Intravitreal topotecan for vitreous seeds in retinoblastoma: A long-term review of 91 eyes.

OBJECTIVE: To study the long-term safety and efficacy of intravitreal topotecan (IVT) against vitreous seeds in eyes with retinoblastoma and risk factors for their recurrence. DESIGN: Retrospective, non-comparative, interventional study. SUBJECTS: 91 eyes of 90 patients with retinoblastoma treated between January 2013 to April 2019. INTERVENTION: Patients with recurrent or refractory vitreous seeds following completion of intravenous or intra-arterial chemotherapy were treated with IVT (30µg/0.15ml) by the safety enhanced technique. The injection was repeated every 4 weeks till the regression of seeds. Patients with a minimum follow up of 12 months were included in the analysis. MAIN OUTCOME MEASURES: Primary outcome measures were vitreous seed regression, and eye salvage. Secondary outcomes were risk factors for vitreous seed recurrence following treatment with IVT, vision salvage and complications of IVT. RESULTS: The median age of the patients was 18 months, majority having group D (58, 64%) and group E (26, 29%) retinoblastoma. Vitreous seeds were refractory in 46 (51%) and recurrent in 45 (49%) eyes. A total of 317 IVT injections were given, median being 3. The median number of IVT injections required were 2.5 for dust, 3 for sphere and 5 for cloud morphology. Recurrence of vitreous seeds following IVT was seen in 17 eyes (19%) at a mean follow up of 7.9 months. At a mean follow up 34 months, vitreous seed regression was achieved in 88 (97%) eyes and eye salvage in 77 (85%) eyes. Older age (p=0.018) and recurrence of retinal tumor (15/17 eyes) (p<0.01) significantly increased the risk of vitreous seed recurrence. Cataract was the most common complication seen in 17 (9%) eyes. CONCLUSION: Intravitreal topotecan at a 3-4-weekly regimen is effective against both refractory and recurrent vitreous seeds. The vitreous seed morphology corresponds to the number of injections required for regression. Increasing age and recurrence of retinal tumor increase the risk of vitreous seed recurrence following treatment with IVT.

Primary Hyperparathyroidism in Young and Adolescents: Alike or Unlike Adult Hyperparathyroidism? - A Series from South India.

Background: Primary hyperparathyroidism (PHPT) is a common endocrine condition but rare in the pediatric and adolescent populations. The presentations can be unique, accounting for significant morbidity in the case of untimely detection. Aim: To study surgically treated pediatric PHPT retrospectively. Methods: Surgically treated children of PHPT up to 20 years of age between 2010 to 2022 were analyzed. All of them were operated on by an endocrine surgeon and team. Results: There was a total of 712 parathyroidectomies over 12 years, out of which there were 52 children (7.3%) had PHPT at less than 20 years of age. This group included 32 male children. The mean age was 16.1 years, including 7 cases of neonatal severe HPT. Multiple Endocrine Neoplasia type 1 was confirmed in 12 children. Presentations were more severe like bone pain (35.13%), renal stones (27.02%), incidental asymptomatic detection (18.9%), failure to thrive (10.8%), and pancreatitis (8.1%) as compared to adults. Mean serum calcium was 12.9 mg/dl (highest-14.1, N-8.8-10.8 mg/dl), mean parathormone levels were 386.91 pg/ml (N-10-65) and vitamin D levels ranged from 2.9-22.8 ng/ml. Localization was done with ultrasound and 99mTc- SESTAMIBI scans. Mean serum calcium levels in NSPHPT were 28.6 mg/dl (N-8.8-10.8 mg/dl). There were a total of 45 cases (6.32%) of PHPT less than 20 years of age, excluding the cases of NSPHPT. All children underwent parathyroidectomy, with 14 cases having an additional thymectomy, 2 cases with thyroidectomy, and a single case of hemithyroidectomy. The cure rate was 97.3%, while one baby with NSPHPT had persistent disease (postop PTH-110 pg/ml). The uniglandular disease was seen in 54.05% and the rest had a multiglandular disease. Adults accounted for 559/660 cases with 80% uniglandular disease. All cases had a postoperative histopathological confirmation with an average follow-up of 1 year. Conclusion: Childhood PHPT has a few features same as the adult population. Symptomatic presentations like adults, though pancreatitis and fatigue were more commonly seen as compared to bone pain. Calcium, phosphorus, and parathormone levels were comparable. Uniglandular involvement was seen just like the adult population. There are a few others that make them a distinct subtype like their symptoms of bone pain and being more common among boys. One-fourth of them had MEN1. Fewer cases in this age group make them unique.

Extramammary Paget's Disease of the Penis and Scrotum.

Extramammary Paget's disease (EMPD) is an adenocarcinoma arising from the skin or skin appendages which is sometimes associated with an underlying malignancy. EMPD is most commonly seen in the vulva, followed by perianal region, and the male genitalia. In most cases, patient presents with eczematous lesion persisting for long duration. A 77-year-old gentleman had a history of chronic eczematous lesion over penis and scrotum for the last 10 years. Examination revealed an erythematous plaque like eczematous lesion over the penis and scrotum. Biopsy with IHC of lesion is suggestive of EMPD. Wide local excision of lesion and left inguinal lymph node dissection with pedicled left superficial circumflex iliac perforator flap cover was done. The final histopathology with IHC confirmed the diagnosis of EMPD. The postoperative period was uneventful, and patient was discharged. EMPD of the penis and scrotum is a rare presentation, and it is ideally treated with wide excision.

A Case of "Nonunion Distal Tibia and Fibula Malleoli Fracture with posterior Malleoli Fracture" Treated with Ilizarov: A Case Report.

Introduction: Orthopedic surgeons have long acknowledged the difficulty of treating distal tibia and fibula fractures with posterior malleoli fractures in individuals with medical comorbidities due to a lack of inadequate blood supply. Aged Type 2 diabetic individuals, with distal tibia and fibula fracture with posterior malleoli fracture, are more prone to complications such as non-union, wound infection, and delayed bone healing. It is debatable whether surgical or non-invasive treatment is preferable for diabetic complex fractures. Case Report: A 62-year-old male suffered a right distal tibia and fibula fracture with posterior malleoli fracture following an incidental fall followed by a hit over the iron rod. The patient was treated conservatively with POP for 6 weeks due to the patient's refusal of surgical management. Radiography after 6 weeks revealed features of non-union. Conclusion: The Ilizarov external fixation with bone graft was planned later to treat the non-union distal tibia and fibula fracture with posterior malleoli fracture. About 18 months after the Ilizarov fixation radiography reviewed the features of the union and clinically also patient improved.

To study the expression of estrogen, progesterone receptor and p53 immunohistochemistry markers in subtyping endometrial carcinoma.

Background: Endometrial cancer is one of the most commonly diagnosed cancers in women worldwide. Aim and Objectives: To study the expression of estrogen receptor (ER), progesterone receptor (PR) and p53 immunohistochemistry (IHC) markers in subtyping endometrial carcinoma. Materials and Methods: A total of 100 cases of carcinoma endometrium submitted during January 2016 to October 2018 were included in our study. The ER, PR and p53 expressions were scored as per the adopted scoring system. Agreement between ER, PR and p53 IHC expression and the consensus HE diagnosis, FIGO grading and tumour staging were assessed using Chi square tests. Results: There was a statistical association between ER, PR and p53 status and tumour histologic type with a P value < 0.01. There was no statistical significance observed between ER and PR expressions and different FIGO grades. Statistical significance (P = 0.036) between p53 and different FIGO grades seen. No statistical significance was observed between ER, PR and p53 expressions and different tumour stages and tumour invasiveness. There was a statistical association between ER and PR status and lymph node metastasis. p53 did not show a statistical significance. Conclusion: Combination of ER, PR and p53 IHC markers can be used to distinguish type 1 and type 2 endometrial cancers. PR expression is more specific than ER in endometrioid carcinomas. p53 expression is more specific in serous carcinoma, however, p53 IHC alone cannot be used to distinguish different grades of endometrioid carcinomas as there is variability of staining in endometrioid carcinomas.

Cardiovascular Adverse Events Associated With Second-generation Bruton Tyrosine Kinase Inhibitor Therapy: A Systematic Review and Meta-analysis.

PURPOSE: Cardiovascular adverse events (CVAEs) are common adverse effects of first-generation Bruton tyrosine kinase inhibitors (BTKis) and limit their use considerably. This led to the development of second-generation BTKis-acalabrutinib and zanubrutinib-which are more selective, potent, and presumed to have better safety profiles than the previous group of medications. However, there have been sporadic reports of CVAEs associated with second-generation BTKis in clinical practice. To address this issue, a comprehensive meta-analysis to pool the documented CVAEs was performed, including major hemorrhage, any bleeding, atrioventricular block, atrial fibrillation/flutter, pericardial effusion, pericarditis, heart failure, cardiac arrest, myocardial infarction, hypertension, hypotension, and stroke. This meta-analysis incorporated 8 studies. Among these, 6 were Phase III trials and 2 were Phase II trials. These studies collectively enrolled a total of 2938 patients. METHODS: Multiple databases, including PubMed, MEDLINE, Cochrane Library, Scopus, and EMBASE, were systematically searched for relevant clinical trials from inception through January 14, 2023. The effect measure used was odds ratio (OR) and 95% CI. FINDINGS: Of a total of 1774 studies identified during the initial database search, 8 were included in the meta-analysis. The incidence of overall and cardiovascular mortality was comparable between the 2 groups. There were no significant differences observed for cardiovascular mortality (OR = 0.36; 95% CI, 0.08-1.65; n = 2588; I2 = 45%; P = 0.19). Similar results were found for all-cause mortality (OR = 0.85; 95% CI, 0.67-1.07), any bleeding (OR = 1.90; 95% CI, 0.88-4.09), major bleeding (OR = 1.07; 95% CI, 0.65-1.76), atrioventricular block (OR = 0.74; 95% CI, 0.15-3.68), atrial fibrillation/flutter (OR = 0.74; 95% CI, 0.37-1.50), and other CVAEs associated with second-generation BTKis. IMPLICATIONS: Based on the available evidence, there is no indication of worse cardiovascular outcomes or superiority of second-generation BTKis compared with standard treatments in terms of safety profile. However, additional large-scale controlled trials are needed to provide robust support for the superior tolerability of new-generation BTKis.

Metastatic retinoblastoma at presentation: Clinical presentation, treatment, and outcomes.

The aim of this study was to retrospectively determine clinical features, treatment outcomes, and overall survival in four patients with metastatic retinoblastoma at presentation. The mean age at diagnosis was 63 months (range: 24-108 months). Three patients had overt orbital disease of at least one eye and one patient had microscopic orbital disease with scleral infiltration on histopathology. Metastatic sites included regional lymph nodes (RLN) (n = 4), bone marrow (BM) (n = 2), and cerebrospinal fluid (CSF) (n = 1). The most common sites of RLN were ipsilateral preauricular nodes (two patients) and contralateral parotid gland involvement (one patient). The treatment administered included primary enucleation (n = 1), high-dose intravenous chemotherapy (n = 4), secondary enucleation (n = 2), orbital external beam radiotherapy (n = 3), and intrathecal chemotherapy (n = 1). High-risk features included massive choroidal and microscopic scleral infiltration in the eye that underwent primary enucleation. At a mean follow-up of 33 months (range, 4-68 months), one patient with CSF involvement deceased in 4 months. The remaining three patients were alive and disease-free at the last mean follow-up period of 43 months (range, 18-68 months). The results of our study showed that RLN and BM metastasis respond well to treatment while CSF metastasis is associated with poor prognosis.

Ultrathin, biodegradable polymer-coated everolimus-eluting stents for patients undergoing percutaneous coronary intervention: Final three-year results of the PERFORM-EVER registry.

The registry reports 3-year safety and clinical performance of the ultrathin strut (60 µm) biodegradable polymer-coated Tetrilimus, an everolimus-eluting stent (EES) (Sahajanand Medical Technologies Limited, India), in 'real-world' patients with coronary artery disease. A total of 815 Tetrilimus EES were implanted in 735 lesions in 594 patients. At 3-year follow-up, primary endpoint (target lesion failure, TLF) was reported in 8.6 % patients, including 2.6 % cardiac deaths, 3.5 % myocardial infarction and 2.6 % target lesion revascularization. At three-year, no cases of definite stent thrombosis were reported. The final three-year results of PERFORM-EVER registry endorse the continuous safety and effectiveness Tetrilimus EES.

A Case Report Of "Synovial Chondromatosis Of Elbow" Treated With Synovectomy.

Introduction: Synovial chondromatosis is a rare non- malignant bone tumor. Most commonly middle aged people are affected . This condition most commonly occurs in knee joints, and rarely, it may occur in other joints. Patient usually complaints of pain, swelling and restrictions of movements at the affected joint. Diagnosis is made through thorough clinical examination and Radiological investigation. Condition is treated with open synovectomy with the removal of loose bodies. If not treated in time the patient might develop early osteoarthritic changes and rarely develop into malignancy in few cases. Case Report: A 43 year old female came with complaints of pain and stiffness over the right elbow which aggravates on movements without alleged history of trauma. The patient was diagnosed with synovial chondromatosis after appropriate radiological investigation. The patient underwent open synovectomy and post operatively adequate physiotherapy was initiated at the operated elbow. After 6 months of follow-up, the patient improved clinically and functionally. Conclusion: Synovial chondromatosis of the elbow is a rare benign orthopedic condition that appears as multiple hyaline cartilage nodules within sub synovial connective tissue. Complete excision of synovium is necessary to prevent the recurrence and for better clinical outcome.

Negative impact on bone homeostasis in postmenopausal women with non-metastatic breast cancer during cytotoxic chemotherapy.

INTRODUCTION: The burden and mechanisms of endocrine therapy-related bone loss are well known, while there are limited data on chemotherapy-induced bone resorption. The study aimed to evaluate the effect of cytotoxic chemotherapy on bone homeostasis among postmenopausal women with non-metastatic breast cancer. MATERIALS AND METHODS: Early and locally advanced postmenopausal non-metastatic breast cancer patients aged 45 to 65 planned for three cycles of anthracycline and four cycles of taxane chemotherapy administered along with dexamethasone (cumulative dose-256 mg) as an antiemetic from June 2018 to December 2021 were included. Bone mineral density (BMD), bone turnover markers, calciotropic hormones, pro-inflammatory cytokines, oxidative stress, and total antioxidant levels (TAS) were measured. RESULTS: We recruited 109 patients, with early 34 (31.2%) and locally advanced breast cancer 75 (68.8%) with median age 53 (45-65) years. There was a significant decrease in the % BMD at the lumbar spine, neck of the femur, and total hip post-chemotherapy. There was a significant increase in serum C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels post-chemotherapy. PINP/CTX ratio significantly decreased post-chemotherapy. Serum 25-OH vitamin D was significantly reduced with a compensatory increase in plasma iPTH levels. The change in CTX, PINP/CTX ratio, 25-OH vitamin D, iPTH, and oxidative stress index was more pronounced during anthracycline as taxane chemotherapy. There were no significant changes in pro-inflammatory cytokine levels. CONCLUSION: Chemotherapy and dexamethasone as antiemetic resulted in significant bone loss, as evidenced by bone turnover markers. Further studies are required to understand the mechanism of chemotherapy-induced bone loss and the need for bone-strengthening agents during chemotherapy.

Acute Portal Vein Thrombosis as an Initial Presentation of Protein C Deficiency: A Case Report.

Protein C (PC) is an essential vitamin K-dependent protein that regulates thrombosis and hemostasis in the body. A mutation in the PROC gene on chromosome 2q14.3 results in PC deficiency. The clinical presentation of PC deficiency can vary, ranging from a single vein thrombosis to disseminated intravascular coagulation, purpura fulminans, or even life-threatening complications such as sepsis. Here, we present a case of a 37-year-old female who was found to have acute portal vein thrombosis as an initial presentation of PC deficiency. She presented to the hospital with acute onset of abdominal pain associated with nausea, blood-streaked emesis, and bloody bowel movement.

Plaque brachytherapy - Radiating positivity.

Background: Plaque brachytherapy is an evolving, yet effective globe and vision-sparing modality for the treatment of intraocular tumors by transscleral irradiation of the tumor base with a radioactive implant. The American Brachytherapy Society (ABS) along with the collaboration of the international multicenter Ophthalmic Oncology Task Force (OOTF) was assembled to reach a consensus regarding establishing practice guidelines and setting standards of care for intraocular tumors. The advent of plaque brachytherapy has revolutionized the outcomes of intraocular tumors, thus ensuring globe salvage, reducing morbidity and mortality, and avoiding cosmetic disfigurement. A well-planned dosimetry for plaque brachytherapy results in achieving local tumor control and excellent prognosis. Purpose: This technique provides the advantage of focal radiation, thus eliminating the damage to the adjacent structures, minimal periorbital tissue damage, absence of cosmetic disfigurement owing to lack of retarded bone growth as seen in external beam radiotherapy. Thus, it reduces the risk of metastasis, and with the recent advances, it provides a shorter duration of treatment. Synopsis: : In this video, we shall display the concept of plaque brachytherapy, the various types of plaques available, different radiations sources, planning dosimetry and calculations, target disease spectrum, surgical placement, and post-radiation outcomes in terms of local tumor control and prognosis. Highlights: This video highlights the history, basic principles and techniques of plaque brachytherapy and provides an understanding of its applications in the world of ocular oncology. Video link: https://youtu.be/7PX0mDQETRY.

Brachytherapy training in India: Results from the GEC-ESTRO-India survey.

INTRODUCTION: Brachytherapy (BT) is integral in treatment of gynecological malignancies and is also an option for many other cancers. Data on training and proficiency levels of early career oncologists is limited. Like other continents a survey was conducted for early career oncologists in India. METHODS AND MATERIALS: An online survey was conducted from November 2019 to February 2020, through Association of Radiation Oncologists of India (AROI) for early career radiation oncologists expected to be within 6 years of training. The survey used a 22 item questionnaire that was also used for European survey. Responses to individual statements were recorded on a 1-5 Likert-type scale. Descriptive statistics were used to describe proportions. RESULTS: One-hundred twenty-four (17%) of 700 recipients responded to the survey. Majority of the respondents (88%) stated that being able to perform BT at the end of their training was important. Two-thirds of the respondents (81/124) had performed >10 intracavitary procedure and 22.5% had performed >10 intracavitary-interstitial implants. Many respondents had not performed nongynecological procedure- breast (64%), prostate(82%), gastro-intestinal (47%). Respondents predicted that in next 10 years, the role of BT is likely to increase. Lack of dedicated curriculum and training was perceived as the greatest barriers to achieving independence in BT (58%). Respondents suggested that BT training should be prioritized during conferences (73%) and online teaching modules (56%), along with development of BT skills labs (65%). CONCLUSION: This survey identified a lack of proficiency in gynecological intracavitary-interstitial brachytherapy and non-gynecological brachytherapy, despite BT training being regarded as highly important. Dedicated programs, including standardized curriculum and assessment need to be developed for training early- career radiation oncologists in BT.

A Multi-centric retrospective study into the epidemiological distribution of breast cancer patients in India.

BACKGROUND: A multicentric private hospital-based retrospective study was conducted to understand the epidemiology of breast cancer in terms of demographics and clinical characteristics (staging and hormone receptor status) at the time of diagnosis. METHODS: The data for 5,688 female breast cancer patients were collected from the hospital and clinical records of four study centres. All statistical analysis was performed using Microsoft Excel 2016 and R software. Survival was estimated by the Kaplan-Meier method and compared by the log-rank test. A P value of <.05 was considered statistically significant. RESULTS: The mean and median age of the study population was 52.6 (± 12.4) years and 53.0 (range 51-54 across the four centers) years, respectively. About 68% of patients were in the age category of 41 65 years, 17.6% were <40 years old among whom 23.4% of patients reported a positive family history. Most of the patients (66.3%) were diagnosed at an early stage (Stage I and II). The 3-year OS probability was 100%, 97.5%, 94.1%, and 74.7% for TNM Stages I, II, III, and IV, respectively. The 3-year RFS was 95.7%, 95.5%, 84.5%, and 49% for TNM Stages I, II, III, and IV, respectively. CONCLUSION: The present study highlights the epidemiological distribution of breast cancer patients. It emphasizes the importance of disease awareness among the urban and educated female population as most patients were diagnosed at earlier stages and demonstrated higher OS and RFS than reported in government registries.

Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes.

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist 12 (MK-1462), which was advanced into clinical trials.

Discovery of Insulin/GLP-1/Glucagon Triagonists for the Treatment of Diabetes and Obesity.

The combination of insulin and incretin-based therapies has emerged as a potential promising tactic for the treatment of diabetes. Here we report the first example of a unimolecular triagonist to simultaneously target insulin, GLP-1, and glucagon receptors, aiming for better glycemic control and superior weight loss. The strategy for constructing such a unimolecular triagonist is the conjugation of the insulin moiety and GLP-1R/GCGR coagonist peptide via alkyne-azide click chemistry. Two tractable series differentiated by insulin conjugation sites, B1F and B29K, were identified. Triagonist 13 prepared through the conjugation at insulin B1F and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity comparable to that of insulin degludec and potent and balanced GLP-1R and GCGR activities. Pharmacokinetic profiles of 13 in both rat and minipig were also discussed.

Development and validation of an LC-MS/MS method for determination of a novel anticancer agent (CPI-613) in human plasma.

Background: This article describes the development and validation of a bioanalytical assay to quantify CPI-613 and its major metabolites, CPI-2850 and CPI-1810, in human plasma matrix using LC-MS/MS. Methodology: Sample extraction procedure following protein precipitation with acetonitrile was optimized to extract all three analytes from plasma with maximum recovery. The final extracted supernatants were diluted with water and injected onto an Xbridge C18 (50 × 2.1 mm; 5 µm) column for analysis. The analytes were separated by a gradient elution, and detection was performed on a triple quadrupole mass spectrometer (Sciex API 5000) operating in the negative ion mode. Results: The assay was linear over a range of 50-50,000 ng/ml for CPI-613, 250-250,000 ng/ml for CPI-2850 and 10-10,000 ng/ml for CPI-1810. Benchtop stability was established for 24 h, and four freeze-thaw cycles were evaluated for CPI-613 and its metabolites. Long-term freezer (-60 to -80°C) stability for about 127 days was established in this validation. Mean matrix recovery was more than 80% for all analytes. Conclusion: A robust LC-MS/MS method was developed for the quantification of CPI-613 and its major metabolites. The current assay will be used to support ongoing and future CPI-613 clinical trials.

To achieve the pharmacokinetic objectives of clinical trials, it was necessary to determine the concentrations of CPI-613 and its metabolites in human plasma samples. In this article, the authors describe the development and validation of a highly sensitive and selective LC-MS/MS assay method for the simultaneous quantification of CPI-613 and its major metabolites, CPI-2850 and CPI-1810, in human plasma. Concentration ranges were selected based on previous data where CPI-613 was detected using the HPLC method (rather than LC-MS/MS).

A Case of Advanced Non-Small-Cell Lung Cancer With Response to Alectinib and Favorable Quality of Life.

Lung cancer is the leading cause of cancer death globally and in the United States. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. A progressive increase in morbidity and mortality is seen with advanced disease. Identifying specific driver mutations, such as anaplastic lymphoma kinase (ALK) mutations and directed therapy, has improved the quality of life and survival in ALK-positive NSCLC patients. Here, we present the case of a 37-year-old female who was diagnosed with stage IV NSCLC (adenocarcinoma) with a positive ALK mutation six years ago. Our case report highlights a rare ALK mutation NSCLC treated with targeted ALK inhibitor therapy. Despite having advanced-stage cancer, the treatment significantly impacted her survival with an improved quality of life.