Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer.

Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of urothelial cancer. Previously approved systemic therapies, including chemotherapy and immunotherapy, are often impractical due to comorbidities, and outcomes for patients with advanced disease remain poor, even when receiving systemic therapy. In this setting, antibody-drug and bicycle toxin conjugates have emerged as novel treatments, dramatically altering the therapeutic landscape. These drugs harness unique designs consisting of antibody or bicycle peptide, linker, and cytotoxic payload with more targeted delivery than conventional chemotherapy, thus eliminating malignant cells while reducing systemic toxicities. Potential targets investigated in urothelial cancer include Nectin-4, TROP2, HER2, and EphA2. Initial clinical trials demonstrated efficacy in treatment of refractory advanced urothelial cancer, as well as improvement in quality of life. These initial studies led to FDA approval of two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. Moreover, antibody-drug and bicycle toxin conjugates are being studied in ongoing clinical trials in frontline treatment of advanced disease as well as for localized cancer. These studies highlight the potential for additional future therapies with novel targets, novel antibodies, cytotoxic and immunomodulatory payloads, and unique structural designs enhancing efficacy and safety. There is increasing evidence that combinations with other cancer therapies, especially immunotherapy, improve treatment outcomes. The combination of enfortumab vedotin and pembrolizumab was recently approved for first-line treatment of advanced urothelial carcinoma. Despite the great promise of these novel drugs, robust predictive biomarkers are needed to determine the patients who would maximally benefit. This review surveys the rationale and current state of the evidence for these new drugs and describes future directions actively being explored.

Review of recent advances in novel treatments of urothelial cancer Two new types of drugs, called antibody-drug conjugates (ADCs) and bicycle toxin conjugates (BTCs) have shown great promise in treating urothelial cancer. Both types of drugs consist of a structure targeting a specific protein on bladder cancer cells, linked to a drug that can kill cells. This allows for effective treatment of cancer with potentially less toxicity due to the targeted nature of these treatments. We discuss the potential targets in urothelial cancer and the drugs in these classes that could treat each target. Two of these drugs, enfortumab vedotin and sacituzumab govitecan, are in clinical use for cancers that have spread, while the others are in clinical trials. Moreover, the combination of enfortumab vedotin and pembrolizumab, an immunotherapy drug, has excellent results and was recently approved for first-line treatment of urothelial cancer that has spread. Additional studies are looking into these treatments for cancers that have not spread. In the future, management of side effects, determination of which patients benefit, and overcoming when the drugs become no longer effective will be important.

Establishing an Integrative Oncology Service: Essential Aspects of Program Development.

PURPOSE OF REVIEW: Over the last 2 decades, integrative oncology (IO) has seen exponential growth within cancer care. It aims to combine evidence-based complementary therapies with conventional treatments to improve the well-being and quality of life for individuals dealing with cancer. The proliferation of integrative medicine programs in major cancer centers globally reflects varying approaches shaped by cultural, demographic, and resource-based factors. RECENT FINDINGS: Drawing upon the expertise of leaders in IO from the Society for Integrative Oncology (SIO) Clinical Practice Committee, this manuscript serves as a practical guide for establishing an IO practice. Collating insights from diverse professionals, including oncologists, integrative oncologists, supportive care physicians, researchers, and clinicians, the paper aims to provide a comprehensive roadmap for initiating and advancing IO services. The primary objective is to bridge the gap between conventional cancer care and complementary therapies, fostering a patient-centric approach to address the multifaceted challenges encountered by individuals with cancer. This paper delineates several key sections elucidating different aspects of IO practice. It delves into the core components necessary for an IO service's foundation, outlines the initial medical consultation process, and presents crucial tools essential for successful consultations. By consolidating insights and expertise, this manuscript seeks to facilitate the integration of IO into mainstream cancer care, ultimately enhancing patient outcomes and experiences.

Artificial intelligence applications in prostate cancer.

Artificial intelligence (AI) applications have enabled remarkable advancements in healthcare delivery. These AI tools are often aimed to improve accuracy and efficiency of histopathology assessment and diagnostic imaging interpretation, risk stratification (i.e., prognostication), and prediction of therapeutic benefit for personalized treatment recommendations. To date, multiple AI algorithms have been explored for prostate cancer to address automation of clinical workflow, integration of data from multiple domains in the decision-making process, and the generation of diagnostic, prognostic, and predictive biomarkers. While many studies remain within the pre-clinical space or lack validation, the last few years have witnessed the emergence of robust AI-based biomarkers validated on thousands of patients, and the prospective deployment of clinically-integrated workflows for automated radiation therapy design. To advance the field forward, multi-institutional and multi-disciplinary collaborations are needed in order to prospectively implement interoperable and accountable AI technology routinely in clinic.

Multicenter analysis to assess risk of major adverse cardiac events in patients undergoing high-sensitivity troponin testing in the emergency department.

Study hypothesis: Our objective was to evaluate 30-day major adverse cardiac events (MACE) in emergency department (ED) patients with normal high-sensitivity troponins (hs-trop). We hypothesized that MACE rates would be <1% in patients with (1) two normal troponins regardless of change in troponin (delta) and (2) index hs-trop below the limit of quantitation (LOQ) regardless of the institution modified HEART score. Methods: This was a multicenter, retrospective, cohort study of adult patients who presented to 1 of 18 EDs between July 2020 and April 2021 with acute coronary syndrome as defined by an institutional-modified HEART score completed by their treating physician or midlevel, no evidence of ST-elevation myocardial infarction, and an index or serial gender-adjusted hs-trop within normal limits. The primary outcome was MACE within 30 days of index ED encounter. A detailed case review was then performed for those patients experiencing a MACE. Results: Of the 9084 patients who had single or serial normal troponins, 31 (0.34%; confidence interval [CI] 0.23%-0.48%) experienced MACE. Of the 6140 patients with 2 normal hs-trop and a delta (change in troponin) <4, 27 patients (0.44%; CI 0.29%-0.64%) experienced MACE. Only 1 of the 69 patients with 2 normal hs-trop results but delta (change in troponin) ≥ 4 (1.45%; CI 0.04%-7.81%) suffered MACE. This patient was classified as non-low risk by our institutional HEART score. Of 7498 patients with an index hs-trop 

5-HT3 Receptors on Mitochondria Influence Mitochondrial Function.

The 5-hydroxytryptamine 3 (5-HT3) receptor belongs to the pentameric ligand-gated cation channel superfamily. Humans have five different 5-HT3 receptor subunits: A to E. The 5-HT3 receptors are located on the cell membrane, but a previous study suggested that mitochondria could also contain A subunits. In this article, we explored the distribution of 5-HT3 receptor subunits in intracellular and cell-free mitochondria. Organelle prediction software supported the localization of the A and E subunits on the inner membrane of the mitochondria. We transiently transfected HEK293T cells that do not natively express the 5-HT3 receptor with an epitope and fluorescent protein-tagged 5HT3A and 5HT3E subunits. Fluorescence microscopy and cell fractionation indicated that both subunits, A and E, localized to the mitochondria, while transmission electron microscopy revealed the location of the subunits on the mitochondrial inner membrane, where they could form heteromeric complexes. Cell-free mitochondria isolated from cell culture media colocalized with the fluorescent signal for A subunits. The presence of A and E subunits influenced changes in the membrane potential and mitochondrial oxygen consumption rates upon exposure to serotonin; this was inhibited by pre-treatment with ondansetron. Therefore, it is likely that the 5-HT3 receptors present on mitochondria directly impact mitochondrial function and that this may have therapeutic implications.

Phylogenetic analyses of 5-hydroxytryptamine 3 (5-HT3) receptors in Metazoa.

The 5-hydroxytrptamine 3 (5-HT3) receptor is a member of the 'Cys-loop' family and the only pentameric ligand gated ion channel among the serotonin receptors. 5-HT3 receptors play an important role in controlling growth, development, and behaviour in animals. Several 5-HT3 receptor antagonists are used to treat diseases (e.g., irritable bowel syndrome, nausea and emesis). Humans express five different subunits (A-E) enabling a variety of heteromeric receptors to form but all contain 5HT3A subunits. However, the information available about the 5-HT3 receptor subunit occurrence among the metazoan lineages is minimal. In the present article we searched for 5-HT3 receptor subunit homologs from different phyla in Metazoa. We identified more than 1000 5-HT3 receptor subunits in Metazoa in different phyla and undertook simultaneous phylogenetic analysis of 526 5HT3A, 358 5HT3B, 239 5HT3C, 70 5HT3D, and 173 5HT3E sequences. 5-HT3 receptor subunits were present in species belonging to 11 phyla: Annelida, Arthropoda, Chordata, Cnidaria, Echinodermata, Mollusca, Nematoda, Orthonectida, Platyhelminthes, Rotifera and Tardigrada. All subunits were most often identified in Chordata phylum which was strongly represented in searches. Using multiple sequence alignment, we investigated variations in the ligand binding region of the 5HT3A subunit protein sequences in the metazoan lineage. Several critical amino acid residues important for ligand binding (common structural features) are commonly present in species from Nematoda and Platyhelminth gut parasites through to Chordata. Collectively, this better understanding of the 5-HT3 receptor evolutionary patterns raises possibilities of future pharmacological challenges facing Metazoa including effects on parasitic and other species in ecosystems that contain 5-HT3 receptor ligands.

Anti-angiogenesis Revisited: Combination with Immunotherapy in Solid Tumors.

PURPOSE OF REVIEW: Both anti-angiogenesis and immunotherapy are well-established therapeutic options in solid tumors. Here, we review the rationale as well as clinical evidence of combining these two approaches. RECENT FINDINGS: There is strong rationale and substantial preclinical and clinical evidence that anti-angiogenesis plays a pivotal role in overcoming immunotherapy resistance. The combination of an anti-angiogenic agent and a checkpoint inhibitor offers a more robust treatment option in many clinical trials in a wide variety of solid tumor types. Combination of anti-angiogenesis and immunotherapy has emerged as a standard of care in some tumor types and the indication is expected to expand to more tumor types in the years to come.

Integrative Oncology: An International Perspective from Six Countries.

In June 2019, a meeting was held in Paris in which experts from different countries (Israel, Spain, Belgium, Italy, USA, and France) met to discuss a selection of topics in integrative oncology (IO). The objectives were to draw on the delegates' experience and expertise to begin an international collaboration, sharing details of differing existing models and discussing future perspectives to help define and guide practice in IO and define unmet needs. This report presents a summary of the meeting's main presentations, and also reports on the experts' responses to a questionnaire examining different aspects of IO service delivery, infrastructure, and utilization.

Rosette-forming Glioneuronal Tumor in the Optic Pathway of a Child.

Rosette-forming glioneuronal tumor is a rare World Health Organization grade I neoplasm, primarily involving the posterior fossa. Most cases have been reported in young adults. Although maximal surgical resection is advocated, a precise treatment modality is yet to be established. We describe an unusual presentation of rosette-forming glioneuronal tumor occurring in the optic pathway in a child. As the site of the tumor was not amenable to resection, he underwent radiotherapy and is currently well on follow-up.

Profile and Outcome of Pediatric Brain Tumors - Experience from a Tertiary Care Pediatric Oncology Unit in South India.

CONTEXT: Tumors of the central nervous system (CNS) constitute the second most common pediatric cancers. Unlike leukemia, management of CNS tumors requires a good multidisciplinary team. Higher rates of treatment abandonment are documented in view of complexity of the treatment with long duration, involving neurosurgery, radiation, chemotherapy, and high cost of treatment. Morbidity associated with CNS tumors may be significant in terms of physical deficits as well as neuropsychological and neuroendocrine sequelae. Pediatric neurooncology is still at a very nascent stage in the developing countries. There are only a few reports on the multidisciplinary approach and outcomes of pediatric brain tumors in developing countries. AIMS: The aim of this study is to identify the clinicopathological profile of Pediatric CNS tumors in a tertiary care center located in South India in comparison with reports from other low-and middle-income Countries. SETTINGS AND DESIGN: A retrospective analysis of medical records of all children diagnosed with brain tumors from January 2012 to November 2016 at our institute was done. SUBJECTS AND METHODS: A retrospective study of clinical, pathological profile, and outcomes of children <18 years diagnosed with brain tumors at our institute from January 2012 to November 2016 was done. Histopathological categorization was done as per the WHO classification 2007. The multidisciplinary treatment with respect to surgery, radiation, and chemotherapy was noted and the outcomes were recorded. STATISTICAL ANALYSIS USED: R for Statistical Computing (Version 3.0.2; 2013-09-25). RESULTS: A total of 52 children were diagnosed with male preponderance of 66.6%. Highest incidence was noted in the age group of 0-4 years (50%). Majority of them were supratentorial (59.6%). CNS embryonal tumors contributed to 48% of all our brain tumors. 73% of them underwent either resection or biopsy. Eight (15.3%) of them died due to the progression of disease, but 44% abandoned treatment due to the progression/recurrence of disease. Those lost to follow-up were mostly among the high-risk groups with poor prognosis such as pontine glioma, medulloblastoma (high risk), and primitive neuroectodermal tumor. CONCLUSIONS: Although brain tumors constituted 30% of all our solid tumors, only 56% of them received appropriate treatment and 25% abandoned treatment. High rates of abandonment were a consequence of late diagnosis, complex multidisciplinary treatment involved, high treatment cost, lack of uniformity in management between different oncology centers and poor prognosis of the tumor subtype.

A Prospective Study of Different Methods of Inferior Turbinate Reduction.

INTRODUCTION: All the functions of nasal cavities are performed through mucosa and contours of the turbinates. Hypertrophied inferior turbinate is one of the major and common causes of nasal obstruction. In these patients nasal obstruction is relieved by inferior turbinate reduction. Many procedures on turbinate reduction have been described earlier. AIM: To compare and evaluate the better method for inferior turbinate reduction among submucosal diathermy using monopolar cautery and bipolar cautery, complete turbinectomy, inj. sodium tetradecylsulphate infiltration. MATERIALS AND METHODS: Eighty patients of either sex between 17-50 years of age having inferior turbinate hypertrophy were included in the study. The patients were divided into four groups with 20 patients in each group. Each group had 20 patients. Group A was subjected to submucosal diathermy using monopolar cautery, Group B to bipolar cautery, Group C to complete inferior turbinectomy and group D to injection sodium tetradecylsulphate. Patients were assessed for nasal patency and symptomatic relief, postoperative bleeding, pain, crusting and synachiae. Follow up was done on 7th day, 21st day and 3rd month postoperatively. Statistical analysis was carried out using IBM SPSS Version 20.0 for windows. Mean and standard deviations were calculated for quantitative data, for categorical variables frequencies and percentages were calculated, within the group comparisons were done with paired t-tests. RESULTS: The mean reduction in postoperative nasal obstruction was found to be maximum with bipolar cautery when compared with the other modalities and this difference was found to be statistically significant (p<0.001). Bipolar cautery was found to be associated with minimum after effects when compared to other modalities except for postoperative pain which was found more in the patients operated by the bipolar cautery method. CONCLUSION: We found inferior turbinate reduction using bipolar cautery was better and safe method, when compared to monopolar cautery, complete turbinectomy and inj. sodium tetradecylsulphate, however further studies are required with larger sample size.

Acquired Toxoplasmosis Presenting with a Brainstem Granuloma in an Immunocompetent Adolescent.

BACKGROUND: Toxoplasmosis is an uncommon disease in immunocompetent people. CASE CHARACTERISTICS: We report an adolescent boy with central nervous system toxoplasmosis who presented with progressive lower cranial nerve palsies and a ring-enhancing lesion on neuroimaging. INTERVENTION: Diagnosis of toxoplasmosis was confirmed on histopathology of the excised lesion. MESSAGE: Toxoplasmosis should be considered in the differential diagnosis of focal brain lesions irrespective of immune status.

Craniostenosis: a neurosurgeon's perspective.

In pediatric neurosurgery departments in India, craniosynostosis is being increasingly identified and dealt with during the past several years. The management of this problem is well established in units that have a strong pediatric bias, whereas it is still in infancy in certain departments. Some misconceptions exist regarding this condition with reference to clinical, genetic aspects and management-in particular, the surgical indications. The experience gained for more than 2 decades of treating this condition as well as the problems faced in the management of this condition will be discussed. Although the terms craniostenosis and craniosynostosis do not mean quite the same thing, the terms are used interchangeably and will be done so in this communication.

Management of CSF leak following spinal surgery.

PURPOSE: Postoperative CSF leak is a known complication of spinal surgery especially after surgery for neural tube defects (NTD). The problem can metamorphose into a severe infection. This article hopes to shed some light on the management of these problems and suggests precautions so as to reduce their occurrence. MATERIALS AND METHODS: A retrospective analysis of 102 children, between the ages of 1 day and 12 years, operated for various spinal pathologies, over the past 2.5 years by the same surgeon (CB) was done. The various methods of dural closure were noted. The methods of management of postoperative CSF leaks were analysed, and the patients were followed till discharge. RESULTS: The incidence of CSF leak was found to be 12.7%. The methods of management included lumbar drain only (n = 7), lumbar drain with re-exploration (n = 3), lumbar drain followed by lumboperitoneal shunt (n = 2) and only lumboperitoneal shunt (n = 1). The use of fibrin glue did not seem to significantly prevent the incidence of CSF leak in cases. CONCLUSIONS: Primary and meticulous dural closure is sine qua non in preventing postoperative CSF leak. A lumbar drain is a convenient and economical method of managing the problem initially failing which more invasive methods like re-exploration may be employed.

Sleep duration and breast cancer phenotype.

Emerging evidence suggests that short sleep is associated with an increased risk of cancer; however, little has been done to study the role of sleep on tumor characteristics. In this study, we evaluated the relationship between sleep duration and tumor phenotype in 972 breast cancer patients. Sleep duration was inversely associated with tumor grade (univariate P = 0.032), particularly in postmenopausal women (univariate P = 0.018). This association did not reach statistical significance after adjustments for age, race, body mass index, hormone replacement therapy use, alcohol consumption, smoking, and physical activity in the entire study sample (P = 0.052), but it remained statistically significant (P = 0.049) among post-menopausal patients. We did not observe a statistically significant association between sleep duration and stage at diagnosis, ER, or HER2 receptor status. These results present a modest association between short duration of sleep and higher grade breast cancer in post-menopausal women. Further work needs to be done to validate these findings.

A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults.

There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18-65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis-Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (p<0.001). Gabapentin was also associated with significantly greater improvement in overall performance on tests of executive function (p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin for treatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal.