Hemolytic Anemia and Pancytopenia Secondary to Vitamin B12 Deficiency: Evaluation and Clinical Significance.

Severe vitamin B12 deficiency presents a diagnostic challenge due to its diverse clinical manifestations, which can mimic serious hematologic disorders such as thrombotic thrombocytopenic purpura (TTP) or leukemia. The case we present here illustrates the unique characteristics of severe B12 deficiency, highlighting key differentiators from other conditions, including decreased reticulocyte counts and markedly elevated lactate dehydrogenase levels indicative of suppressed erythropoiesis. Advanced cobalamin deficiency affects all cell lines, leading to peripheral pancytopenia. Proposed mechanisms include fragile red blood cells prone to shearing, resulting in schistocyte formation, and hyperhomocysteinemia-induced oxidative stress exacerbating hemolysis. Prompt recognition and treatment with B12 replacement are critical, as illustrated by this case of hemolytic anemia and pancytopenia secondary to pernicious anemia, to prevent severe hematologic complications.

Hydrogen peroxide bladder irrigation: A simple, safe and effective management option for clot retention.

While the historical benefits of hydrogen peroxide on wounds and wound healing have recently been questioned, physicians have started to explore its other potential medicinal benefits. We present a case of a 14-year-old girl who presented to our urology unit with macroscopic haematuria and clot retention. Ultrasonography confirmed a large organised intravesical blood clot. Despite numerous attempts, manual bladder irrigation was unsuccessful and caused significant discomfort to the patient. Her clot retention was relieved after 4 irrigation cycles with a 3 % hydrogen peroxide solution. She experienced no complications or side effects post intravesical instillation of hydrogen peroxide.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer.

BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gynecologic cancer.

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer.

Cytomegalovirus haemorrhagic cystitis in a pregnant patient with AIDS.

Cytomegalovirus (CMV), an AIDS defining disease, has a high seroprevalence in the general population, while symptomatic infections occur mostly in immunocompromised individuals. Symptomatic CMV infections commonly include pneumonia, encephalitis, retinitis and colitis, while urinary tract involvement is a rare entity. We present a rare case of massive macroscopic haematuria due to CMV haemorrhagic cystitis in a 29-year-old woman in her second trimester of pregnancy. She was treated with intravenous Ganciclovir after initial resuscitation, and her symptoms promptly resolved. Timely diagnosis and treatment of symptomatic CMV infection is necessary to prevent associated morbidity, and this is especially significant during pregnancy in order to prevent foetal transmission. Both our patient and her baby remained symptom free at the 6-month follow-up post-delivery. Clinicians should have a high index of suspicion to biopsy the bladder urothelium of at-risk patients who present with haemorrhagic cystitis and have non-specific cystoscopy findings as histopathological analysis is the mainstay of diagnosing CMV-cystitis.

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

BACKGROUND: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. METHODS: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. RESULTS: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy. CONCLUSIONS: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).

A Real World Perspective of PARP Inhibitor Use in Gynecological Cancer Patients.

Introduction: Over the last few years, targeted therapy has become the mainstay maintenance treatment of patients with ovarian cancer including patients with BRCA1/BRCA2 mutations. Poly ADP ribose polymerase inhibitors (PARPi) are effective in the treatment of patients who are in complete or partial remission. PARPi are known to cause hematological adverse events (AEs), but have not been compared directly to each other. Objective: Primary objective was to compare the incidence of hematological and non-hematological AEs associated with the use of PARPi. Methods: This was a single institution, retrospective study evaluating patients who were treated with PARPi for ovarian cancer from January 2017 to October 2020. Patients were stratified according to which PARP inhibitor they received. Results: Ninety-two patients were included in final analysis. Thirty-one (33.7%) patients received niraparib and 61 (66.3%) patients received olaparib. Median age of patients were 64.3 (range, 33.8 to 92.3) years, 66 (71.7%) were white, and 84 (91.3%) had an ECOG PS of 0/1. Patients in the niraparib group experienced a higher rate of hematologic AEs, with 11 (35.5%), 20 (64.5%), and 18 (58.1%) experiencing neutropenia, anemia, and thrombocytopenia, respectively. Eight (13.1%), 24 (39.3%), and 16 (26.2%) patients in the olaparib group experienced neutropenia, anemia, and thrombocytopenia, respectively. Conclusion: This single institution retrospective study outlines the hematological toxicities observed between two PARPi. Our results suggested that niraparib tended to be associated with a higher risk for hematologic toxicities than olaparib. Anemia was the most common hematologic toxicity which was consistent with what has been widely documented in the literature.

Olaparib-Induced Immune-Mediated Liver Injury.

Immune-mediated drug-induced liver injury can be triggered by multiple classes of medications including immunotherapies. Olaparib is a first-in-class oral inhibitor of poly (adenosine diphosphate-ribose) polymerase (an enzyme involved in DNA replication and repair) that is approved as maintenance treatment in platinum-sensitive, epithelial ovarian, tubal, or primary peritoneal cancers with breast cancer 1/2 mutation. We report the first case in the United States of an acute and severe liver injury with associated jaundice and liver synthetic dysfunction secondary to olaparib. The liver injury was resolved with drug cessation and treatment with prednisone taper.

Clinical Implications of Genomic Loss of Heterozygosity in Endometrial Carcinoma.

PURPOSE: Homologous recombination deficiency, identified by homologous recombination deficiency gene alterations or high percentage of genome-wide loss of heterozygosity (gLOH), is associated with improved prognosis, platinum sensitivity (PS), and poly (ADP-ribose) polymerase inhibitor response in high-grade ovarian cancer. Since the copy number-high (CN-H) endometrial cancer molecular subtype (EC-MS) shares molecular features with high-grade ovarian cancer, our aim was to assign EC-MS on the basis of comprehensive genomic profiling (CGP) results and evaluate the gLOH status with clinical behavior of EC. METHODS: Eighty-two epithelial EC tumor tissues were sequenced by hybrid capture-based CGP, and results were used to assign EC-MS (ultramutated, microsatellite instability-high, CN-low; CN-high). Retrospective chart review established clinical characteristics, including PS. Relationships of PS, EC-MS, gene alterations, and gLOH were assessed statistically. RESULTS: PS and EC-MS of CN-H showed statistically significant difference in overall survival (OS). Most notably, when the CN-H EC-MS was subcategorized by gLOH status, there was a significant difference in OS with gLOH-H being associated with longer survival. Cox semi-proportional hazard modeling showed that gLOH, stage, and race were significant in modeling OS. CONCLUSION: The method of assigning EC-MS by CGP demonstrates similar clinical features to previous reports of EC-MS assigned by other methods. CGP can also assess gLOH status with gLOH-H most commonly seen in CN-H tumors. CN-H, gLOH-H patients showed significantly improved OS (hazard ratio, 0.100 [0.02-0.51 95% CI]). Thus, gLOH status may be a meaningful prognostic biomarker within the CN-H tumors and possibly across EC-MS.

Malignant struma ovarii with late recurrence harbouring high microsatellite instability.

Struma ovarii (SO) is a rare ovarian teratoma containing abundant mature thyroid tissue. Malignant transformation is even less common and distant metastasis is documented in about 5%-10%. The time from diagnosis of primary SO to metastatic disease varies. As malignant SO is rare, there are no uniform diagnostic criteria or treatment guidelines. Management is usually extrapolated from that of thyroid malignancy. We report a patient who relapsed 12 years from the initial diagnosis and metastasised to the lungs 5 years after the first recurrence. Our patient was treated with total thyroidectomy followed by radioactive iodine, and retreated on progression in the lungs. The tumour harboured high microsatellite instability and treatment with programmed cell death protein 1 inhibitor was initiated. This case shows the long latency of SO with the rare phenomenon of metastasis. It also highlights the importance of molecular testing for rare cancers such as this.

Bi-specific and tri-specific antibodies- the next big thing in solid tumor therapeutics.

Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin's Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come.

Metastatic Malignant Ovarian Steroid Cell Tumor: A Case Report and Review of the Literature.

We report a case of malignant ovarian steroid cell tumor not otherwise specified (NOS) in a 47-year-old female who presented with hirsutism, virilization, and amenorrhea. At the time of laparotomy, the tumor had already spread to the pelvic cul-de-sac. She underwent a total hysterectomy, bilateral salpingo-oophorectomy, and tumor resection with no residual disease. She received three cycles of bleomycin, etoposide, and cisplatin (BEP) and is now free of disease 24 months after surgery. Literature review of ovarian steroid cell tumors NOS including clinicopathological features and clinical management was performed.

Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer.

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.

Percutaneous insertion of peritoneal ports.

OBJECTIVE: To describe a technique for image-guided percutaneous insertion of peritoneal ports in patients without ascites who have undergone surgical debulking for stage III ovarian cancer. MATERIALS AND METHODS: Between 2006 and 2010, 29 intraperitoneal ports were placed percutaneously in 29 patients who presented after debulking surgery for stage III ovarian cancer. Ultrasound and fluoroscopy guidance were used to assist in the port placement. RESULTS: We demonstrated a technical success rate of 100% in 29 patients. The ports remained in place for an average of 186 days; and during that time, only 2 complications (6.9%) arose. One patient presented with kinking and looping of the catheter/port reservoir connection, and the redundant loop was removed. The other patient presented with a suspected wound infection over the port pocket, and the port was removed. CONCLUSIONS: Placement of percutaneous intraperitoneal ports is feasible with an acceptably low complication rate of 6.9% in patients without abdominal ascites.

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines.

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5'DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.

Hyperparathyroidism accompanying multiple myeloma.

Hypercalcemia is a manifestation of a variety of both benign and malignant diseases. These conditions are not mutually exclusive, and we present a case report of a patient first diagnosed with the classic findings of multiple myeloma who, after appropriate therapy, demonstrated persistent hypercalcemia and was found on further testing to have an elevated parathormone level (PTH) and scintigraphic evidence of a benign parathyroid adenoma. Hypercalcemia responded to excision of the parathyroid adenoma. There are only 18 similar cases reported in the medical literature.

Pharmacological factors influencing anticancer drug selection in the elderly.

Persons over the age of 65 years are the fastest growing segment of the US population. In the next 30 years this segment will represent more than 20% of the population. Fifty percent of all cancers occur in this age group and therefore the total cancer burden is expected to rise. Data are becoming available that will better guide the use of chemotherapy in the older patient population. Studies are presented discussing pharmacokinetic data on a number of chemotherapeutic agents with an emphasis on those that have entered clinical practice over the past few years. Many of these agents seem to have a beneficial therapeutic index, particularly in regard to older patients. Aging can affect the pharmacokinetics of chemotherapy in a number of ways. Absorption is only modified minimally by age. The greater concern with the use of oral drugs is patient compliance. Volume of distribution is affected by changes in body composition, anaemia and decreased plasma albumin concentration. There are many drugs in which renal excretion plays an important role. Decline in glomerular filtration is a consistent phenomenon with aging. Drug metabolism is primarily affected by changes in the P450 system and coadministration of drugs which also interact with this important enzyme system. The selection of chemotherapy in the elderly is frequently determined by degree of comorbidity and the patients' functional status. These factors are critical and can often determine response and toxicity. This article discusses the changes that occur with antimetabolites, camptothecins, anthracyclines, taxanes, platinum compounds, epipodophyllotoxins and vinca alkaloids. There has also been an increasing trend toward the use of oral chemotherapy. Factors that must be considered in selecting chemotherapeutic agents include limitations of saturability of absorption, patient compliance and the pharmacokinetic and pharmacodynamic changes that occur in older patients. Interpatient variability and age-related changes in drug metabolism are discussed. Careful attention to the physiological changes with age and dose adjustments necessary for end-organ dysfunction (renal, hepatic) are needed to ensure the safe administration of chemotherapy. In this article specific diseases are discussed (breast, colon, ovarian and non-small lung cancers) with recommendations for drug selection in adjuvant chemotherapy and the treatment of metastatic disease. Future studies will need to incorporate these various factors to properly evaluate chemotherapy in older patients. Research and educational initiatives targeted to this population will need to be a priority.