a 4-year-old girl, who had dysplasia of the hip in the left hip. Eleven subjects were called to report measures on six key anatomical features on the hips. The reporting time and the accuracy were compared between the two models, along with the gaze characteristics of subjects while inspecting the models. The variables were analysed using a 2 × 2 within subject ANOVA to examine the difference between viewing the models (on-screen vs. printed-out) and the side of the hip (right vs. left). Interacting with the printed 3D model required shorter times and yielded more accurate visual judgments than viewing the virtual models on most of the anatomical features. Subjects performed a fewer number of fixations but with a longer mean fixation duration when interacting the printed than inspecting the virtual on-screen 3D model. Results confirmed the value of the printed 3D model on improving the clinical judgement on patient anatomy. Confidence in collecting information from the physical world and the cross-model sensor integration may explain why participants performed better with the printed model compared to the virtual model.

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Role of Adenoid-Nasopharyngeal Ratio in Assessing Adenoid Hypertrophy

Abstract

Most of the time, pediatrician is the first to see children with adenotonsillar hypertrophy (AH) and they mostly rely on clinical assessment with or without some investigation to refer these children to otorhinolaryngologist. Numerous methods have been described for evaluation of AH, but many of these methods are not possible to follow in busy pediatric outpatient unit either because of lack of cooperation from child or due to limited availability of test or due to cost constraints. This study has been conducted to determine the diagnostic accuracy of lateral neck X-ray (LNX) for assessing AH and to assess the correlation between adenoid size in LNX and clinical symptoms in a pediatric unit. Prospective study conducted in Department of ENT, Pathmavathy Medical Foundation, Kollam, Kerala, India from January 2015 to March 2016. 60 consecutive children of both genders, between the age group of 5 to 14 years, attending Department of Pediatrics with a provisional diagnosis of AH were included in the study. The symptom scores, radiographic ratio of adenoid to nasopharynx and endoscopic scorings were calculated. Lateral neck X-ray with calculation of adenoid-to-nasopharynx ratio is found to have significant correlation with patient reported symptoms and findings in nasal endoscopic examination (NE). LNX can be considered as a useful objective tool in evaluation of children with adenoid hypertrophy. Primary care physicians or pediatricians can confidently use lateral neck X-ray for making clinical decisions and can consider nasopharyngoscopy when clinical picture remains unclear or more evaluation is needed.

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Laryngectomy With or Without Partial Pharyngectomy: A Systematic Review

Abstract

Complications following the total laryngectomy with or without partial pharyngectomy with neck dissection for laryngeal and pyriform fossa malignancies like aspiration, pharyngocutaneous fistula wound infection, flap necrosis, haematoma, chyle fistula and carotid blowout can cause serious implication on the final outcome of the treatment, which leads to increased postoperative morbidity, hospital stay and hospital cost. A prospective study in the Department of Otolaryngology and Head–Neck Surgery, JSS Hospital, Mysore, from November 2014 to July 2016. 30 patients undergoing Total laryngectomy with or without partial pharyngectomy for laryngeal and pyriform fossa were included in this study. The presentation, diagnosis, and management of the complications that were occurred, were discussed. The age of the patients vary between 32 and 76. Also, male preponderance was seen with approximately M:F ratio 3:1. Out of these 30 patients, 6 patients developed complications. The most common complication was pharyngocutaneous fistula (2 patients, 6%), which was developed after the 7th day. It was managed conservatively in both patients, wound infection was a second complication (2, 6%). Other complications were drain failure (1, 3%) and chylous fistula (1, 3%). The Most common complications after total laryngectomy with or without partial pharyngectomy with neck dissection in our study were wound infection and pharyngocutaneous fistula. Assessment of risk factors, early recognition of complications per operative protocols with improvised techniques are necessary to reduce incidence of complication after total laryngectomy with or without partial pharyngectomy with neck dissection.

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Barbed Reposition Pharyngoplasty in Indian Population: A New Palatal Surgery for OSAS

Abstract

Obstructive sleep apnoea (OSA) is a common problem affecting almost 4% of the population. Although continuous positive airway pressure (CPAP) is considered the standard of care, the patient compliance for long term use is poor. Clinicians have explored surgical options for cure with varying success. Uvulopalatopharyngoplasty was considered as a standard of surgical care but long-term results were not satisfactory. Surgical researchers have explored newer techniques to improve outcomes in the past decade with less morbidity and better quality of life outcomes. One of such development is Barbed Reposition Pharyngoplasty (BRP). We would like to discuss the technique of BRP for OSA patients step by step.

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Editorial Board

Publication date: June 2018
Source:Atmospheric Environment, Volume 182





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Transcriptome Network Analysis Reveals Aging-Related Mitochondrial and Proteasomal Dysfunction and Immune Activation in Human Thyroid

Thyroid, Ahead of Print.


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Blimp-1 prolongs allograft survival without regimen via influencing T cell development in favor of regulatory T cells while suppressing Th1

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Aline Yen Ling Wang, Charles Yuen Yung Loh, Shyi-Jou Chen, Huang-Kai Kao, Cheng-Hung Lin, Sheng-Hao Chuang, Chin-Ming Lee, Huey-Kang Sytwu, Fu-Chan Wei
BackgroundB lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is expressed in multiple cell lineages and in particular, T cells. However, the role of Blimp-1 in T cell-mediated allograft tolerance is still unknown.MethodsThis study is the first to investigate transplanted skin allograft survival using transgenic (Tg) mice with T cell overexpression of Blimp-1.ResultsWithout any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. Allograft lymphocytic infiltration was decreased in Tg(+) mice and a dampened donor-stimulated alloimmune response was seen. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and IL-10-producing T cells, as well as cytolytic proteins, were significantly decreased in lymphoid organs and allograft. Blimp-1 transgenic T cells displayed an increased Treg differentiation capability and enhanced suppression of T cell proliferation. Overexpression of Blimp-1 in T cells promoted the formation of an anti-inflammatory cell-cytokine composition, both systemically and locally via transcription factor modulation such as T-bet downregulation and FoxP3 upregulation.DiscussionAs such, allograft survival was made possible due to Th1 suppression and Treg amplification with the creation of an 'allograft protective microenvironment'.



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From the Editors: Clinical Discourse as Cultural Borderlands

No abstract available

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Issue Editor Foreword: Clinical Discourse as Cultural Borderlands

No abstract available

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Renewing Our Cultural Borderlands: Equitable Population Innovations for Communication (EPIC)

The professions of speech–language pathology and audiology provide valuable services for persons with communication, hearing, and feeding/swallowing disabilities. However, from a global perspective, mainstream practice discourses represent values from colonial perspectives (called Northern here). As such, they remain largely inaccessible to most people in the world. We argue, from a South African perspective, for a postcolonial or Southern discourse in alignment with other Africans, Latin Americans, and Asians who historically have had limited opportunities to shape professional practices. We use ideology critique (a disruptive tool) to reflect and make visible hegemonic Northern practices. Critical science and decoloniality are offered as pivotal axes for transformation. Decoloniality is discussed in relation to (i) Equitable (ii) Population-based (iii) Innovations for (iv) Communication (EPIC) using illustrative examples of emerging South African practices. We argue for redefining communication disorder professions' cultural borderlands to engage Northern with Southern ideologies critically to strengthen professional practice transformation.

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Constructing and Navigating Cultural Borderlands Using Augmentative and Alternative Communication

Individuals who use augmentative and alternative communication (AAC) occupy complex sociocultural and sociolinguistic territories. They are immersed in spoken language communities but to participate as speakers in conversational interactions, they may rely on atypical communication modes, including systems for generating speech that set them apart as what Mattingly (2006) termed "Other." This article explores the challenges and tensions implicit in shifting between cultural roles of Natural Speaker and Aided Communicator using the construct of cultural borderlands. Borderlands are first explored in terms of social participation, focusing on questions such as whether aided communication offers a bridge across borderlands or constitutes a marker of cultural difference and on the question of ownership of aided communication. The borderlands of speaker–listener roles that are negotiated within interactions involving aided communication are then considered. Possible implications of how the construct of cultural borderlands supports understanding of interactions involving aided communication are suggested.

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“Well, You Are the One Who Decides”: Attempting Shared Decision Making at the End of Aphasia Therapy

Clinical borderlands manifest themselves through encounters between people deemed to be in need of health care and health care providers (Mattingly, 2010). This article addresses the problem of inherent asymmetry in the clinical discourse between clinical providers, such as speech–language pathologists (SLPs), and persons with aphasia. Speech–language pathologists, communicating as experts, tend to dominate the discourse regarding the course of treatment, particularly with clients with aphasia who may lack the necessary communicative skills to participate in decision making. Such patterns of communication were apparent in a study reported here that involved thematic analysis of the views of 12 SLPs regarding involving people with aphasia in shared decision making and in analysis of 33 video recordings of these 12 SLPs and 28 people with aphasia during clinical interactions. Although the SLPs stated that they wanted to involve their clients in decision making and took steps to do so, the discourse sample analysis revealed that the SLPs controlled the interaction through their initiations, topic selection, and presentation of limited choices. Alternatives for supporting greater decision-making participation among people with aphasia with their clinicians are discussed.

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“It's Not the Asperger's That Causes the Anxiety, It's the Communication”: Person-Centered Outcomes of Hope and Recovery in a Cultural–Clinical Borderland

This article focuses on a narrative account of a therapeutic journey experienced by 2 of the authors: an individual (P.D.) with a diagnosis in adulthood of autism spectrum disorder (ASD) and a speech–language pathologist/researcher (I.W.). Instead of adopting a traditional expert clinician treating an impaired patient stance in a highly formalized clinical setting, with concomitant role expectations of power and perceived inequality, a cultural–clinical borderland was coconstructed. The figurative notion of borderland in this context is used to describe a physical and psychological space characterized by a more flexible, informal, and authentically shared therapeutic relationship, influenced by a merging of cultures. The cultures at play in this context were an ASD and non-ASD culture and the culture and practice of speech–language pathology. Accounts of social communication experiences, challenges, and anxieties focused on personal reflections, when misunderstandings and miscommunications surfaced from perceived cultural differences. Instead of reinforcing experiences of otherness and difference—which may be an inadvertent by-product of impairment-focused therapy—a positive trajectory of hope and recovery emerged from these interactions when they were placed within a person-centered context.

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Continuing Education Instructions and Questions

No abstract available

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Combination Therapy and the Evolution of Resistance: The Theoretical Merits of Synergism and Antagonism in Cancer

The search for effective combination therapies for cancer has focused heavily on synergistic combinations because they exhibit enhanced therapeutic efficacy at lower doses. Although synergism is intuitively attractive, therapeutic success often depends on whether drug resistance develops. The impact of synergistic combinations (vs. antagonistic or additive combinations) on the process of drug-resistance evolution has not been investigated. In this study, we use a simplified computational model of cancer cell numbers in a population of drug-sensitive, singly-resistant, and fully-resistant cells to simulate the dynamics of resistance evolution in the presence of two-drug combinations. When we compared combination therapies administered at the same combination of effective doses, simulations showed synergistic combinations most effective at delaying onset of resistance. Paradoxically, when the therapies were compared using dose combinations with equal initial efficacy, antagonistic combinations were most successful at suppressing expansion of resistant subclones. These findings suggest that, although synergistic combinations could suppress resistance through early decimation of cell numbers (making them "proefficacy" strategies), they are inherently fragile toward the development of single resistance. In contrast, antagonistic combinations suppressed the clonal expansion of singly-resistant cells, making them "antiresistance" strategies. The distinction between synergism and antagonism was intrinsically connected to the distinction between offensive and defensive strategies, where offensive strategies inflicted early casualties and defensive strategies established protection against anticipated future threats. Our findings question the exclusive focus on synergistic combinations and motivate further consideration of nonsynergistic combinations for cancer therapy.Significance: Computational simulations show that if different combination therapies have similar initial efficacy in cancers, then nonsynergistic drug combinations are more likely than synergistic drug combinations to provide a long-term defense against the evolution of therapeutic resistance. Cancer Res; 78(9); 1–13. ©2018 AACR.

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Workshop Report for Cancer Research: Defining the Shades of Gy: Utilizing the Biological Consequences of Radiotherapy in the Development of New Treatment Approaches—Meeting Viewpoint

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Cycling Towards Progress: Ribociclib, CDK 4/6 inhibitor for Breast Cancer

Ribociclib is an orally active, highly selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6. It is the second CDK 4/6 inhibitor approved for hormone receptor-positive breast cancer. The addition of ribociclib to an aromatase inhibitor has resulted in marked improvements in progression-free survival for patients with metastatic breast cancer.

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Integrative kinome profiling identifies mTORC1/2 inhibition as treatment strategy in ovarian clear cell carcinoma

Purpose: Advanced stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in OCCC patients and test druggability of downstream affected pathways in OCCC models. Experimental Design: In a large set of OCCC patients (n=124), the human kinome (518 kinases) and additional cancer related genes were sequenced and copy number alterations were determined. Genetically characterized OCCC cell lines (n=17) and OCCC patient-derived xenografts (n=3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib and the mTORC1/2 inhibitor AZD8055. Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway or the ERBB family of receptor tyrosine kinases and 82% in the DNA repair pathway. Strong p-S6 staining in OCCC patients suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not towards drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models. Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC.

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Clinicopathological risk factors for an invasive breast cancer recurrence after ductal carcinoma in situ - A nested case-control study

Purpose: Ductal carcinoma in situ (DCIS) is treated to prevent progression to invasive breast cancer. Yet, most lesions will never progress, implying that overtreatment exists. Therefore, we aimed to identify factors distinguishing harmless from potentially hazardous DCIS using a nested case-control study. Experimental Design: We conducted a case-control study nested in a population-based cohort of DCIS patients treated with breast conserving surgery (BCS) alone (n=2,658) between 1989-2005. We compared clinical, pathological, and immunohistochemical DCIS characteristics of 200 women who subsequently developed ipsilateral invasive breast cancer (iIBC; cases) and 474 women who did not (controls), in a matched setting. Median follow-up time was 12.0 years (interquartile range 9.0-15.3). Conditional logistic regression models, were used to assess associations of various factors with subsequent iIBC risk after primary DCIS. Results: High COX-2 protein expression showed the strongest association with subsequent iIBC (odds ratio [OR]=2.97, 95% confidence interval [95%CI] 1.72-5.10). In addition, HER2 overexpression (OR=1.56, 95%CI 1.05-2.31) and presence of periductal fibrosis (OR=1.44, 95%CI 1.01-2.06) were associated with subsequent iIBC risk. Patients with HER2+/COX-2high DCIS had a 4-fold higher risk of subsequent iIBC (vs. HER2-/COX-2low DCIS), and an estimated 22.8% cumulative risk of developing subsequent iIBC at 15 years. Conclusions: With this unbiased study design and representative group of DCIS patients treated by BCS alone, COX-2, HER2, and periductal fibrosis were revealed as promising markers predicting progression of DCIS into iIBC. Validation will be done in independent data sets. Ultimately, this will aid individual risk stratification of women with primary DCIS.

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21-gene recurrence score assay predicts benefit of post-mastectomy radiotherapy in T1-2 N1 breast cancer

Purpose: Post-mastectomy radiotherapy (PMRT) yields improvements in both locoregional control and overall survival (OS) for women with T1-2 N1 breast cancer. The value of PMRT in this population has been questioned given advances in systemic therapy. The 21-gene Recurrence Score (RS) assay was evaluated as a predictor of OS among women with T1-2 N1 breast cancer who received or did not receive PMRT. Experimental Design: An observational cohort study was performed on women with T1-2 N1 estrogen receptor-positive breast cancer from the National Cancer Database (NCDB) and, as a validation cohort, from the Surveillance, Epidemiology, and End Results (SEER) registry who underwent mastectomy and were evaluated for RS. Multivariable parametric accelerated failure time models were used to estimate associations of RS and PMRT with OS using propensity score-adjusted matched cohorts. Results: In both the NCDB (N=7,332) and SEER (N=3,087) cohorts, there was a significant interaction of RS and PMRT with OS (P=0.009 and P=0.03, respectively). PMRT was associated with longer OS in women with a low RS (NCDB: time-ratio (TR)=1.70, 95% CI=1.30-2.22, P<0.001; SEER: TR=1.85, 95% CI=1.33-2.57, P<0.001), but not in women with an intermediate RS (NCDB: TR=0.89, 95% CI=0.69-1.14, P=0.35; SEER: TR=0.84, 95% CI=0.62-1.14, P=0.26), or a high RS (NCDB: TR=1.10, 95% CI=0.91-1.34, P=0.33; SEER: TR=0.79, CI=0.50-1.23, P=0.28). Conclusions: Longer survival associated with PMRT was limited to women with a low RS. PMRT may confer the greatest OS benefit for patients at lowest risk of distant recurrence. These results caution against omission of PMRT among women with low RS.

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A model of overall survival predicts treatment outcomes with atezolizumab vs chemotherapy in non-small cell lung cancer based on early tumor kinetics

Purpose: Standard endpoints often poorly predict overall survival (OS) with immunotherapies. We investigated the predictive performance of model-based tumor growth inhibition (TGI) metrics using data from atezolizumab clinical trials in patients with non-small cell lung cancer. Methods: OS benefit with atezolizumab vs docetaxel was observed in both POPLAR (phase II) and OAK (phase III) although progression-free survival was similar between arms. A multivariate model linking baseline patient characteristics and on-treatment tumor growth rate constant (KG), estimated using time profiles of sum of longest diameters (RECIST 1.1) to OS, was developed using POPLAR data. The model was evaluated to predict OAK outcome based on estimated KG at TGI data cutoffs ranging from 10 to 122 weeks. Results: In POPLAR, TGI profiles in both arms crossed at 25 weeks, with more shrinkage with docetaxel and slower KG with atezolizumab. A log-normal OS model, with albumin and number of metastatic sites as independent prognostic factors and estimated KG, predicted OS hazard ratio (HR) in sub-populations of patients with varying baseline PD-L1 expression in both POPLAR and OAK: model-predicted OAK HR (95% prediction interval): 0.73 (0.63-0.85) vs 0.73 observed. The POPLAR OS model predicted greater than 97% chance of success of OAK (significant OS HR, P < 0.05) from the 40-week data cutoff onward with 50% of the total number of tumor assessments when a successful study was predicted from 70 weeks onward based on observed OS. Conclusions: KG has potential as a model-based early endpoint to inform decisions in cancer immunotherapy studies.

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Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients With Melanoma Treated With Pembrolizumab

Purpose: To assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations. Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1-89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites) (all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs 23%; P < 0.001) and improved OS (hazard ratio, 0.38; P < 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS (P < 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1-positive tumors were independently associated with higher ORR and longer OS. Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma.

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The first step of patient-specific design calvarial implant: A quantitative analysis of fresh parietal bones

Abstract

Background

Accurate knowledge of the fracture of cranial bone can provide insight into the prevention of skull fracture injuries and help aid the design of energy-absorbing head protection systems and safety helmets. When cranial bone needs to be removed or is lost, subsequent reconstruction of the defect is necessary to protect the underlying brain, or correct esthetic deformities, or both. Ideal reconstruction of defected bone is possible utilizing a biocompatible implant with a bone-like design individualized for the specific patient. The purpose of this study is to investigate the anatomical and mechanical characteristics of fresh frozen human parietal bones and determine compliance of polylactic acid-based personalized three-dimensional implants in terms of mechanical properties in order to replace such defective bones.

Methods

Parietal bone specimens were extracted from 19 fresh frozen cadavers. Morphological parameters of individual bone specimens were measured using Image J software. Three-point bend tests were performed to extract Young's modulus and tensile strength of the specimens from the measured force and displacement data by modeling the bone specimens as curved linear elastic beams. Also, three-point bend tests were performed to polylactic acid-based three-dimensional replicas mimicking geometry of the bone specimens in order to determine whether the material's Young's modulus and tensile strength properties comply with parietal bones.

Results

Entire fresh parietal specimens were observed to be comprised of a three-layered structure: external layers consisting of compact, high-density cortical bone and the central layer consisting of low-density, irregularly porous bone structure. Mean thickness of three-layered structure was 6.25 ± 1.46 mm. Mean Young's modulus and tensile strength of the specimens were 1.40 ± 1.34 GPa and 44.56 ± 21.94 MPa, respectively where no statistically significant differences among genders were detected (p > 0.05). Mean Young's modulus and tensile strength of the polylactic acid-based three-dimensional implants mimicking geometry of the bone specimens were 1.8 ± 0.7 GPa and 72.8 ± 2.5 MPa, respectively.

Conclusions

Polylactic acid-based three-dimensional implants can be considered as acceptable candidates for temporary replacement of parietal defects in terms of mechanical properties.

Level of Evidence: Not ratable.

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Is single-stage implant-based breast reconstruction (SSBR) with an acellular matrix safe?

Abstract

Background

Acellular matrices (AM) might enable a direct single-stage breast reconstruction procedure resulting in an improved efficacy of the reconstruction phase for patients. Safety concerns are an important issue due to a recent study which shows that single-stage breast reconstruction with Strattice™ resulted in more complications versus a two-stage reconstruction. Therefore, the goal of this study is to compare the short- and long-term complications of a single-stage breast reconstruction with the use of two types of AM (Strattice™ and Meso Biomatrix®) versus two-stage breast reconstruction without the use of an AM.

Methods

Cohort study with single-stage breast reconstruction with Strattice™ (n = 28) or Meso BioMatrix® (n = 20) or two-stage breast reconstruction without an AM (n = 36) at the Maastricht Academic Hospital, the Netherlands. All complications, in particular major complications with the need for re-admission to the hospital, re-exploration, and implant explantation, were the primary outcome measures. A 1-year follow-up was achieved for all patients.

Results

Baseline characteristics of all 52 patients were similar between groups. There was a significantly higher complication rate in the single-stage AM groups with loss of the implant in 40.0% of the breasts from the Meso BioMatrix® group and in 10.7% of the Strattice™ group compared to no implant loss in the control group.

Conclusions

This cohort study clearly suggests that the use of a single-stage breast reconstruction is not safe with the use of these AMs. Well-designed prospective studies that guarantee the safety of those matrices should be published before these AMs are used in implant-based surgery.

Level of Evidence: Level III, risk / prognostic study.

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Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study

Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study

Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study, Published online: 24 April 2018; doi:10.1038/s41416-018-0052-7

Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study

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Multicentre, cross-cultural, population-based, case-control study of physical activity as risk factor for amyotrophic lateral sclerosis

Objective

To investigate the association between physical activity (PA) and amyotrophic lateral sclerosis (ALS) in population-based case–control studies in three European countries using a validated and harmonised questionnaire.

Methods

Patients with incident ALS and controls were recruited from five population-based registers in The Netherlands, Ireland and Italy. Demographic and data regarding educational level, smoking, alcohol habits and lifetime PA levels in both leisure and work time were gathered by questionnaire, and quantified using metabolic equivalent of task scores. Logistic regression models adjusting for PA-related factors were used to determine the association between PA and ALS risk, and forest plots were used to visualise heterogeneity between regions.

Results

1557 patients and 2922 controls were included. We found a linear association between ALS and PA in leisure time (OR 1.07, P=0.01) and occupational activities (OR 1.06, P<0.001), and all activities combined (OR 1.06, P<0.001), with some heterogeneity between regions: the most evident association was seen in the Irish and Italian cohorts. After adjustment for other occupational exposures or exclusion of patients with a C9orf72 mutation, the ORs remained similar.

Conclusion

We provide new class I evidence for a positive association between PA and risk of ALS in a large multicentre study using harmonised methodology to objectively quantify PA levels, with some suggestions for population differences.

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Physical activity as a risk factor in ALS

Can physical activity induce excitoxicity and increase the risk of ALS?

Even from the time of the earliest descriptions of ALS, environmental causation was considered possible. For example, Charcot mentioned that a third of his patients considered exposure to cold and damp was responsible, and he singled out one man who had sustained a fractured clavicle a few months before the onset of the disease.1 Trauma, occupational or sports-related physical activity, cigarette smoking, exposure to electromagnetic fields or electric shocks, military service and exposure to environmental lead or organic solvents have all been reported to increase the risk of acquiring ALS.2 3 However, many of these studies are based on small case numbers, or have been criticised on other methodological grounds and, for now, only an association with smoking history, pesticide exposure and dietary factors, especially premorbid fat intake have been consistent, although at...

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Assessing the carcinogenic potential of E-cigarette

Past decade has seen a significant rise in the use of E-cigarette especially among youngsters. The increasing popularity of E-cigarette is largely due to its marketing as a safe alternative to conventional smoking. Recent studies have shown that the health hazards posed by e-cigarette are comparable to that of conventional smoking. Studies have also shown the presence of several potential carcinogens including tobacco-specific nitrosamines, carbonyls (formaldehyde, acetaldehyde) in e-cigarettes [1].

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Articles highlighted

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Assessing the carcinogenic potential of E-cigarette

Past decade has seen a significant rise in the use of E-cigarette especially among youngsters. The increasing popularity of E-cigarette is largely due to its marketing as a safe alternative to conventional smoking. Recent studies have shown that the health hazards posed by e-cigarette are comparable to that of conventional smoking. Studies have also shown the presence of several potential carcinogens including tobacco-specific nitrosamines, carbonyls (formaldehyde, acetaldehyde) in e-cigarettes [1].

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Moderators of angiogenesis in muscle flaps: a non-randomised animal study

A muscle flap can survive a pedicle injury under favourable conditions. In the reconstruction of compound limb injuries, the wound milieu is variable and may affect the rate and manner of neovascularisation. Our aim is to determine the effect of some key clinical variables on neovascularisation in muscle flaps in an animal model.

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Developmental trends in susceptibility to perceptual illusions: Not all illusions are created equal

Abstract

This study examined the development of the utilization of contextual information in visuospatial integration during childhood. We examined four contextual size illusions in children and adults asking whether young children's sensitivity to context is reduced or varies with the perceptual mechanisms or the levels of integration involved. We tested susceptibility to contextual illusions in four-year-olds, seven-year-olds, and adults, employing two psychophysical paradigms, perceptual estimation and a 2AFC discrimination task. We tested susceptibility to Ebbinghaus and Ponzo illusions to estimate the effect of the interaction of object size with its contextual background on the rescaling of its perceived size; we also tested susceptibility to the rectangle and 3D-cube illusions to estimate the effect of the interaction of two dimensions of the target object on the rescaling of its perceived size. While four-year-olds were affected by the Ebbinghaus and Ponzo illusions, they showed no susceptibility to the rectangle or 3D-cube illusion. The results show that, overall, sensitivity to context is not reduced in early childhood; rather, it varies with the perceptual mechanisms or the levels of integration involved. In particular, development is protracted for size illusions in which contextual effects entail the extraction of the relations of dimensions within an object.

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Visual memory, the long and the short of it: A review of visual working memory and long-term memory

Abstract

The majority of research on visual memory has taken a compartmentalized approach, focusing exclusively on memory over shorter or longer durations, that is, visual working memory (VWM) or visual episodic long-term memory (VLTM), respectively. This tutorial provides a review spanning the two areas, with readers in mind who may only be familiar with one or the other. The review is divided into six sections. It starts by distinguishing VWM and VLTM from one another, in terms of how they are generally defined and their relative functions. This is followed by a review of the major theories and methods guiding VLTM and VWM research. The final section is devoted toward identifying points of overlap and distinction across the two literatures to provide a synthesis that will inform future research in both fields. By more intimately relating methods and theories from VWM and VLTM to one another, new advances can be made that may shed light on the kinds of representational content and structure supporting human visual memory.

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The detrimental influence of attention on time-to-contact perception

Abstract

To which extent is attention necessary to estimate the time-to-contact (TTC) of a moving object, that is, determining when the object will reach a specific point? While numerous studies have aimed at determining the visual cues and gaze strategy that allow this estimation, little is known about if and how attention is involved or required in this process. To answer this question, we carried out an experiment in which the participants estimated the TTC of a moving ball, either alone (single-task condition) or concurrently with a Rapid Serial Visual Presentation task embedded within the ball (dual-task condition). The results showed that participants had a better estimation when attention was driven away from the TTC task. This suggests that drawing attention away from the TTC estimation limits cognitive interference, intrusion of knowledge, or expectations that significantly modify the visually-based TTC estimation, and argues in favor of a limited attention to correctly estimate the TTC.

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Dissecting stimulus–response binding effects: Grouping by color separately impacts integration and retrieval processes

Abstract

In selection tasks, target and distractor features can be encoded together with the response into the same short-lived memory trace, or event file (see Hommel, 2004), leading to bindings between stimulus and response features. The repetition of a stored target or distractor feature can lead to the retrieval of the entire episode, including the response—so-called "binding effects." Binding effects due to distractor repetition are stronger for grouped than for nongrouped target and distractor stimulus configurations. Modulation of either of two mechanisms that lead to the observed binding effects might be responsible here: Grouping may influence either stimulus–response integration or stimulus–response retrieval. In the present study we investigated the influences of grouping on both mechanisms independently. In two experiments, target and distractor letters were grouped (or nongrouped) via color (dis)similarity separately during integration and retrieval. Grouping by color similarity affected integration and retrieval mechanisms independently and in different ways. Color dissimilarity enhanced distractor-based retrieval, whereas color similarity enhanced distractor integration. We concluded that stimulus grouping is relevant for binding effects, but that the mechanisms that contribute to binding effects should be carefully separated.

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Occupational dermatitis: how to identify the exposures, make the diagnosis, and treat the disease.

Key messages:

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Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study

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The Impact of Hormonal Contraceptives on Breast Cancer Pathology

Abstract

This retrospective case series study, using data obtained through questionnaires and histopathological diagnoses from 656 patients enrolled in the Department of Defense (DoD) Clinical Breast Care Project (CBCP), evaluated associations between hormonal contraceptive use and breast cancer pathology including benign breast pathologies. Three combination hormonal contraceptive agents (COCs) Lo Ovral (LO), Ortho Novum (ON), and Ortho Tri-Cyclen (OTC) were evaluated as they represented the most commonly used hormonal contraceptives in our cohort. The results of this study suggest that the ever use of LO + ON + OTC does not influence the overall incidence of benign breast condition or malignant disease compared to other COCs; however, patients that have used OTC had an association with a diagnosis of benign or luminal A pathologies whereas ON was associated with a diagnosis of benign and DCIS; LO showed no association with any diagnosis—benign or malignant. Patients that have used LO or ON were more likely to be diagnosed with breast cancer at age ≥ 40 years whereas patients that had ever used OTC were likely to be diagnosed before the age of 40. Caucasians were less likely to have used OTC and more likely to have used ON; however, use of either hormonal agent positively correlated with premenopausal status at diagnosis and having a benign condition. Age at diagnosis, ethnicity, BMI, family history, menstruation status, and duration of use were all independent predictors of different histopathological subtypes. We conclude that patient-specific variables should be considered when deciding on which type of hormonal contraceptive to use to minimize the risk of developing breast cancer or a breast-related pathology.

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Are lexical tones musical? Native language’s influence on neural response to pitch in different domains

Publication date: May–July 2018
Source:Brain and Language, Volumes 180–182
Author(s): Ao Chen, Varghese Peter, Frank Wijnen, Hugo Schnack, Denis Burnham
Language experience shapes musical and speech pitch processing. We investigated whether speaking a lexical tone language natively modulates neural processing of pitch in language and music as well as their correlation. We tested tone language (Mandarin Chinese), and non-tone language (Dutch) listeners in a passive oddball paradigm measuring mismatch negativity (MMN) for (i) Chinese lexical tones and (ii) three-note musical melodies with similar pitch contours. For lexical tones, Chinese listeners showed a later MMN peak than the non-tone language listeners, whereas for MMN amplitude there were no significant differences between groups. Dutch participants also showed a late discriminative negativity (LDN). In the music condition two MMNs, corresponding to the two notes that differed between the standard and the deviant were found for both groups, and an LDN were found for both the Dutch and the Chinese listeners. The music MMNs were significantly right lateralized. Importantly, significant correlations were found between the lexical tone and the music MMNs for the Dutch but not the Chinese participants. The results suggest that speaking a tone language natively does not necessarily enhance neural responses to pitch either in language or in music, but that it does change the nature of neural pitch processing: non-tone language speakers appear to perceive lexical tones as musical, whereas for tone language speakers, lexical tones and music may activate different neural networks. Neural resources seem to be assigned differently for the lexical tones and for musical melodies, presumably depending on the presence or absence of long-term phonological memory traces.



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In This Issue [IN THIS ISSUE]

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IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

Rapid initiation and timely resolution of inflammatory response in macrophages are synergistic events that are known to be equally critical to optimal host defense against pathogen infections. However, the regulation of these processes, in particular by a specific cellular metabolic program, has not been well understood. In this study, we found that IFN regulatory factor 2 (IRF2) underwent an early degradation in a proteasome-mediated pathway in LPS-treated mouse macrophages, followed by a later recovery of the expression via transactivation. We showed that IRF2 was anti-inflammatory in that knockdown of this protein promoted the production of LPS-induced proinflammatory mediators. Mechanistically, although IRF2 apparently did not target the proximal cytoplasmic signaling events upon LPS engagements, it inhibited HIF-1α–dependent expression of glycolytic genes and thereby cellular glycolysis, sequential events necessary for the IRF2 anti-inflammatory activity. We found that macrophages in endotoxin tolerant state demonstrated deficiency in LPS-augmented glycolysis, which was likely caused by failed downregulation of IRF2 and the ensuing upregulation of the glycolytic genes in these cells. In contrast to observations with LPS, knockdown of IRF2 decreased IL-4–induced macrophage alternative activation. The pro–IL-4 activity of IRF2 was dependent on KLF4, a key mediator of the alternative activation, which was transcriptionally induced by IRF2. In conclusion, our data suggest that IRF2 is an important regulator of the proinflammatory response in macrophages by controlling HIF-1α–dependent glycolytic gene expression and glycolysis. This study also indicates IRF2 as a novel therapeutic target to treat inflammatory disorders associated with dysregulations of macrophage activations.

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Comment on "Therapeutic Application of an Extract of Helicobacter pylori Ameliorates the Development of Allergic Airway Disease" [LETTERS TO THE EDITOR]

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Local Stimulation of Liver Sinusoidal Endothelial Cells with a NOD1 Agonist Activates T Cells and Suppresses Hepatitis B Virus Replication in Mice [INFECTIOUS DISEASE AND HOST RESPONSE]

Functional maturation of liver sinusoidal endothelial cells (LSECs) induced by a NOD1 ligand (diaminopimelic acid [DAP]) during viral infection has not been well defined. Thus, we investigated the role of DAP-stimulated LSEC maturation during hepatitis B virus (HBV) infection and its potential mechanism in a hydrodynamic injection (HI) mouse model. Primary LSECs were isolated from wild-type C57BL/6 mice and stimulated with DAP in vitro and in vivo and assessed for the expression of surface markers as well as for their ability to promote T cell responses via flow cytometry. The effects of LSEC maturation on HBV replication and expression and the role of LSECs in the regulation of other immune cells were also investigated. Pretreatment of LSECs with DAP induced T cell activation in vitro. HI-administered DAP induced LSEC maturation and subsequently enhanced T cell responses, which was accompanied by an increased production of intrahepatic cytokines, chemokines, and T cell markers in the liver. The HI of DAP significantly reduced the HBsAg and HBV DNA levels in the mice. Importantly, the DAP-induced anti-HBV effect was impaired in the LSEC-depleted mice, which indicated that LSEC activation and T cell recruitment into the liver were essential for the antiviral function mediated by DAP application. Taken together, the results showed that the Ag-presenting ability of LSECs was enhanced by DAP application, which resulted in enhanced T cell responses and inhibited HBV replication in a mouse model.

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Response to Comment on "Therapeutic Application of an Extract of Helicobacter pylori Ameliorates the Development of Allergic Airway Disease" [LETTERS TO THE EDITOR]

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Mitocryptides from Human Mitochondrial DNA-Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor Preference and Signaling Properties [INNATE IMMUNITY AND INFLAMMATION]

Phagocytic neutrophils express formyl peptide receptors (FPRs; FPR1 and FPR2) that distinctly recognize peptides starting with an N-formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA–encoded proteins is an fMet. Mitochondrial cryptic peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs. In this study, we determined the neutrophil-recognition profiles and functional output of putative MCTs originating from the N termini of the 13 human mitochondrial DNA–encoded proteins. Six of the thirteen MCTs potently activated neutrophils with distinct FPR-recognition profiles: MCTs from ND3 and ND6 have a receptor preference for FPR1; MCTs from the proteins ND4, ND5, and cytochrome b prefer FPR2; and MCT-COX1 is a dual FPR1/FPR2 agonist. MCTs derived from ND2 and ND4L are very weak neutrophil activators, whereas MCTs from ND1, ATP6, ATP8, COX2, and COX3, do not exert agonistic or antagonistic FPR effects. In addition, the activating MCTs heterologously desensitized IL-8R but primed the response to the platelet-activating factor receptor agonist. More importantly, our data suggest that MCTs have biased signaling properties in favor of activation of the superoxide-generating NADPH oxidase or recruitment of β-arrestin. In summary, we identify several novel FPR-activating peptides with sequences present in the N termini of mitochondrial DNA–encoded proteins, and our data elucidate the molecular basis of neutrophil activation by MCTs.

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Specialized Antitumor Functions for Skin {gamma}{delta} T Cells [PILLARS OF IMMUNOLOGY]

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Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling [IMMUNOTHERAPY AND VACCINES]

Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT safety and efficacy is the use of new or improved adjuvants. This study investigates immune responses produced by microcrystalline tyrosine (MCT)–based vaccines as compared with conventional aluminum hydroxide (alum). Wild-type, immune-signaling–deficient, and TCR-transgenic mice were treated with different Ags (e.g., OVA and cat dander Fel d 1), plus MCT or alum as depot adjuvants. Specific Ab responses in serum were measured by ELISA, whereas cytokine secretion was measured both in culture supernatants by ELISA or by flow cytometry of spleen cells. Upon initiation of AIT in allergic mice, body temperature and further clinical signs were used as indicators for anaphylaxis. Overall, MCT and alum induced comparable B and T cell responses, which were independent of TLR signaling. Alum induced stronger IgE and IL-4 secretion than MCT. MCT and alum induced caspase-dependent IL-1β secretion in human monocytes in vitro, but inflammasome activation had no functional effect on inflammatory and Ab responses measured in vivo. In sensitized mice, AIT with MCT-adjuvanted allergens caused fewer anaphylactic reactions compared with alum-adjuvanted allergens. As depot adjuvants, MCT and alum are comparably effective in strength and mechanism of Ag-specific IgG induction and induction of T cell responses. The biocompatible and biodegradable MCT seems therefore a suitable alternative adjuvant to alum-based vaccines and AIT.

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Pillars Article: Regulation of Cutaneous Malignancy by {gamma}{delta} T Cells. Science. 2001. 294: 605-609 [PILLARS OF IMMUNOLOGY]

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S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis [INNATE IMMUNITY AND INFLAMMATION]

Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. In this article, we show that S100A8/A9 is increased in the brains of patients who died of sepsis and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. S100A9 expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, S100A9 deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.

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Contribution of the Immune Response to Phage Therapy [BRIEF REVIEWS]

Therapeutic phages are being employed for vaccination and treatment of cancer and bacterial infections. Their natural immunogenicity triggers intertwined interactions with innate and adaptive immune cells that might influence therapy. Phage- and bactierial-derived pathogen-associated molecular patterns released after bacterial lysis have been proposed to stimulate local innate immune responses, which could promote antitumor immunity or bacterial clearance. Conversely, immunogenicity of phages induces phage-specific humoral memory, which can hamper therapeutic success. This review outlines the current knowledge on the different types of immune responses elicited by phages and their potential benefits and adverse side effects, when applied therapeutically. This review further summarizes the knowledge gaps and defines the key immunological questions that need to be addressed regarding the clinical application of antibacterial phage therapy.

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Mycobacterium tuberculosis Transfer RNA Induces IL-12p70 via Synergistic Activation of Pattern Recognition Receptors within a Cell Network [INNATE IMMUNITY AND INFLAMMATION]

Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a cell-mediated immune response against the foreign invader. The culture filtrate of Mycobacterium tuberculosis contains ligands, such as M. tuberculosis tRNA, that activate the innate immune response and secreted Ags recognized by T cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intracellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK cells to respond to IL-18 and produce IFN-, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that M. tuberculosis tRNA activates a gene network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct cell types to induce IL-12p70.

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Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming [CUTTING EDGE]

The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1–dependent secretion of the proinflammatory cytokines IL-1β and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome.

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Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1+ T Cells in Human Colorectal Cancer [TUMOR IMMUNOLOGY]

Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8⁺ T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3⁺ Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma–associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium. Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients may facilitate the development of new therapeutics against malignancies.

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Characterization of the Antigenic Heterogeneity of Lipoarabinomannan, the Major Surface Glycolipid of Mycobacterium tuberculosis, and Complexity of Antibody Specificities toward This Antigen [ANTIGEN RECOGNITION AND RESPONSES]

Lipoarabinomannan (LAM), the major antigenic glycolipid of Mycobacterium tuberculosis, is an important immunodiagnostic target for detecting tuberculosis (TB) infection in HIV-1–coinfected patients, and is believed to mediate a number of functions that promote infection and disease development. To probe the human humoral response against LAM during TB infection, several novel LAM-specific human mAbs were molecularly cloned from memory B cells isolated from infected patients and grown in vitro. The fine epitope specificities of these Abs, along with those of a panel of previously described murine and phage-derived LAM-specific mAbs, were mapped using binding assays against LAM Ags from several mycobacterial species and a panel of synthetic glycans and glycoconjugates that represented diverse carbohydrate structures present in LAM. Multiple reactivity patterns were seen that differed in their specificity for LAM from different species, as well as in their dependence on arabinofuranoside branching and nature of capping at the nonreducing termini. Competition studies with mAbs and soluble glycans further defined these epitope specificities and guided the design of highly sensitive immunodetection assays capable of detecting LAM in urine of TB patients, even in the absence of HIV-1 coinfection. These results highlighted the complexity of the antigenic structure of LAM and the diversity of the natural Ab response against this target. The information and novel reagents described in this study will allow further optimization of diagnostic assays for LAM and may facilitate the development of potential immunotherapeutic approaches to inhibit the functional activities of specific structural motifs in LAM.

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Elastin Shapes Small Molecule Distribution in Lymph Node Conduits [IMMUNOGENETICS]

The spatial and temporal Ag distribution determines the subsequent T cell and B cell activation at the distinct anatomical locations in the lymph node (LN). It is well known that LN conduits facilitate small Ag distribution in the LN, but the mechanism of how Ags travel along LN conduits remains poorly understood. In C57BL/6J mice, using FITC as a fluorescent tracer to study lymph distribution in the LN, we found that FITC preferentially colocalized with LN capsule–associated (LNC) conduits. Images generated using a transmission electron microscope showed that LNC conduits are composed of solid collagen fibers and are wrapped with fibroblastic cells. Superresolution images revealed that high-intensity FITC is typically colocalized with elastin fibers inside the LNC conduits. Whereas tetramethylrhodamine isothiocyanate appears to enter LNC conduits as effectively as FITC, fluorescently-labeled Alexa-555–conjugated OVA labels significantly fewer LNC conduits. Importantly, injection of Alexa-555–conjugated OVA with LPS substantially increases OVA distribution along elastin fibers in LNC conduits, indicating immune stimulation is required for effective OVA traveling along elastin in LN conduits. Finally, elastin fibers preferentially surround lymphatic vessels in the skin and likely guide fluid flow to the lymphatic vessels. Our studies demonstrate that fluid or small molecules are preferentially colocalized with elastin fibers. Although the exact mechanism of how elastin fibers regulate Ag trafficking remains to be explored, our results suggest that elastin can be a potentially new target to direct Ag distribution in the LN during vaccine design.

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ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis [AUTOIMMUNITY]

ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS⁺ T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr¹⁸¹-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr¹⁸¹-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.

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Lysosome-Mediated Plasma Membrane Repair Is Dependent on the Small GTPase Arl8b and Determines Cell Death Type in Mycobacterium tuberculosis Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Mycobacterium tuberculosis is an extremely successful pathogen, and its success is widely attributed to its ability to manipulate the intracellular environment of macrophages. A central phenomenon of tuberculosis pathology enabling immune evasion is the capacity of virulent M. tuberculosis (H37Rv) to induce macrophage necrosis, which facilitates the escape of the mycobacteria from the macrophage and spread of infection. In contrast, avirulent M. tuberculosis (H37Ra) induces macrophage apoptosis, which permits Ag presentation and activation of adaptive immunity. Previously, we found that H37Rv induces plasma membrane microdisruptions, leading to necrosis in the absence of plasma membrane repair. In contrast, H37Ra permits plasma membrane repair, which changes the host cell death modality to apoptosis, suggesting that membrane repair is critical for sequestering the pathogen in apoptotic vesicles. However, mechanisms of plasma membrane repair induced in response to M. tuberculosis infection remain unknown. Plasma membrane repair is known to induce a Ca²⁺-mediated signaling, which recruits lysosomes to the area of damaged plasma membrane sites for its resealing. In this study, we found that the small GTPase Arl8b is required for plasma membrane repair by controlling the exocytosis of lysosomes in cell lines and in human primary macrophages. Importantly, we found that the Arl8b secretion pathway is crucial to control the type of cell death of the M. tuberculosis–infected macrophages. Indeed, Arl8b-depleted macrophages infected with avirulent H37Ra undergo necrotic instead of apoptotic cell death. These findings suggest that membrane repair mediated by Arl8b may be an important mechanism distinguishing avirulent from virulent M. tuberculosis–induced necrotic cell death.

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Downregulation of CD3{zeta} in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype [AUTOIMMUNITY]

Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3, an important molecule for NK cell activation, is downregulated in SLE T cells and contributes to their altered function. However, little is known about the role of CD3 in SLE NK cells. We studied CD3 levels and its contribution to cytotoxic, degranulation, and cytokine production capacity of NK cells from patients with SLE. Furthermore, we studied the human NK cell line, NKL, in which manipulation of CD3 levels was achieved using small interfering RNA and NK cells from Rag2 mice deficient in CD3. We found reduced CD3 expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3 expression in NK cells is mediated, at least in part, by Caspase 3, the activity of which is higher in NK cells from patients with SLE compared with NK cells from healthy donors. CD3 levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN- and TNF. In contrast, CD3 levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3-silenced NKL and CD3-deficient NK cells from Rag2 mice confirmed the dependence of NK cell function on CD3 levels. Our results demonstrate a differential role for CD3 in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3 confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE.

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The Effects of Reflux on the Elderly

Reflux-related complaints are a frequent cause for otolaryngology consultation, and with the aging population the concerns specific to the elderly reflux patient are critical. The elderly patient is less likely to present with typical laryngopharyngeal reflux (LPR) or gastroesophageal reflux disease (GERD) symptoms. Importantly, elderly patients typically have objective findings more severe than the level of the symptoms. Therefore, upfront invasive esophageal testing as opposed to an initial medical therapy trial is the recommended management strategy. For all patients irrespective of age, lifestyle and diet modifications continue to represent the cornerstone of medical management for LPR and GERD.

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Endocrine Surgery in the Geriatric Population

Age must be a factor when considering endocrine surgery. Age itself is a risk factor for complications after thyroidectomy, specifically pulmonary, infectious, and cardiac complications. For this reason, in patients with nodular thyroid disease or thyroid microcarcinoma, length of observation must be measured against age and surgical risk. Outcomes of thyroid surgery in geriatric patients can be improved with several measures, including careful preoperative risk stratification based on comorbidities and frailty. In this population subset, it is imperative to have an earnest discussion with patients, their families, and any surrogate decision maker regarding potential outcomes of treatment versus observation.

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Mechanism Underlying the Effects of Estrogen Deficiency on Otoconia

Abstract

Otoconia-related vertigo and balance deficits, particularly benign paroxysmal positional vertigo (BPPV), are common. Our recent studies in humans show that, while BPPV prevalence greatly increases with age in both genders, peri-menopausal women are especially susceptible. In the present study, we show that bilateral ovariectomized (OVX) mice have significant balance behavioral deficits, and that estrogen deficiency compromises otoconia maintenance and anchoring by reducing the expression of otoconial component and anchoring proteins. There is ectopic debris formation in the ampulla under estrogen deficiency due to aberrant matrix protein expression. Furthermore, phytoestrogen is effective in rescuing the otoconia abnormalities. By comparing the expression levels of known estrogen receptor (Esr) subtypes, and by examining the otoconia phenotypes of null mice for selected receptors, we postulate that Esr2 may be critical in mediating the effects of estrogen in otoconia maintenance.

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Survival of Patients With Multiple Intracranial Metastases Treated With Stereotactic Radiosurgery: Does the Number of Tumors Matter?

Background: Defining prognostic factors is a crucial initial step for determining the management of patients with brain metastases. Randomized trials assessing radiosurgery have commonly limited inclusion criteria to 1 to 4 brain metastases, in part due to multiple retrospective studies reporting on the number of brain metastases as a prognostic indicator. The present study reports on the survival of patients with 1 to 4 versus ≥5 brain metastases treated with radiosurgery. Methods: We evaluated a retrospective multi-institutional database of 1523 brain metastases in 507 patients who were treated with radiosurgery (Gamma Knife or Cyberknife) between 2001 and 2014. A total of 243 patients were included in the analysis. Patients with 1 to 4 brain metastases were compared with patients with ≥5 brain metastases using a standard statistical analysis. Cox hazard regression was used to construct a multivariable model of overall survival (OS). To find covariates that best separate the data at each split, a machine learning technique Chi-squared Automated Interaction Detection tree was utilized. Results: On Pearson correlation, systemic disease status, number of intracranial metastases, and overall burden of disease (number of major involved organ systems) were found to be highly correlated (P

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Retrospective Analysis of Cisplatin Nephrotoxicity in Patients With Head and Neck Cancer Receiving Outpatient Treatment With Concurrent High-dose Cisplatin and Radiotherapy

Objectives: Cisplatin remains the pivotal chemotherapy in squamous cell carcinoma of the head and neck (SCCHN), with nephrotoxicity considered the dose-limiting toxicity. The purpose of our study was to propose an outpatient high-dose cisplatin protocol aimed at preventing nephrotoxicity and to analyze the results of its utilization in patients with SCCHN treated with concurrent radiotherapy. Materials and Methods: We retrospectively evaluated 82 SCCHN patients treated with outpatient high-dose cisplatin concurrent with radiotherapy at our institution. Acute kidney injury (AKI) and chronic kidney disease were defined by Kidney Disease Improving Global Outcomes criteria. Associated factors were identified using analysis of covariance models for categorical variables and adjusted Pearson correlations for continuous variables. Results: The incidence of AKI during treatment was 34.2%. With a median follow-up of 25.7 months, the average decrease in estimated glomerular filtration rate was 12.57 mL/min/1.73 m2 (SD=18.58). At 1 year and at last follow-up, 5.4% and 4.4% of patients had estimated glomerular filtration rate

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Targeted Prostate Biopsy Gleason Score Heterogeneity and Implications for Risk Stratification

Objectives: To quantify Gleason score (GS) heterogeneity within multiparametric magnetic resonance imaging (MRI)-targeted prostate biopsies and to determine impact on National Comprehensive Cancer Network (NCCN) risk stratification. Methods: An Institutional Review Board-approved retrospective study was performed on men who underwent Artemis (MRI-transrectal–ultrasound fusion) targeted biopsy (TB) for suspected prostate cancer between 2012 and 2015. Intratarget heterogeneity was defined as a difference in GS between 2 cores within a single target in patients with ≥2 positive cores. Prostate specific antigen, maximum tumor diameter, apparent diffusion coefficient, MRI suspicion score, prostate volume, systematic biopsy (SB) GS, and T-stage were analyzed for correlation with heterogeneity. Changes in NCCN risk based on high versus low GS on TB, SB alone, and SB+TB were compared. Results: Fifty-three patients underwent TB of 73 suspected lesions. Seventy percent (51/73) had ≥2 positive cores, thus meeting inclusion criteria for heterogeneity analysis. Fifty-five percent (28/51) of qualifying targets showed GS heterogeneity. None of the evaluated factors showed a significant relationship with heterogeneity. NCCN low-risk, intermediate-risk, and high-risk groups were 30%, 49%, and 21%, respectively, with SB alone. Adding low GS TB to SB resulted in 17%, 55%, 28% in each risk group, while using high GS+SB resulted in 4%, 54%, and 42%. Overall, the addition of TB resulted in higher NCCN risk groups in 38% of cases. Conclusions: Over half of multiparametric MRI-defined targets demonstrated GS heterogeneity. The addition of high GS from TB leads to risk inflation compared with using SB alone. Further research is needed on how to integrate these findings into current risk stratification models and clinical practice.

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Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer

Objectives: Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. Methods: Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. Results: Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. Conclusions: Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

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Comparison of Demographics, Tumor Characteristics, and Survival Between Pancreatic Adenocarcinomas and Pancreatic Neuroendocrine Tumors: A Population-based Study

Objective: The objective of this study is to compare the incidence, demographics, tumor characteristics, and survival between patients with pancreatic neuroendocrine tumors (PNETs) and pancreatic adenocarcinomas. Materials and Methods: Between 2004 and 2012, all cases of pancreatic adenocarcinomas and PNETs were extracted from the population-based cancer registries of the Surveillance Epidemiology and End Results program. To identify the cases, a combination of topographical and histology codes based on ICD-O-3 were used. Incidence, demographics, tumor characteristics, and survival was then compared between these 2 histologic subtypes of pancreatic cancer. Results: A total of 57,688 patients with pancreatic cancer were identified, of which 53,753 (93%) had pancreatic adenocarcinoma and 3935 (7%) had PNET. The overall age-adjusted incidence of PNETs between 2004 and 2012 was 0.52 per 100,000 per year, whereas that for pancreatic adenocarcinomas during the same period was 7.34 per 100,000 per year. PNETs had a significantly younger median age at diagnosis (61 vs. 69 y). A significant proportion of PNETs were diagnosed at stage I (20.5% vs. 6.0%) and were well differentiated (32.8% vs. 4.5%) compared with adenocarcinomas. Five-year cause-specific survival was 51.3% and 5.0% for PNETs and pancreatic adenocarcinomas, respectively. In multivariate analysis, pancreatic adenocarcinomas had a hazard ratio for death of 4.02 (95% confidence interval, 3.79-4.28) when compared with PNETs. Conclusions: PNETs present with favorable features such as higher proportion of early-stage tumor, higher proportion of well differentiated tumors, and younger age at diagnosis. PNETs have a significantly better survival than pancreatic adenocarcinomas even after adjusting for age, sex, race, site, grade, and stage.

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Locally Advanced Cervical Cancer: Outcomes With Variable Adherence to Treatment

Objective: Adherence to treatment regimen and schedule is recommended to improve control of disease and overall survival (OS) in locally advanced cervical cancer. However, treatment-related toxicities and patient and physician factors all impact timely completion of treatment. We sought to correlate adherence to treatment plan with survival and toxicities of patients treated for locally advanced cervical cancer. Materials and Methods: A retrospective review of patients treated for advanced cervical cancer at our institution between 2003 and 2011 was performed. Demographics, clinicopathologic variables, treatment, and disease outcomes were collected. Endpoints of disease outcome were disease-free survival and OS. Statistical analyses were performed using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: A total of 162 patients met the inclusion criteria and were included in study analysis. A total of 95% of patients were treated with both radiation and concurrent chemotherapy. Mean radiation dose to point A was 72 Gy. In total, 77% had complete response to primary therapy. Severe (grade 3/4) late radiation toxicities were seen in 10.5% of patients. Stage and total radiation dose to point A were significant predictors of survival for the entire cohort. Among patients receiving at least 72 Gy and brachytherapy, duration of treatment was significantly associated with both disease-free survival and OS. Conclusions: Adherence to both optimal treatment time and radiation dose is significantly associated with improved survival. Total radiation dose is an independent predictor of survival among patients with locally advanced cervical cancer.

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Patient-reported Adherence to Adjuvant Aromatase Inhibitor Therapy Using the Morisky Medication Adherence Scale: An Evaluation of Predictors

Objectives: Endocrine therapy is part of standard adjuvant therapy for patients with hormone receptor-positive breast cancer and has been shown to improve recurrence-free and overall survival. However, adherence to endocrine therapy is suboptimal and is difficult to measure. In this study we evaluate the feasibility of using the Morisky Medication Adherence Scale (MMAS) to assess patient adherence to aromatase inhibitor (AI) therapy. Methods: Patients with stage 1 to 3, hormone receptor-positive breast cancer receiving adjuvant AI therapy were prospectively enrolled on an Institutional Review Board approved protocol. The MMAS questionnaire was administered to each patient and adherence was measured. Information on duration of AI therapy, patient and tumor characteristics, and treatment was collected. A multivariable logit model approach was utilized to evaluate potential barriers to adherence. Results: Between 2011 and 2014, 100 patients were enrolled. The distribution of adherence levels was 13% low, 37% medium, and 50% high. High adherence was reported more frequently in white women (58%), patients with stage 2 and 3 disease (54%), and patients who did not receive chemotherapy (62%). Multivariable analysis demonstrated that higher adherence was more likely in white women compared with African American women (estimated odds ratio=2.8). Conclusions: Using the MMAS, only 50% of women with stage 1 to 3 breast cancer reported high adherence to AI therapy, consistent with other reports showing suboptimal adherence to adjuvant endocrine therapy. The MMAS allows for the rapid assessment of adherence to oral adjuvant endocrine therapy and is valuable in a busy clinical setting.

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Utilization of Postoperative Chemoradiotherapy Among Women in the United States With High-risk Cervical Cancer

Objective: Prospective randomized data demonstrates that chemoradiotherapy (CRT) improves overall survival in women with high-risk pathologic features following radical hysterectomy. Despite this, not all high-risk patients receive adjuvant CRT and the patterns of care in this patient population are unknown. We sought to investigate the rates of adjuvant therapy utilization through analysis of the National Cancer Database. Materials and Methods: The National Cancer Database was queried for women with cervical cancer treated initially with hysterectomy from 2002 to 2012. Patients without high-risk pathologic features were excluded: pN+, positive surgical margins, and parametrial invasion (Peters' criteria). Among the 5947 evaluable patients, univariable analysis and multivariable analysis were performed to investigate potential factors associated with CRT utilization and overall survival following diagnosis. Results: Adjuvant CRT was performed in 41.8% of women and adjuvant radiotherapy, chemotherapy, and no adjuvant therapy was utilized in 9.8%, 23.6%, and 24.8% of women, respectively. On multivariable analysis, CRT utilization was associated with younger age, race, lower facility volume, pN+, parametrial invasion, and a negative surgical margin. Residence distance to treating facility, year of diagnosis, household income, insurance status, and facility type did not predict for CRT utilization. Conclusions: Despite level I evidence supporting its use, less than half of women in this large US cohort with high-risk cervical cancer received adjuvant CRT. Use of adjuvant CRT for women did not significantly increase between 2002 and 2012. Patient age, race, and pathologic risk factors were associated with use of adjuvant CRT.

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Perioperative Mortality in Nonelderly Adult Patients With Cancer: A Population-based Study Evaluating Health Care Disparities in the United States According to Insurance Status

Objectives: The purpose of this study was to evaluate whether insurance status predicts for perioperative mortality (death within 30 d of cancer-directed surgery) for the 20 most common surgically treated cancers. Methods: The SEER database was examined for the 20 most common surgically resected cancers and included nonelderly adults, aged 18 to 64 years. The database was queried from 2007 to 2011, with a total of 506,722 patients included in the analysis. Results: Insurance status for all patients were the following: non-Medicaid insurance (83%), any Medicaid (10%), uninsured (4%), and unknown (3%). In univariate analyses, predictors for perioperative mortality included insurance status (P

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Secondary Surgery Versus Chemotherapy for Recurrent Ovarian Cancer

Objective: The best course of treatment for recurrent ovarian cancer is uncertain. We sought to determine whether secondary cytoreductive surgery for first recurrence of ovarian cancer improves overall survival compared with other treatments. Materials and Methods: We assessed survival using Surveillance, Epidemiology and End Results-Medicare data for advanced stage ovarian cancer cases diagnosed from January 1, 1997 to December 31, 2007 with survival data through 2010 using multinomial propensity weighted finite mixture survival regression models to distinguish true from misclassified recurrences. Of 35,995 women ages 66 years and older with ovarian cancer, 3439 underwent optimal primary debulking surgery with 6 cycles of chemotherapy; 2038 experienced a remission. Results: One thousand six hundred thirty-five of 2038 (80%) women received treatment for recurrence of whom 72% were treated with chemotherapy only, 16% with surgery and chemotherapy and 12% received hospice care. Median survival of women treated with chemotherapy alone, surgery and chemotherapy, or hospice care was 4.1, 5.4, and 2.2 years, respectively (P

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Vulvar Recurrences After Intensity-modulated Radiation Therapy for Squamous Cell Carcinoma of the Anus

Objectives: The objective is to determine localregional control (LRC), distant metastasis free survival, disease-free survival, overall survival (OS), and toxicity for patients with squamous cell carcinoma of the anus treated with definitive chemotherapy and intensity-modulated radiation therapy (IMRT). Materials and Methods: We conducted a retrospective review of patients treated using IMRT for squamous cell carcinoma of the anus at our institution since 2005. Patients with local recurrences were identified and reviewed. The Kaplan-Meier curves were used for LRC and OS. Results: From 2005 to 2014, 52 patients were treated with IMRT-based chemoradiation for squamous cell carcinoma of the anus. Median dose to the primary tumor was 54 Gy. LRC, distant metastasis free survival, OS, and disease-free survival were 92.3%, 88.5%, 86.5%, and 84.6%, respectively, with a median follow-up of 20 months. Two local failures occurred at the anal primary site and 2 in the vulva. Despite subsequent palliative radiotherapy and chemotherapy, neither patient with a vulvar recurrence achieved disease control. Conclusions: In a cohort of patients treated with IMRT-based chemoradiation, 2 vulvar recurrences were identified within the avoided external genitalia despite limited recurrence rates within the cohort overall. This experience suggests that for patients with a locally advanced primary tumor and bulky bilateral inguinal or pelvic disease, the in-transit vulvar dermal lymphatics may be at risk for subclinical involvement and subsequent recurrence. If substantiated by a similar pattern of recurrence at other institutions, the external genitalia may need to be reclassified from an avoidance structure to a clinical treatment volume in patients with locally advanced anal cancer.

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Malignant Peripheral Nerve Sheath Tumors: A Single Institution’s Experience Using Combined Surgery and Radiation Therapy

Purpose: The purpose of this study is to investigate local control (LC), survival outcomes, and associated prognostic factors for patients with malignant peripheral nerve sheath tumors (MPNSTs) treated with combined surgery and radiation therapy (RT). Methods: We reviewed the medical records of 71 consecutive patients treated with surgery and RT for localized MPNST between 1965 and 2012. Preoperative RT was used to treat 23 patients (32%) to a median dose of 50 Gy (range, 50 to 60 Gy), whereas 48 (68%) received postoperative RT to a median dose of 64 Gy (range, 45 to 70 Gy). Results: Median follow-up for living patients was 118 months (range, 21 to 512 mo). The 5-year LC, distant metastatic free survival, and disease-specific survival rates were 84%, 62%, and 66%, respectively. To identify predictors of outcome, several multivariate models were constructed: (1) positive/uncertain surgical margin status was the only factor adversely associated local relapse at 5 years (28% vs. 5% for negative margins; P=0.02; hazard ratios 5.92; 95% confidence interval, 1.3-27.4). (2) No factors were significantly associated with distant metastatic free survival. Of the 35 patients (49%) who sustained disease relapse, only 3 were ultimately salvaged. Only 2 patients had grade 2 late toxicities (necrosis, fibrosis) based on Common Terminology Criteria for Adverse Events version 4.03 criteria, and 1 patient had grade 1 edema. Conclusions: Combination therapy with surgery and RT provides favorable LC. Distant recurrences, however, continue to be challenging with limited salvage success at the time of relapse.

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A Pooled Analysis of Biochemical Failure in Intermediate-risk Prostate Cancer Following Definitive Stereotactic Body Radiotherapy (SBRT) or High-Dose-Rate Brachytherapy (HDR-B) Monotherapy

Objectives: To investigate biochemical relapse-free survival (BRFS) in men with National Comprehensive Cancer Network-defined intermediate-risk prostate cancer (PC) treated with either stereotactic body radiotherapy (SBRT) or high-dose-rate brachytherapy (HDR-B) monotherapy. Materials and Methods: A retrospective, multi-institutional analysis of 437 patients with intermediate-risk PC treated with SBRT (N=300) or HDR-B (N=137) was performed. Men who underwent SBRT were treated to 35 to 40 Gy in 4 to 5 fractions. A total of 95.6% who underwent HDR-B were treated to 42 Gy in 6 fractions. Baseline patient characteristics were compared using a T test for continuous variables and the Mantel-Haenszel χ2 metric or Fisher exact test for categorical variables. Kaplan-Meier curves were generated to estimate 5-year actuarial BRFS. Multivariate analysis using a Cox proportional-hazards model was used to evaluate factors associated with biochemical failure. Results: The mean age at diagnosis was 68.4 (SD±7.8) years. T-category was T1 in 63.6% and T2 in 36.4%. Mean initial prostate-specific antigen was 7.4 (SD±3.4) ng/mL. Biopsy Gleason score was ≤3+4 in 82.8% and 4+3 in 17.2%. At a median of 4.1 years of follow-up, the BRFS rate (Phoenix definition) was 96.3%, with no difference when stratifying by treatment modality or biologically equivalent dose (BED1.5). On multivariate analysis, age (hazard ratio 1.08, P=0.04) and biopsy Gleason score (hazard ratio 2.48, P=0.03) were significant predictors of BRFS. Conclusions: With a median follow-up period of 4 years, SBRT and HDR-B monotherapy provide excellent BRFS in intermediate-risk PC. Longer-term follow-up is necessary to determine the ultimate efficacy of these hypofractionated approaches, but they appear promising relative to standard fractionation outcomes.

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Disparity in Outcomes for Adolescent and Young Adult Patients Diagnosed With Pediatric Solid Tumors Across 4 Decades

Objective: Cancer mortality is a leading cause of disease-related death in the adolescent and young adult (AYA) population. Compared with older and younger patients, AYA patients often experience worse cancer-specific outcomes. Here, we compare AYA and pediatric overall survival (OS) in the most common pediatric extracranial solid tumors. Materials and Methods: Using the US Surveillance, Epidemiology, and End Results database, we studied patients (age, 0 to 39 y) diagnosed with Ewing sarcoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, and Wilms tumor. Results: A total of 12,375 patients (age, 0 to 39 y) were diagnosed between 1973 and 2010 (8247 pediatric and 4128 AYA patients). AYA patients with rhabdomyosarcoma and Ewing sarcoma were more likely to present with metastatic disease. OS was significantly worse in the AYA cohort for all tumor types (P

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