Multi-Institutional Clinical Outcomes of Biopsy Gleason Grade Group 5 Prostate Cancers Treated With Contemporary High-Dose Radiation and Long-Term Androgen Deprivation Therapy.

AIMS: This multicentric retrospective study reports long-term clinical outcomes of non-metastatic grade group 5 prostate cancers treated with external beam radiotherapy (EBRT) alone with long-term androgen deprivation therapy (ADT). MATERIALS AND METHODS: Patients treated across 19 institutions were studied. The key endpoints that were evaluated were 5-year biochemical recurrence-free survival (bRFS), metastases-free survival (MFS), overall survival, together with EBRT-related acute and late toxicities. The impact of various prognostic factors on the studied endpoints was analysed using univariate and multivariate analyses. RESULTS: Among the 462 patients, 88% (405) had Gleason 9 disease and 31% (142) had primary Gleason pattern 5. A prostate-specific membrane antigen positron emission tomography-computed tomography scan was used for staging in 33% (153), 80% (371) were staged as T3/T4 and 30% (142) with pelvic nodal disease. The median ADT duration was 24 months; 66% received hypofractionated EBRT and 71.4% (330) received pelvic nodal irradiation. With a median follow-up of 56 months, the 5-year bRFS, MFS and overall survival were 73.1%, 77.4% and 90.5%, respectively. Primary Gleason pattern 5 was associated with worse bRFS, MFS and overall survival with hazard ratios of 0.51 (95% confidence interval 0.35 to 0.73, P < 0.001), 0.64 (95% confidence interval 0.43 to 0.96, P = 0.031) and 0.52 (95% confidence interval 0.28 to 0.97, P = 0.040), respectively, whereas pelvic nodal disease was associated with worse bRFS (hazard ratio 0.67, 95% confidence interval 0.46 to 0.98, P = 0.039) and MFS (hazard ratio 0.56, 95% confidence interval 0.37 to 0.85, P = 0.006). The acute and late radiation-related toxicities were low overall and pelvic nodal irradiation was associated with higher toxicities. CONCLUSION: Contemporary EBRT and long-term ADT led to excellent 5-year clinical outcomes and low rates of toxicity in this cohort of non-metastatic grade group 5 prostate cancers. Primary Gleason pattern 5 and pelvic node disease portends inferior clinical outcomes.

Dermoid Cyst with Intracranial Extension Presenting With Headache.

Dermoid cysts (DC) are benign cutaneous developmental anomalies comprising of hair follicles, sweat glands and sebaceous glands, and lined by stratified squamous epithelium. They are most commonly found on the face, lower back, and ovaries. We present a case of DC with intracranial extension in a 9 year old boy who presented with headache and a fluctuant scalp swelling. Magnetic resonance imaging revealed a midline scalp mass with intracranial extension. The lesion was excised with superior sagittal sinus preservation; and confirmed as DC by histopathological examination. The boy made good recovery.

Antimicrobial therapy during cancer treatment: Beyond antibacterial effects.

Cancer treatment options have evolved to include immunotherapy and targeted therapy, in addition to traditional chemoradiation. Chemoradiation places the patient at a higher risk of infection through a myelosuppressive effect. High clinical suspicion and early use of antimicrobials play a major role in decreasing any associated morbidity and mortality. This has led to a widespread use of antimicrobials in cancer patients. Antimicrobial use, however, does not come without its perils. Dysbiosis caused by antimicrobial use affects responses to chemotherapeutic agents and is prognostic in the development and severity of certain cancer treatment-related complications such as graft-versus-host disease and Clostridioides difficile infections. Studies have also demonstrated that an intact gut microbiota is essential in the anticancer immune response. Antimicrobial use can therefore modulate responses and outcomes with immunotherapy targeting immune checkpoints. In this review, we highlight the perils associated with antimicrobial use during cancer therapy and the importance of a more judicious approach. We discuss the nature of the pathologic changes in the gut microbiota resulting from antimicrobial use. We explore the effect these changes have on responses and outcomes to different cancer treatment modalities including chemotherapy and immunotherapy, as well as potential adverse clinical consequences in the setting of stem cell transplant.

A contemporary review of Clostridioides difficile infections in patients with haematologic diseases.

Clostridioides (Clostridium) difficile (C. difficile) infection is one of the most common causes of increased morbidity and mortality. Approximately 500 000 C. difficile infections (CDIs) occur each year in the United States, and they result in more than 29 000 deaths. Patients with haematologic diseases are at a higher risk for this infection due to frequent hospitalization and exposure to treatment-associated risk factors. Whilst several currently available antimicrobial agents offer resolution, recurrence of infection remains a major concern. Recent advancement in deciphering C. difficile virulence mechanisms and identification of its allies in contributing to the infection has led to the development of alternative treatment strategies. Here, we will provide a contemporary discussion of how major risk factors in haematologic diseases, such as immunosuppression, chemoradiation, use of antibiotic, proton pump inhibitor and opioid, and deficiency in butyrate and antimicrobial peptides contribute to C. difficile infection. Next, we will highlight different approaches to control and mitigate this infection such as antibiotic stewardship and faecal microbiota transplantation. Finally, we will explore several emerging treatments such as use of pre- and probiotics, immunotherapy and microbiome-sparing agents.

Ketogenic diet in endocrine disorders: Current perspectives.

Ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that leads to nutritional ketosis, long known for antiepileptic effects and has been used therapeutically to treat refractory epilepsy. This review attempts to summarize the evidence and clinical application of KD in diabetes, obesity, and other endocrine disorders. KD is usually animal protein based. An empiric vegetarian Indian variant of KD has been provided keeping in mind the Indian food habits. KD has beneficial effects on cardiac ischemic preconditioning, improves oxygenation in patients with respiratory failure, improves glycemic control in diabetics, is associated with significant weight loss, and has a beneficial impact on polycystic ovarian syndrome. Multivitamin supplementations are recommended with KD. Recently, ketones are being proposed as super-metabolic fuel; and KD is currently regarded as apt dietary therapy for "diabesity."

[Point mutations in the DNA binding domain of p53 contribute to glioma progression and poor prognosis].

TP53 mutations play a significant role in glioma tumorigenesis. When located in in the DNA binding domain, these mutations can perturb p53 protein conformation and its function, often culminating in altered downstream signaling. Here we describe prevalent pattern of TP53 point mutations in a cohort of 40 glioma patients and show their relevance to gliomagenesis. Point mutations in exon 5-9 of TP53 gene were detected by DNA sequencing. Possible influence of identified mutations at the function of p53 was studied computationally and correlated with the survival. Point mutations in TP53 were detected in 10 glioma samples (25%), out of which 70% were from high grade glioma. A total of 19 TP53 point mutations were identified, out of which 42% were found to be in the DNA binding region of p53. Computational analysis predicted 87.5% of these mutations to be "probably damaging". In three patients with tumors possessing point mutations R273H, R248Q, Y163H and R175H and poor survival times, structural analysis revealed the nature of these mutations to be disruptive and associated with high risk for cancer progression. In high grade glioma, recurrent TP53 point mutations may be the key to tumor progression, thus, emphasizing their significance in gliomagenesis.

Adenosine monophosphate-activated protein kinase-based classification of diabetes pharmacotherapy.

The current classification of both diabetes and antidiabetes medication is complex, preventing a treating physician from choosing the most appropriate treatment for an individual patient, sometimes resulting in patient-drug mismatch. We propose a novel, simple systematic classification of drugs, based on their effect on adenosine monophosphate-activated protein kinase (AMPK). AMPK is the master regular of energy metabolism, an energy sensor, activated when cellular energy levels are low, resulting in activation of catabolic process, and inactivation of anabolic process, having a beneficial effect on glycemia in diabetes. This listing of drugs makes it easier for students and practitioners to analyze drug profiles and match them with patient requirements. It also facilitates choice of rational combinations, with complementary modes of action. Drugs are classified as stimulators, inhibitors, mixed action, possible action, and no action on AMPK activity. Metformin and glitazones are pure stimulators of AMPK. Incretin-based therapies have a mixed action on AMPK. Sulfonylureas either inhibit AMPK or have no effect on AMPK. Glycemic efficacy of alpha-glucosidase inhibitors, sodium glucose co-transporter-2 inhibitor, colesevelam, and bromocriptine may also involve AMPK activation, which warrants further evaluation. Berberine, salicylates, and resveratrol are newer promising agents in the management of diabetes, having well-documented evidence of AMPK stimulation medicated glycemic efficacy. Hence, AMPK-based classification of antidiabetes medications provides a holistic unifying understanding of pharmacotherapy in diabetes. This classification is flexible with a scope for inclusion of promising agents of future.

Src kinase function controls progenitor cell pools during regeneration and tumor onset in the Drosophila intestine.

Src non-receptor kinases have been implicated in events late in tumor progression. Here, we study the role of Src kinases in the Drosophila intestinal stem cell (ISC) lineage, during tissue homeostasis and tumor onset. The adult Drosophila intestine contains only two progenitor cell types, division-capable ISCs and their daughters, postmitotic enteroblasts (EBs). We found that Drosophila Src42a and Src64b were required for optimal regenerative ISC division. Conversely, activation of Src42a, Src64b or another non-receptor kinase, Ack, promoted division of quiescent ISCs by coordinately stimulating G1/S and G2/M cell cycle phase progression. Prolonged Src kinase activation caused tissue overgrowth owing to cytokine receptor-independent Stat92E activation. This was not due to increased symmetric division of ISCs, but involved accumulation of weakly specified Notch(+) but division-capable EB-like cells. Src activation triggered expression of a mitogenic module consisting of String/Cdc25 and Cyclin E that was sufficient to elicit division not only of ISCs but also of EBs. A small pool of similarly division-capable transit-amplifying Notch(+) EBs was also identified in the wild type. Expansion of intermediate cell types that do not robustly manifest their transit-amplifying potential in the wild type may also contribute to regenerative growth and tumor development in other tissues in other organisms.

Serum fetuin-A concentration predicts glycaemic outcomes in people with prediabetes: a prospective study from eastern India.

AIM: To evaluate the role of fetuin-A levels in predicting glycaemic outcomes (progression to diabetes or reversion to normoglycaemia) in people with prediabetes. METHODS: A total of 2119 people were screened, of whom 144 people with prediabetes, 50 people with normoglycaemia and 66 people with newly diagnosed diabetes underwent estimation of fasting insulin, fetuin-A, interleukin-6, interleukin-1ß, tumour necrosis factor-α, lipid and 25-hydroxyvitamin-D levels and assessment of non-alcoholic fatty liver disease using ultrasonography and the fatty liver index. People with prediabetes were followed and analysed according to glycaemic outcome and quartile of fetuin-A level. RESULTS: Fetuin-A, interleukin-1ß, interleukin-6, tumour necrosis factor-α and triglyceride levels and presence of non-alcoholic fatty liver disease increased across the glycaemic spectrum and were highest in people with diabetes. A total of 32 people with prediabetes reverted to normoglycaemia, 23 progressed to diabetes and 65 remained with prediabetes over a mean ± sd follow-up of 32.12 ± 8.4 months. People progressing to diabetes had higher baseline glycaemia rates, fetuin-A levels, interleukin-1ß levels, fatty liver index scores and prevalence of non-alcoholic fatty liver disease and lower 25-hydroxyvitamin-D levels. People with prediabetes in the highest fetuin-A quartile had the highest risk of progression to diabetes (relative risk 2.68, 95% CI 0.95-7.55; P = 0.06) and the lowest rate of reversion to normoglycaemia (relative risk 0.27, 95% CI 0.08-0.85; P = 0.03). Fetuin-A levels correlated with interleukin-1ß levels (r = 0.420; P < 0.001), interleukin-6 levels (r = 0.231; P = 0.022) and fatty liver index scores (r = 0.319; P < 0.001). Cox regression showed that higher fetuin-A levels and higher BMI and lower 25-hydroxyvitamin-D levels were predictive of lower rates of reversion to normoglycaemia. Age, triglyceride levels, and interleukin-6 and interleukin-1ß levels were predictive of progression to diabetes. CONCLUSIONS: Increased fetuin-A level has an adverse impact on glycaemic outcomes in prediabetes. This study highlights the importance of fetuin-A as a predictor of glycaemic outcomes in prediabetes.

Subcutaneous panniculitis-like T-cell lymphoma with unusual eschar-like crusting.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of non-Hodgkin's lymphoma of the skin. Clinically, SPTCL presents as subcutaneous tumors located on the extremities or trunk, often associated with systemic symptoms like fever or fatigue. The therapeutic regimen for SPTCL is at present not standardized. We describe herein a case of a young woman who presented with intermittent fever and skin rash and was diagnosed later with SPTCL. The case is reported here for its rarity and rapidly changing unusual clinical manifestations. This case also highlights that monotherapy with systemic steroid can be a valuable treatment option for the management of SPTCL, especially in those without hemophagocytic syndrome.

Ovotesticular disorder of sexual development due to 47,XYY/46,XY/45,X mixed gonadal dysgenesis in a phenotypic male presenting as cyclical haematuria: clinical presentation and assessment of long-term outcomes.

Ovotesticular disorder of sexual differentiation (OTDSD) is a rare cause of disorder of sexual differentiation predominantly having 46,XX karyotype, female phenotype and ambiguous genitalia. We report a 15-year-old having male body habitus, axillary and pubic hair, well-developed penis and right-descended testis with history of penoscrotal hypospadias correction, presenting with three episodes of cyclical haematuria, who biochemically had normal serum testosterone (338 ng dl(-1) ) which increased following hCG stimulation (614 ng dl(-1) ), elevated estradiol (17.35 pg ml(-1) ) along with elevated luteinising hormone (11.3 mIU l(-1) ) and follicle-stimulating hormone (31 mIU l(-1) ). Ultrasonography followed by micturating cystourethrogram and cystoscopy confirmed the presence of prostate, uterus, cervix and vagina draining into the urogenital sinus continuing till the penile urethra and left intra-abdominal gonad. Patient underwent hysterectomy and left gonadectomy. Histopathologic study of resected gonad confirmed presence of ovotestis. Low estradiol (1.2 pg ml(-1) ) following gonadectomy confirmed the ovotestis origin of estradiol. Chromosomal analysis revealed complex karyotype predominant being 47,XYY (50%) followed by 46,XY (26%) and 45,X (24%). This is perhaps the first report of 47,XYY/46,XY/45,X causing OTDSD in a phenotypic male.

A gas-jet transport and catcher technique for on-line production of radioactive ion beams using an electron cyclotron resonance ion-source.

Radioactive ion beams (RIB) have been produced on-line, using a gas-jet recoil transport coupled Electron Cyclotron Resonance (ECR) ion-source at the VECC-RIB facility. Radioactive atoms∕molecules carried through the gas-jet were stopped in a catcher placed inside the ECR plasma chamber. A skimmer has been used to remove bulk of the carrier gas at the ECR entrance. The diffusion of atoms∕molecules through the catcher has been verified off-line using stable isotopes and on-line through transmission of radioactive reaction products. Beams of (14)O (71 s), (42)K (12.4 h), (43)K (22.2 h), and (41)Ar (1.8 h) have been produced by bombarding nitrogen and argon gas targets with proton and alpha particle beams from the K130 cyclotron at VECC. Typical measured intensity of RIB at the separator focal plane is found to be a few times 10(3) particles per second (pps). About 3.2 × 10(3) pps of 1.4 MeV (14)O RIB has been measured after acceleration through a radiofrequency quadrupole linac. The details of the gas-jet coupled ECR ion-source and RIB production experiments are presented along with the plans for the future.

Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Although it is accepted that metastatic colorectal cancers (mCRCs) that carry activating mutations in KRAS are unresponsive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, a significant fraction of KRAS wild-type (wt) mCRCs are also unresponsive to anti-EGFR therapy. Genes encoding EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are promising gene expression-based markers but have not been incorporated into a test to dichotomise KRAS wt mCRC patients with respect to sensitivity to anti-EGFR treatment. METHODS: We used RT-PCR to test 110 candidate gene expression markers in primary tumours from 144 KRAS wt mCRC patients who received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS). RESULTS: Expression of many of the tested candidate genes, including EREG and AREG, strongly associate with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Strikingly, patients below the classifier cutpoint had PFS and disease control rates similar to those of patients with KRAS mutant mCRC. CONCLUSION: Gene expression appears to identify KRAS wt mCRC patients who receive little benefit from cetuximab. It will be important to test this model in an independent validation study.

Assessment of compliance to treatment and efficacy of a resource-sparing hypofractionated radiotherapy regimen in patients with poor-prognosis high-grade gliomas.

INTRODUCTION: The optimal radiotherapeutic management of poor-prognosis (elderly and/or poor performance status) high-grade gliomas (HGG) remains controversial. Hypofractionated radiotherapy (hypoRT) has been shown to be non-inferior to daily conventionally fractionated radiotherapy. This study aimed to assess the compliance to treatment and efficacy of a resource-sparing hypoRT regimen in this subset. MATERIALS AND METHODS: The resource-sparing hypoRT regimen was delivered once weekly (5Gy/fraction) for seven fractions to a total dose of 35Gy in seven fractions over six weeks. Compliance to planned treatment and factors that could potentially influence it were analyzed. RESULTS: Between January 2004 and October 2009, 63 patients with poor-prognosis HGG (age range 40-78 years; Karnofsky performance score ≤70) were offered resource-sparing hypoRT regimen. Twenty eight of 63 patients completed planned course of treatment giving a treatment compliance rate of 44%. Six (9.5%) patients did not receive even a single fraction of radiation after simulation/planning. Thirty eight patients (60%) received ≥3 fractions and were on treatment for at least two weeks. Performance status (P = 0.05) and grade (P = 0.04) significantly impacted upon compliance. Median overall survival for the cohort of 28 patients who completed planned course of treatment was 7.4 months (95% confidence interval: 4.4-10.5 months). CONCLUSIONS: The treatment compliance to a resource-sparing once-weekly hypoRT regimen in poor-prognosis HGG has been somewhat suboptimal and discouraging, possibly due to the protracted scheduling over six weeks. Over 60% of patients were on treatment for two weeks, suggesting that short-course schedules could more likely ensure compliance.

An atypical presentation of recurrent temporal lobe meningioma with external auditory canal mass.

Extracranial spread of recurrent meningiomas involving the middle ear is rare. We present the case of a 59-year-old woman with headache and swelling of scalp over the right temporal region. MRI revealed a lesion in the right temporal lobe suggestive of meningioma. She underwent complete surgical excision of the lesion followed by post-operative radiotherapy. After 1 year, she presented with right-sided otalgia and a middle-ear mass extruding into the external auditory canal. She was re-operated and histopathology was anaplastic meningioma. We are discussing this unusual pattern of recurrence in our patient with a review of literature.

Langerhans cell histiocytosis of the thyroid: a report of two cases and review of the literature.

Langerhans cell histiocytosis (LCH) is a monoclonal disease of histiocytes that can involve many or very few organ systems. It is a relatively benign disorder with a 3% mortality in adults. LCH rarely involves the thyroid gland. We report two cases, both presenting in males with a goiter. Both patients were treated with subtotal thyroidectomy. The first patient also received radiotherapy to his thyroid bed and scalp. We summarize the prior reported cases of LCH involving the thyroid and review the current treatment modalities used for LCH.