A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

BACKGROUND: Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. METHODS: This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. RESULTS: The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. CONCLUSION: Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Phase I Trial of Combination Therapy With Avelumab and Cabozantinib in Patients With Newly Diagnosed Metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND: Combination immunotherapy is now considered the standard first-line therapy for patients with metastatic clear cell renal cell carcinoma (mccRCC) after multiple clinical trials demonstrated improved overall survival compared with single-agent tyrosine kinase inhibitors. Cabozantinib modulates critical components of the immune system, such as decreasing regulatory T cells and increasing T-effector cell populations, and is approved for the treatment of mRCC. Avelumab is a human IgG1 monoclonal antibody that binds to programmed death-ligand 1 protein and inhibits the interaction with PD-1. This phase I trial assessed the safety and clinical activity of avelumab and cabozantinib combination therapy in mccRCC. METHODS: This study was a phase I, 3+3 dose escalation clinical trial. The primary endpoint was the safety and identification of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and radiographic progression-free survival (rPFS). There were 3 dose cohorts: cabozantinib 20, 40, and 60 mg/day, each combined with avelumab (10 mg/kg intravenously every 2 weeks). An additional 3 patients were included in the final dose cohort as a confirmation of the RP2D. No dose modifications were allowed for avelumab, but dose delays were permitted. Both dose reductions and holds were allowed for cabozantinib. Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was used to determine ORR, and treatment beyond progression was allowed. RESULTS: Twelve patients with newly diagnosed mccRCC were enrolled from July 2018 until March 2020. Three patients were enrolled in the 20 and 40 mg cohorts each, and 6 were enrolled in the 60 mg cohort. The International Metastatic RCC Database Consortium (IMDC) risk categories for these patients were: 4 patients (favorable risk), 6 patients (intermediate risk), and 2 patients (poor risk). No dose-limiting toxicities (DLTs) were observed in any cohort. Six patients developed serious adverse events related to study treatment after the DLT window period. Immune-related adverse events (iRAEs) were reported in 11 patients; fatigue and diarrhea were the most common (each with n = 4, 33.3%), followed by maculopapular rash and hand-foot syndrome (each with n = 3, 25%). Dose reductions were required in 5 of 6 patients in the cabozantinib 60 mg cohort after the DLT period. One patient discontinued avelumab due to irAE (nephritis), while none discontinued cabozantinib due to toxicity. The ORR was 50%, with one complete response (CR) and 5 partial responses (PR). The disease control rate (CR + PR + stable disease) was noted in 92% of the patients. Radiological PFS survival rate at 6 and 12 months was reported in 67.7% and 33.5% of patients, respectively. CONCLUSION: Combination therapy with avelumab and cabozantinib is safe and showed preliminary clinical activity in mccRCC. Even though the DLT was not met in any of the 3 cohorts, the recommended RP2D dose for the combination is cabozantinib 40 mg/day due to a high incidence of grade 2 toxicity for cabozantinib 60 mg/day after the DLT period. (ClinicalTrials.gov Identifier: NCT03200587).

Understanding the EKG changes in methemoglobinemia.

Methemoglobin is a form of hemoglobin that has been oxidized, changing its heme iron configuration from the ferrous to the ferric state. Unlike normal hemoglobin, methemoglobin does not bind oxygen and as a result, cannot deliver oxygen to the tissues. At the presentation in the emergency department, an electrocardiogram (EKG) is usually performed as a reflex for patients admitted for shortness of breath to rule out acute coronary syndrome. Very limited data is available on EKG abnormalities in patients with methemoglobinemia. In this study, we retrospectively analyzed the pattern of EKG changes in patients with methemoglobinemia.

Real-world experience of anti-D immunoglobulin in immune thrombocytopenia.

In developing countries, anti-D has been used in immune thrombocytopenia (ITP) as a cheaper alternative to human immunoglobulin. We aim to analyze the response and safety profile of anti-D in patients with severe ITP. A retrospective study was conducted at a tertiary care hospital in Northern India. Patients received a single intravenous infusion of 75 µg/kg anti-D. In total, 36 patients (20 females) were included in this study. The median duration from ITP diagnosis to anti-D therapy was 235 days (range 1-1613 days). Four (11.1%) patients received anti-D as an upfront treatment. The patients' platelet counts rose significantly by the end of day three and continued to be significantly high until day 30 of receiving anti-D (p ≤ 0.001). The overall response rate (ORR) by day seven was 88.89%. There was no effect of age, sex, duration of disease, prior therapy, and platelet count on the ORR. Patients were followed up for a median duration of 52 days (longest follow-up: 3080 days). Six (6/36, 16.67%) patients continued to be in remission till the last follow-up. The hemoglobin fall was statistically significant on day three and day seven (p < 0.001 and p = 0.001) and got normalized by day 30. We observed equally good ORR in mixed populations and different phases of ITP along with long-term sustained response. The study demonstrates a quick and high response rate along with good safety profile to anti-D in all forms of ITP.

COVID-19 related immune hemolysis and thrombocytopenia.

The current pandemic due to coronavirus disease 2019 (COVID-19) has posed an unprecedented challenge for the medical communities, various countries worldwide, and their citizens. Severe acute respiratory syndrome coronavirus 2 has been studied for its various pathophysiological pathways and mechanisms through which it causes COVID-19. In this study, we discussed the immunological impact of COVID-19 on the hematological system, platelets, and red blood cells.

Coagulopathy, endothelial dysfunction, thrombotic microangiopathy and complement activation: potential role of complement system inhibition in COVID-19.

Coronavirus disease-2019 (COVID-19) is a rapidly evolving health crisis caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a novel disease entity and we are in a learning phase with regards to the pathogenesis, disease manifestations, and therapeutics. In addition to the primary lung injury, many patients especially the ones with moderate to severe COVID-19 display evidence of endothelial damage, complement activation, which leads to a pro-coagulable state. While there are still missing links in our understanding, the interplay of endothelium, complement system activation, and immune response to the SARS-CoV-2 virus is a surprisingly major factor in COVID-19 pathogenesis. One could envision COVID-19 becoming a novel hematological syndrome. This review is to discuss the available literature with regards to the involvement of the complement system, and coagulation cascade and their interaction with endothelium.

Treatment of Patients with Mental Illness Amid A Global COVID-19 Pandemic.

A newly discovered coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing pandemic of coronavirus disease 2019 (COVID-19), which is not only physically challenging but also has many subtle and overt mental impacts. The concern of being infected, lack of antiviral agents, preventive strategies of social distancing, and home isolation have created unrest in the society. The way of reacting to emergencies varies from individual to individual, and that this variability lies in our unique personality traits. The COVID-19 pandemic is testing the mental stability of all of us, and hence it is crucial to recognize the vulnerable population and support them to prevent or minimize the catastrophe like post-traumatic stress disorder (PTSD), emotional trauma, and suicides. In this context, the role of psychiatrists, psychotherapists, and other mental healthcare providers is indispensable.

Challenges of Cellular Therapy During the COVID-19 Pandemic.

Currently, coronavirus disease 2019 (COVID-19) has spread worldwide and continues to rise. There remains a significant unmet need for patients with hematological malignancies requiring specialized procedures and treatments, like cellular therapy to treat or cure their disease. For instance, chimeric antigen receptor T (CAR-T) cell therapy is approved for relapsed/refractory (after two or more lines of therapy) diffuse large B cell lymphoma and B cell acute lymphoblastic leukemia that is refractory or in the second relapse in patients younger than 25 years of age. Similarly, hematopoietic stem cell transplantation (HSCT) can be a lifesaving procedure for many patients, such as those with acute myeloid leukemia with high-risk cytogenetics. Unfortunately, the COVID-19 pandemic has thrust upon the hematologists and transplant specialists' unique challenges with the implementation and management of cellular therapy. One of the significant concerns regarding this immunocompromised patient population is the significant risk of acquiring SARS-CoV-2 infection due to its highly contagious nature. Experts have recommended that if medically indicated, especially in high-risk disease (where chemotherapy is unlikely to work), these lifesaving procedures should not be delayed even during the COVID-19 pandemic. However, proceeding with CAR-T cell therapy and HSCT during the pandemic is a considerable task and requires dedication from the transplant team and buy-in from the patients and their family or support system. Open conversations should be held with the patients about the risks involved in undergoing cellular therapies during current times and the associated future uncertainties.

COVID-19 in Patients with Cancer.

With more than 5 million cases and 333,212 deaths, COVID-19 (or SARS-CoV-2) continues to spread. General symptoms of this disease are similar to that of many other viral respiratory diseases, including fever, cough, dyspnea, and fatigue, with a chance of progression to more severe complications. However, the virus does not affect all people equally, and cases with comorbidities such as malignancies, cardiovascular diseases, respiratory diseases, and kidney diseases are at higher risk of developing severe events, including requiring intensive ventilation, intensive care unit (ICU) admission, and death. Patients with cancer are more likely to be infected with COVID-19, which is possibly due to their immunological dysfunction or frequent clinic visits. Also, there is a higher chance that these patients experience severe events because of the medication they receive. In this chapter, we will review the main clinical manifestations of COVID-19 in patients with cancer. Recommendations and challenges for managing resources, organizing cancer centers, treatment of COVID-19-infected cancer patients, and performing cancer research during this pandemic will also be discussed.

A challenging case of esophageal perforation.

Esophageal perforation is a fatal entity if not diagnosed in a timely fashion. Once diagnosed, it requires collaborative effort of team of doctors including radiologists, thoracic surgeons and general surgeons. We share hereby our experience with esophageal perforation and successful outcome.

COVID-19 and clinical mimics. Correct diagnosis is the key to appropriate therapy.

As of 29 April 2020, across the globe, there are 3,216,353 confirmed Coronavirus disease 2019 (COVID-19 disease) with 227,894 deaths. The health care infrastructure of most of the countries is overwhelmed due to the gigantic upsurge of the new cases within a short time period. Most of the beds in the regular wards and critical care units are currently occupied by either people under investigation (PUI) or COVID-19 confirmed cases. We hereby discuss the challenges faced while approaching any case of shortness of breath, or other common upper respiratory symptoms during the current COVID-19 pandemic era.

Quantifying and reporting cardiac findings in imaging of COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a public health emergency and a pandemic of international concern. As of April 31st,  the reported cases of COVID-19 are three million in 186 countries. Reported case fatality has crossed 200 thousand among which more than fifty thousand has been in the USA. Most patients present with symptoms of fever, cough, and shortness of breath following exposure to other COVID-19 patients. Respiratory manifestations predominate in patients with mild, moderate, severe illness. Imaging of patients with COVID-19 consistently reports various pulmonary parenchymal involvement. In this article we wanted to reinforce and review the various reported imaging patterns of cardiac and mediastinal involvement in COVID-19 patients. Among patients with COVID 19 who underwent various imaging of chest various cardiac findings including pericardial effusion, myocarditis, cardiomegaly has been reported. Most of these findings have been consistently reported in patients with significant acute myocardial injury, and fulminant myocarditis. Acute biventricular dysfunction has also been reported with subsequent improvement of the same following clinical improvement. Details of cardiac MRI is rather limited. In a patient with clinical presentation of acute myocarditis, biventricular myocardial interstitial edema, diffuse biventricular hypokinesia, increased ventricular wall thickness, and severe LV dysfunction has been reported. Among patients with significant clinical improvement in LV structure and function has also been documented. With increasing number of clinical cases, future imaging studies will be instrumental in identifying the various cardiac manifestations, and their relation to clinical outcome.

COVID-2019: update on epidemiology, disease spread and management.

With each passing day, more cases of Coronavirus disease (COVID-2019) are being detected and unfortunately the fear of novel corona virus 2019 (2019-nCoV) becoming a pandemic disease has come true. Constant efforts at individual, national, and international level are being made in order to understand the genomics, hosts, modes of transmission and epidemiological link of nCoV-2019. As of now, whole genome sequence of the newly discovered coronavirus has already been decoded. Genomic characterization nCoV-2019 have shown close homology with bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21. Structural analysis of the receptor binding site has confirmed that 2019-nCoV binds with the same ACE 2 receptor protein as human SARS virus. Compared to the previous coronavirus outbreaks, the overall mortality rate is relatively low for COVID-2019 (2-3%). Suspected cases must be quarantined till their test comes positive or they clear infection. At present, treatment of COVID-2019 is mostly based on the knowledge gained from the SARS and MERS outbreaks. Remdesivir, originally develop as a treatment for Ebola virus disease and Marburg virus infections, is being studied for it effectiveness against 2019-nCoV infection. Many other antiviral agents and vaccines are being tested but most of them are in phase I or II and hence unlikely to be of any benefit immediately with regards to current outbreak. Hence, the standard infection control techniques and preventive steps for healthy individuals and supportive care for the confirmed cases is the best available strategy to deal with current viral outbreak. .

COVID-19 and restrictive lung disease: A deadly combo to trip off the fine balance.

Coronavirus Disease (COVID-19) pandemic has so far led to innumerable deaths worldwide. The risk factors so far that have been most studied as poor prognostic factors are old age, individuals with multiple comorbidities and immunocompromised patients. Amongst the chronic lung diseases, most patients with COVID-19 reported so far had asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease. Herein, we discuss the significance of restrictive lung disease during the COVID-19 pandemic as a potential risk factor via an example of a patient with kyphoscoliosis who succumbed to death due to COVID-19 pneumonia.

Cerebrovascular events in COVID-19 patients.

Neurological manifestations in patients with COVID-19 are more frequently being reported. Cerebrovascular events have been reported in around 3% of patients. In this review we summarize the published literature on cerebrovascular events in patients with COVID-19 as available on the PubMed database. So far, 3 studies have reported cerebrovascular events. Cerebrovascular events were identified on screening patients with decreased consciousness or in the presence of focal neurological deficits. These events were common in elderly, critically ill patients and in patients with prior cardio-cerebrovascular comorbidities. The diagnosis of cerebrovascular events was confirmed with computed tomography of the brain in most studies reporting neurological events. Multiple pathological mechanisms have been postulated regarding the process of neurological and vascular injury among which cytokine storm is shown to correlate with mortality. Patients with severe illness are found to have a higher cardio- cerebrovascular comorbidity. With an increasing number of cases and future prospective studies, the exact mechanism by which these cerebrovascular events occur and attribute to the poor outcome will be better understood.

Methemoglobinemia in a Case of Paint Thinner Intoxication, Treated Successfully with Vitamin C.

BACKGROUND: Methemoglobin (MetHb) is an oxidized form of hemoglobin. It is a poor transporter of oxygen and is unable to deliver oxygen to the tissue. Globally, drug & toxin induced methemoglobinemia is more common as compared with the congenital form. Methemoglobinemia caused by paint thinner intoxication is rare. Methylene blue is well established as the first-line therapy for severe methemoglobinemia. CASE REPORT: A 25-year old man was brought to the Emergency Department after accidental consumption of paint thinner. On clinical examination, he had cyanosis and there were discrepancies in his pulse oximetry and arterial blood gas (ABG) analysis results. With this clue and supporting laboratory investigations, the diagnosis of toxin-induced methemoglobinemia was made. Due to the unavailability of methylene blue, alternative treatment with high-dose vitamin C was attempted, to which the patient responded. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The role of vitamin C in the treatment of methemoglobinemia has not been well established, with only a few published case reports. This patient had severe methemoglobinemia, with MetHb of 46.4%, which responded dramatically to vitamin C therapy, with no side effects. This case shows that high-dose vitamin C is safe and has the potential to be an effective alternative for the treatment of severe methemoglobinemia. In the presence of cyanosis, mismatch of pulse-oximetry and ABG-analysis are the key for the physician to suspect methemoglobinemia.

Tubercular Mycobacterial Spindle Cell Pseudotumour: A Case Report.

Pseudotumour is a benign inflammatory lesion. Mycobacterial spindle cell pseudotumour (MSP) is a rare pseudotumour. It is a benign proliferation of spindle-shaped histiocytes containing acid-fast mycobacterium, commonly reported in immunocompromised patients. MSP is usually associated with mycobacterium avium complex (MAC). Here, we present the case of a 38-year-old gentleman with acquired immune deficiency syndrome (AIDS) who presented with low-grade fever for 1-month duration. Clinically, he had generalised lymphadenopathy. Chest X-ray showed miliary infiltration in bilateral lung fields. Lymph nodal biopsy showed spindle-shaped histiocytes filled with acid-fast bacilli on Ziehl-Neelsen (ZN) stain, suggestive of MSP. Immunohistochemical (IHC) stains were positive for CD68, S-100 and negative for CD31, which are consistent with MSP. Polymerase chain reaction (PCR) of the biopsy tissue was positive for MTB. Highly active antiretroviral therapy (HAART) was continued and anti-tubercular therapy (ATT) was started. The fever resolved within two weeks and there was a resolution of lymph nodal swelling by 6 weeks. The diagnosis of MSP associated with mycobacterium tuberculosis (MTB) makes our case interesting. It is of utmost importance to differentiate MSP from Kaposi's sarcoma (KS) and other pseudotumours and to know whether it is of tubercular or non-tubercular origin, as the treatment is entirely different.