Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

En Bloc Excision of Phyllodes Tumor of the Breast: Radical Approach Heralds Better Outcome

IntroductionSurgery is the primary treatment of phyllodes tumor of the breast, and margins are the most important risk factor associated with local recurrence. We conducted a retrospective audit of 433 patients treated at our center.Patients and MethodsWomen who presented with phyllodes tumors between 1999 and 2017 were included in the analysis. Data was collected from the hospital medical records, telephonic interviews, and electronic mail.ResultsOf the 433 women included in this study, 177 (40.9%) had benign phyllodes tumors, 84 (19.4%) were borderline, 131 (30.3%) were malignant, and 41 (9.5%) had sarcoma. A history of previous excision was noted in 154 (35.6%) patients, of which 104 presented with local recurrence. Of the total patients, 209 (48.3%) underwent breast conservation surgery; the median pT was 6 cm. At a median follow-up of 37.9 months, the 5-year disease-free survival (DFS) was 82.9%. On multivariate analysis, the factors that impacted DFS were histology (hazard ratio, 4.1; 95% confidence interval [CI], 1.5-10.9; P = .005) and history of previous excision biopsy (hazard ratio, 3.39; 95% CI, 1.76-6.52; P < .001). We analyzed 231 women who presented without any prior excision separately, wherein at a median follow-up of 44.1 months, the DFS was 92.1% (95% CI, 92.05%-92.15%). In addition, less recurrences were noted in this cohort (5.6% [13/231] in no-excision biopsy vs. 12.5% with surgery done prior to presentation to our institute).ConclusionA previous history of excision and the histologic subtype of phyllodes tumor are factors that have an impact on DFS, thus emphasizing the need for appropriate surgical planning and en bloc excision of the phyllodes at presentation.     

Menopause in multiple sclerosis: therapeutic considerations

While the onset of multiple sclerosis (MS) typically occurs during the childbearing years, many women living with MS are of perimenopausal age. There is frequent overlap between menopausal and MS-related symptoms and co-morbidities (e.g. sexual dysfunction, mood disorders and bladder function). Furthermore, some MS symptoms may be exacerbated by perimenopausal changes such as hot flashes or sleep disturbance. The MS neurologist may frequently be the first to become aware of these symptoms and to play a role in monitoring and managing them. In this review, we describe immunological and neurologic changes at menopause as they may impact MS. We then review common symptoms, including fatigue, depression, sexual function, pain and insomnia, and provide both behavioral and pharmacological suggestions for their management. Next, we discuss the need for osteoporosis and cancer screening in perimenopausal women with MS. Finally, we highlight important research gaps, including what effect, if any, the menopausal transition may play on MS disease course as well as the potential modulatory role of hormone replacement therapies.     

Pediatric Neuromyelitis Optica Spectrum Disorders

Purpose of review

Neuromyelitis optica spectrum disorders (NMOSDs) are a group of inflammatory and demyelinating disorders of the central nervous system that can occur in children and adults. The classic presentation of NMOSD is characterized by optic neuritis and transverse myelitis, but other presentations are also recognized, expanding the disease as NMO spectrum disorders. The purpose of this review is to discuss the clinical features, along with management and treatment options, including potential future therapeutic options, in pediatric NMOSD.

Recent findings

The aquaporin-4 antibody (AQP4 ab) is specific for NMOSD; however, recently another antibody, the myelin oligodendrocyte glycoprotein (MOG ab) has been found in a subset of AQP4 ab-negative patients including in children. Most treatment studies are reported in adults, but retrospective studies on efficacy and safety of mycophenolate mofetil, azathioprine, and rituximab in pediatric NMOSD are available.

Summary

While some pediatric NMOSD-specific treatment studies are available, more research is needed in the mechanisms of early onset and specific treatment options in children, including whether different treatment considerations are needed for AQP4 ab as opposed to MOG ab-positive disease.

     

A clinical and microbiological study of puerperal sepsis in a tertiary care hospital in India

Objective: This prospective study was carried out to evaluate the clinical profile and bacterial isolates among women with puerperal sepsis in a tertiary hospital in North India.

Materials and methods: Women with puerperal sepsis (n?=?45) admitted from January 2015 to April 2016 were followed prospectively. Cultures were obtained from cervix, blood, urine, and pyoperitoneum. Initial antibiotics were cefotaxime or piperacillin with tazobactam plus amikacin plus clindamycin or metronidazole and were changed according to sensitivity.

Results: Out of 7887 deliveries during this period, 45 (0.2%) women had puerperal sepsis. 16 (35.5%) delivered in the present hospital, 25 (55.5%) at another health care facility, and 4 (8.9%) at home. Delivery was by cesarean section (CS) in 24/45 (53.3%) and vaginal in 21/45 (46.6%). Grade 1 sepsis occurred in 21, grade 2 in two, and grade 3 in 22 women. Majority (29/45 or 64.5%) had no risk factor for puerperal sepsis. There were two (4.4%) deaths and 13/45 (28.8%) had near-miss morbidity. Pathogenic bacteria were isolated in 33/45 (73.3%) in cervical swab (69%), blood, urine, or pus culture with no significant difference in the bacterial yield or species isolated between cotton or polyester swabs (p?>?.05). Escherichia coli were the commonest isolate and was sensitive to amikacin in all. Five had stillbirths and 4/40 neonates developed sepsis but recovered.

Conclusions: Escherichia coli was the commonest pathogen and was uniformly sensitive to amikacin, which may be included among the initial antibiotics to treat puerperal sepsis in India.     

Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon gamma-producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.     

The impact of a recent relapse on patient-reported outcomes in subjects with multiple sclerosis

Purpose

In this study, we estimate the impact of a recent relapse on physical and mental health in subjects with relapsing-remitting multiple sclerosis (RRMS) using validated patient-reported outcome (PRO) measures.

Methods

Subjects enrolled in the Comprehensive Longitudinal Investigation of MS at the Brigham and Women??s Hospital with RRMS were eligible for enrollment. Subjects with a clinical visit within 45?days of a relapse were identified and divided into groups based on whether the relapse occurred before (recent relapse) (n?=?59) or after the visit (pre-relapse) (n?=?31). A group of subjects with no relapses was also identified (remission) (n?=?336). PRO measures in these three groups were compared. All outcomes were compared using a t test and linear regression controlling for age, disease duration, sex, and EDSS.

Results

Subjects with a recent relapse had significantly worse functioning on several physical and mental health scales compared to subjects in remission even after adjusting for potential confounders. Subjects with a recent relapse also showed significant deterioration on PRO measures over 1?year compared to subjects in remission (P?<?0.05 for each comparison). Subjects in the pre-relapse group were not significantly different than subjects in remission.

Conclusions

Clinical relapses have a measurable effect on PRO in subjects with RRMS.     

Effect of vitamin C on platelet adhesiveness and platelet aggregation in coronary artery disease patients

The effect of oral administration of vitamin C on platelet adhesive index (PAI), platelet aggregate ratio (PAg R) and serum ascorbic acid levels was studied. Feeding 75 g of butter to healthy males (group I, n = 10 cases), enhanced the tendency of platelet adhesiveness (PAd) and platelet aggregation (PAg) to a significant level at the end of 4 h. This was distinctly prevented when 1 g of vitamin C was added to the fatty meal. In coronary artery disease (CAD) patients (group II, n = 20 cases) 10 days of vitamin C administration at 1 g every 8 hours decreased the PAd (p less than 0.001) and PAg (p less than 0.05) significantly. There was also a significant (p less than 0.001) rise in the vitamin C levels. The study brings out a property of vitamin C which may be of considerable importance in prevention of chronic thromboatherosclerotic disease of the arteries.     

Epithelioid angiomyolipoma of kidney with atypical nuclear features and intranuclear inclusions on cytology

Described herein are the cytological findings of epithelioid angiomyolipoma (EAML) of the kidney with atypical nuclear features mistaken for renal cell carcinoma (RCC) in a 61‐year‐old male patient. Aspirates from this large renal mass were cellular and showed epithelioid cell clusters with focally crowded nuclei showing moderate anisonucleosis, small nucleoli, and prominent eosinophilic intranuclear inclusions. Failure to recognize the scanty adipose tissue component and preponderance of epithelioid cells with nuclear pleomorphism lead to a diagnosis of RCC on cytology. On histology, the tumor was essentially composed of epithelioid and spindle cells that showed the typical immunoprofile of an angiomyolipoma and only occasional foci of typical AML were seen. The hilar lymph node was involved in contiguity. However, in view of lack of obvious features of malignancy, the tumor was labeled as EAML with atypical features. Immunocytochemistry on the destained cytology aspirates revealed strong smooth muscle actin staining of all cells. To conclude, EAML can mimic a RCC. In such instances, lack of arborizing vasculature, absence of cytoplasmic fatty vacoulation, crowded nuclei with intranuclear inclusions, and lack of prominent nucleoli along with typical immunophenotype of EAML may assist in the cytology diagnosis. Diagn. Cytopathol. 2011;39:278–282. © 2010 Wiley‐Liss, Inc.