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Background: Clear cell renal cell carcinoma (ccRCC) is the main component of renal cell carcinoma (RCC), and advanced ccRCC frequently indicates a poor prognosis. The significance of the CCCH-type zinc finger (CTZF) gene in cancer has been increasingly demonstrated during the past few years. According to studies, targeted radical therapy for cancer treatment may be a revolutionary therapeutic approach. Both lncRNAs and CCCH-type zinc finger genes are essential in ccRCC. However, the predictive role of long non-coding RNA (lncRNA) associated with the CCCH-type zinc finger gene in ccRCC needs further elucidation. This study aims to predict patient prognosis and investigate the immunological profile of ccRCC patients using CCCH-type zinc finger-associated lncRNAs (CTZFLs). Methods: From the Cancer Genome Atlas database, RNA-seq and corresponding clinical and prognostic data of ccRCC patients were downloaded. Univariate and multivariate Cox regression analyses were conducted to acquire CTZFLs for constructing prediction models. The risk model was verified using receiver operating characteristic curve analysis. The Kaplan-Meier method was used to analyze the overall survival (OS) of high-risk and low-risk groups. Multivariate Cox and stratified analyses were used to assess the prognostic value of the predictive feature in the entire cohort and different subgroups. In addition, the relationship between risk scores, immunological status, and treatment response was studied. Results: We constructed a signature consisting of eight CTZFLs (LINC02100, AC002451.1, DBH-AS1, AC105105.3, AL357140.2, LINC00460, DLGAP1-AS2, AL162377.1). The results demonstrated that the prognosis of ccRCC patients was independently predicted by CTZFLs signature and that the prognosis of high-risk groups was poorer than that of the lower group. CTZFLs markers had the highest diagnostic adequacy compared to single clinicopathologic factors, and their AUC (area under the receiver operating characteristic curve) was 0.806. The overall survival of high-risk groups was shorter than that of low-risk groups when patients were divided into groups based on several clinicopathologic factors. There were substantial differences in immunological function, immune cell score, and immune checkpoint expression between high- and low-risk groups. Additionally, Four agents, including ABT737, WIKI4, afuresertib, and GNE 317, were more sensitive in the high-risk group. Conclusion: The Eight-CTZFLs prognostic signature may be a helpful prognostic indicator and may help with medication selection for clear cell renal cell carcinoma.
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Introduction: IgA vasculitis is more commonly seen in the pediatric population than in adults. Rarely IgA vasculitis is associated with malignancy, most commonly solid tumor malignancies, although there are case reports of association with hematologic malignancies. We report a case of large B-cell lymphoma mimicking IgA vasculitis in a 33-year-old immunosuppressed male with a prior history of IgA vasculitis. Case Description/Methods: A 33-year-old Caucasian male post renal transplant from reflux nephropathy on chronic immunosuppression was hospitalized for postprandial epigastric abdominal pain, nausea, vomiting and diarrhea. Two years prior, he was admitted for the same symptoms, palpable purpura of the lower extremities and elevated serum IgA. Enteroscopy had shown duodenal and jejunal ulceration with biopsies staining positive for IgA, confirming IgA vasculitis. He had complete resolution with a steroid taper. His current presentation had resulted in multiple hospital admissions, but empiric trial of steroids failed to alleviate symptoms. Vitals were normal and exam was notable for epigastric tenderness. Labs were notable for WBC 19.00 x103/cmm with normal differential, hemoglobin 9.2 gm/dL (prior 11.0 gm/dL), CRP 20.7 mg/L, serum creatinine 2.7 mg/dL (prior 1.5 mg/dL), and urinalysis with proteinuria, sterile pyuria, and hematuria. CTA abdomen/pelvis revealed thickening of the duodenum with shotty mesenteric lymph nodes without ischemia. Enteroscopy revealed an erythematous duodenum and jejunum (figure A). Jejunal biopsy (figure B) revealed CD20 positive cells consistent with DLCBL (figure C). He was seen by oncology and treated with R-CHOP but later unfortunately expired due to COVID-19 complications. Discussion(s): Non small cell lung cancer and renal cell carcinoma are most commonly associated with IgA vasculitis. It may also be seen in both Hodgkin and Non-Hodgkin lymphomas in adult patients. If IgA vasculitis occurs after a malignancy is diagnosed, it may indicate that metastasis has occurred. Malignancy associated IgA vasculitis is more likely to have an incomplete response to steroids and requires treatment of the underlying malignancy to achieve remission. Our case illustrates posterior probability error and premature closure cognitive biases. We should consider alternative diagnoses rather than anchor on prior diagnoses even when presentations are similar. Our case also highlights the importance of considering occult malignancy in adults with diagnosis of IgA vasculitis.
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Wunderlich syndrome, also known as the spontaneous non-traumatic retroperitoneal hemorrhage, is an uncommon condition characterized by acute, spontaneous, non-traumatic renal hemorrhage into the subcapsular or perirenal spaces. The majority of the cases are caused by renal cell carcinoma or renal angiomyolipoma. Other causes are arteriovenous malformation, cystic renal disease, and anticoagulation medications. The classic presentation is "Lenk's triad" of acute flank pain, palpable flank mass, and hypovolemia. The diagnosis is based on clinical suspicion and confirmed by a CT scan, which is the preferred imaging modality. Due to the rarity of these cases and the wide range of clinical manifestations, the treatment is divergent ranging from conservative management to nephrectomy. Herein, we present a case of massive right renal hemorrhage caused by warfarin toxicity that was initially misdiagnosed as acute renal colic due to the patient's refusal to refer to the clinic during Corona Virus Disease- 19 era and was later managed with a right nephrectomy.
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Hyperglycemia with or without blood glucose in diabetes range is an emerging finding not uncommonly encountered in patients with COVID-19. This work is to investigate the association between serum alpha-1-antitrypsin, hyperglycemia, and clinical outcomes in COVID-19, and community-acquired pneumonia, gastric cancer and renal cell carcinoma. Alpha-1-antitrypsin levels in serum was determined by the immunoturbidimetric method. We have set the level of alpha-1-antitrypsin in patients with community-acquired pneumonia and COVID-19 with or without hyperglycemia. Levels of alpha-1-antitrypsin in COVID-19 patients with hyperglycemia who survived > those who did not survive. Concentration of alpha-1-antitrypsin levels in COVID-19 men-patients with hyperglycemia who survived was significantly higher than compared with COVID-19 women-patients with hyperglycemia who survived. The obtained data convincingly demonstrate the value of testing the level of alpha-1-antitrypsin in the blood as one of the important indicators of the effectiveness of cancer diagnosis and prognosis.
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Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved over recent years with several systemic anti-cancer therapies (SACT) licensed across different lines of treatment. There is ongoing discussion amongst oncology professionals about how best to optimise treatments in terms of sequencing to maximise the potential number of lines or to give the best treatments first. A previous south-west UK audit was completed in 2021 reviewing the drop off rates across 5 UK sites identifying that 69% of patients were able to receive second line therapy and 34% were able to receive third line therapy. Method(s): In this study we conducted retrospective analysis of all patients who commenced treatment with SACT for mRCC between 1st January 2018 and 30th June 2021 in 18 centres across the 4 nations of the United Kingdom. All NHS reimbursed treatment options including the COVID interim treatment guideline options were included. Patients who received SACT as part of a clinical trial were also included. Patients who continued on their respective lines of treatment were censored. We also identified patients who had been on a period of active surveillance before staring SACT in this cohort. Result(s): 1549 patients (71% male: 29% female) were included. IMDC subgroup patients included 21.6%favourable, 52.3% intermediate, 25.1%poor and 1% unavailable. 9.1% of patients had been on active surveillance before starting SACT - defined as a period of longer than 3 months from mRCC diagnosis to starting SACT. Of those patients that started SACT 60.5% of eligible patients had 2nd line therapy, 25.3% had 3rd line, 7.2% received 4th line therapy and only 1% had 5th line therapy. In the 1st line setting 58.9% received single agent VEGF TKI, 24.5% received combination ipilimumab and nivolumab (IO-IO) immunotherapy, 14 % received IO/ VEGF TKI combination and 2.6% received other/trial treatment. The single agent VEGF TKI ratio for 1st line SACT declined year by year with rising IO-IO and IO/VEGF TKI combination ratios seen. In the secondand third-line settings cabozantinib (33.2% 2nd line and 44.4% 3rd line) and nivolumab (32.8% 2nd line and 22.6% 3rd line) were the most common options. Disease progression or death was the most common cause of SACT discontinuation amounting to 57.4%, 62.5% and 79% of SACT cessation in the 1st, 2nd and 3rd lines respectively. Treatment toxicity SACT discontinuation rates were 22.8%, 21.4% and 10.9% for 1st, 2nd and 3rd lines respectively. Conclusion(s): These results suggest that with more treatment options available, including combination/immunotherapy therapies, more patients are able to receive second- and third-line therapies. That said there remains significant drop off rates mostly driven by disease progression that would support the use of our most effective therapies in the upfront setting.
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Background: Cancer patients have increased risk for severe outcomes related to SARS-CoV-2 infection (COVID-19), due to their increased vulnerability to infection, older age, and comorbidities in comparison to the general population. While multiple studies have been completed examining outcomes of COVID-19 infection in cancer patients overall, there has been limited investigation into the outcomes of COVID-19 infection in patients with genitourinary (GU) cancers. Method(s): We completed a single institution retrospective study to examine the outcomes of adults with GU cancers and COVID-19 infection from March 10, 2020 to June 15, 2022. Baseline data included age, sex, BMI, type of malignancy, cancer status (stable or progressive disease, in remission), current and previous anticancer therapy received, and comorbidities. Result(s): Eighty-four patients with a GU cancer diagnosis and laboratory-confirmed SARS-CoV-2 infection were identified. Seventy-nine (94%) were male and the median age was 64 years (range 24-91). Forty-four (52%) were non-Hispanic white, 28 (33%) were Hispanic, and 11 (13%) were African-American. Prostate cancer was the most common (n = 45), followed by renal cell carcinoma (n = 20), testicular (n = 9), bladder (n = 6), and penile cancer (n = 3). Eight patients had >=2 episodes of COVID-19 infection. Sixty-three percent of patients were unvaccinated at the time of infection, while 37% of patients had breakthrough infection. Hospitalization was required for 39.3% (n = 33), with 4.8% (n = 4) requiring ICU admission. Of the patients requiring hospitalization, 26.2% (n = 22) died. Hospitalization was associated with having>=2 comorbidities (OR 18.6 [95% CI, 3.1-111.8], p<0.01) and receiving active cancer treatment (OR 12.4 [95% CI, 1.92- 79.7], p, 0.01). Mortality was associated with advanced age (OR 21.7 [95% CI, 1.40-341.7], p=0.03) and >=2 comorbidities (OR 19.2 [95% CI, 3.02-122.5], p=0.02). Vaccination was negatively associated with both hospitalization (OR 0.04 [95% CI, 0.02-0.91], p=0.04) and mortality (OR 0.14 [95% CI, 0.02-0.84], p=0.03). Conclusion(s): Among patients with GU cancer, advanced age and comorbidities are associated with adverse outcomes of COVID-19 infection;vaccination is protective. With the emergence of variants and waning immunity of vaccines, our findings highlight the importance of development and implementation of enhanced mitigation strategies in cancer patients, especially those undergoing active cancer treatment.
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Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)
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Renal cell carcinomas (RCCs) are the most common renal tumors in adults and are usually sporadic and unilateral. Renal transplant recipients have an increased risk of developing RCC. RCC development after kidney transplantation is very rarely reported in children. We present a 11-year-old boy who had cadaveric kidney transplantation for kidney failure 2 years ago. He was under immunosuppressive therapy and presented with microscopic hematuria. An ultrasound (US) revealed bilateral solid renal masses. Further cross-sectional imaging showed a 60 × 70 × 60-mm right renal mass with claw sign and a 5 × 6 × 6-mm mass in the left renal lower pole. A bilateral radical nephroureterectomy of native kidneys was performed. The pathology revealed bilateral papillary RCC without TFE3 upregulation. The patient was kept on low-dose immunosuppressive therapy in the perioperative period. He received no chemotherapy but a close radiological surveillance was undertaken. He is tumor-free 2 years after the operation. RCC is a rare tumor for children and bilateralism is even rarer. The child had a history of chronic kidney disease, peritoneal dialysis, and immunosuppressive therapy. As there are no standardized protocols regarding imaging in transplanted kidneys routine surveillance, US follow-up should also focus on detecting malignancy.
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SESSION TITLE: Lung Nodule Biopsy: Yield and Accuracy SESSION TYPE: Original Investigations PRESENTED ON: 10/16/2022 10:30 am - 11:30 am PURPOSE: A variety of endpoints have been used to evaluate the diagnostic performance of navigational bronchoscopy for sampling peripheral pulmonary lesions (PPLs), including diagnostic yield (rate of biopsies with a specific diagnosis that facilitates clinical decisions) and diagnostic accuracy (yield plus a follow-up to assess for false negative/positive initial results). There is also significant variation in what non-malignant findings are considered diagnostic, especially regarding nonspecific inflammatory changes. We hypothesized a diagnostic yield definition excluding nonspecific findings as diagnostic would lead to few false negative PPL biopsies. METHOD(S): Our center maintains a prospective cohort of consecutive PPLs targeted via navigational bronchoscopy. Diagnostic yield was defined as specific findings readily explaining the presence of a PPL (malignancy, organizing pneumonia, granulomatous inflammation, frank purulence, other specific finding) permitting management without immediate additional diagnostic intervention. "Other specific finding" required pulmonologist and lung pathologist agreement. All other findings were considered non-diagnostic. RESULT(S): A total of 450 PPLs biopsied 2017-2019 with complete two-year follow-up were included in the analysis. Ultimately, 274 of 450 (60.9%) PPLs were determined to be malignant. Diagnostic biopsies were obtained in 331 cases (73.6%). There was a single false-positive among 228 malignant biopsies (0.4%, carcinoid tumor on cytopathology, alveolar adenoma on resection surgical pathology). Among 223 PPLs without malignant diagnosis at initial bronchoscopy, 48 were later determined to be malignant. Most (n=39) exhibited nonspecific abnormalities on initial pathology. Two of 104 specific benign biopsies were false negative (1.9%). Both demonstrated organizing pneumonia on initial pathology but re-biopsy months after index bronchoscopy revealed Hodgkin's lymphoma and metastatic renal cell carcinoma, respectively. The sensitivity, specificity, and positive predictive value of specific benign findings for an ultimately benign nodule were 58% (95% CI, 51-66%), 95% (86-99%), and 90% (70-97%). The sensitivity, specificity, and positive predictive value of nonspecific benign findings for an ultimately benign PPL diagnosis were 32% (95% CI, 25-39%), 19% (9-33%), and 20% (16-24%). CONCLUSION(S): A definition of diagnostic yield excluding nonspecific benign findings had low false positive/negative rates. If bronchoscopy is not diagnostic of malignancy, a specific benign finding was highly predictive of an ultimately benign PPL, while nonspecific findings poorly predicted benignity. CLINICAL IMPLICATIONS: This definition of diagnostic yield could be used as the primary outcome in future studies, permitting distribution of reliable diagnostic results without requiring years of follow-up. DISCLOSURES: No relevant relationships by Joyce Johnson No relevant relationships by Robert Lentz No relevant relationships by Kaele Leonard No relevant relationships by See-Wei Low PI ofan investigator-initiated study relationship with Medtronic Please note: >$100000 by Fabien Maldonado, value=Grant/Research Support PI on investigator-initiated relationship with Erbe Please note: $5001 - $20000 by Fabien Maldonado, value=Grant/Research Support Consulting relationship with Medtronic Please note: $5001 - $20000 by Fabien Maldonado, value=Honoraria co-I industry-sponsored trial relationship with Lung Therapeutics Please note: $5001 - $20000 by Fabien Maldonado, value=Grant/Research Support Board of director member relationship with AABIP Please note: $1-$1000 by Fabien Maldonado, value=Travel Consultant relationship with Medtronic/Covidien Please note: $1001 - $5000 by Otis Rickman, value=Consulting fee No relevant relationships by Briana Swanner Copyright © 2022 American College of Chest Physicians
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SESSION TITLE: Using Imaging for Diagnosis Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Immunotherapy is now a standard of care in solid-tumor oncology following the approvals of CTLA-4 and PD-1 inhibitors. Belzutifan, a small-molecule HIF-2a inhibitor, has recently gained FDA-approval for the treatment of advanced von Hippel-Lindau (VHL) associated renal cell carcinomas. CASE PRESENTATION: A 63-year-old female presented to our hospital with a one-day history of progressive dyspnea. Medical history is significant for metastatic renal cell carcinoma with pulmonary metastasis. Family and social history were noncontributory. Her cancer diagnosis was established in 2019 and had undergone cytoreductive nephrectomy and treatment with axitinib/pembrolizumab. As she had little improvement with immunotherapy, she was enrolled in a clinical trial at Memorial Sloan Kettering. Due to further disease progression, she was transitioned to lenvatinib/everolimus, though the treatment was discontinued due to anorexia and worsening pulmonary symptoms. Further work up revealed that she had ERG, MPL, VHL gene mutations. Thus, she was started on belzutifan two weeks prior to her presentation. Initial vitals were significant for hypoxia on room air that recovered with high flow nasal cannula (40L/80%). Physical examination was remarkable for severe respiratory distress with coarse breath sounds bilaterally. Laboratory studies revealed an acute leukocytosis with a neutrophilic prominence and a chronic metabolic alkalosis. COVID, flu PCR were negative. Chest x-ray demonstrated diffuse bilateral reticulonodular opacities. CTA revealed innumerable pulmonary nodules with areas of mass-like consolidation and a loculated left-sided pleural effusion. She was covered with azithromycin/ceftriaxone along with high-dose steroids and was admitted to the stepdown unit for further management. While in stepdown, she had a left PleurX catheter placed given her large effusion which was complicated by bloody output that required one unit of blood. Despite high-dose steroids, she had persistent hypoxia. As she remained unstable, goals of care discussions were held, which ultimately led to a change in code status to comfort measures. All aggressive measures were discontinued. She was started on comfort medications and ultimately passed away. DISCUSSION: Currently, neoplasms associated with VHL mutations are managed surgically to minimize the risk of metastatic disease. Nearly 70% of all patients with VHL mutations will develop renal cell carcinomas which means most patients undergo numerous surgical procedures. HIF-2a inhibition therefore offers an effective alternative that could reduce surgical burden and offer a new approach to management of VHL-associated disease. However due to its new approval, several adverse effects have yet to be documented. CONCLUSIONS: We report the only known case of Belzutifan-induced hypersensitivity pneumonitis and hope this case will become a useful contribution to the literature. Reference #1: Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R;MK-6482-004 Investigators. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021 Nov 25;385(22):2036-2046. doi: 10.1056/NEJMoa2103425. PMID: 34818478. DISCLOSURES: No relevant relationships by Garrett Fiscus No relevant relationships by Niala Moallem No relevant relationships by Raj Parikh
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SESSION TITLE: Critical Cardiovascular Disorders SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Hemorrhagic shock is a life-threatening condition in which severe blood loss results in cellular and tissue hypoxia. The bleeding can be external or internal. Internal bleeding to one of the body cavities;retroperitoneum, as well as the proximal thigh. Diagnosing nontraumatic bleeding can be challenging and needs a high index of clinical suspension. Here we present a case of hemorrhagic shock secondary to spontaneous lumbar artery rupture causing retroperitoneal bleeding. CASE PRESENTATION: Here we present a 73-year-old male patient with a history of renal cell carcinoma metastatic to the lungs and stage 3 chronic kidney disease (CKD), who presented with confusion, one day after he tested positive for covid after he had a fever and flu-like symptoms for about 4 days. On admission, he was hemodynamically stable and saturating well on ambient air. Head computed tomography (CT) scan and Chest radiograph were negative for acute insults. On the day after admission, his mental status deteriorated, developed acute hypoxic respiratory failure requiring 4 liters of oxygen per minute, tachycardia, and skin mottling over his hands and feet. Labs revealed elevated serum D-dimer. He was started on full-dose anticoagulation with Enoxaparin, and a CT angiogram of the chest was done and revealed new multifocal infiltrates consistent with COVID pneumonia but no pulmonary embolism. He was treated started on IV antibiotics, in addition to Remdesivir and hydrocortisone were started. On the fourth day of admission, he collapsed suddenly and became profoundly hypotensive. Repeat labs revealed a significant hemoglobin drop from 12 to 7.5 g/dl, and creatinine went up to 2.8 mg/dl. An emergent CT of the abdomen revealed an acute retroperitoneal hematoma with active extravasation. After adequate resuscitation and vasopressor support, an aortic angiogram was done showing lumbar artery bleeding requiring embolization, which was done, however, he remained hypotensive and went into cardiac arrest with failed resuscitation. DISCUSSION: Spontaneous lumbar artery rupture is a rare entity (1). Most of the reported cases had chronic kidney disease and were receiving anticoagulation (2,3). It can result in retroperitoneal hematoma, which can present with abdominal pain, hemodynamic instability, and nonspecific symptoms. Abdomen pelvis CT scan with contrast is needed to evaluate for the presence of retroperitoneal hematoma. In addition to resuscitation with fluid and blood products, urgent angiography is needed to confirm the bleeding site and to control it (e.g. embolization). CONCLUSIONS: Spontaneous Lumbar artery rupture should be considered in patients with chronic kidney disease and/or on anticoagulation who are in shock without obvious cause. It's a life threatening condition that needs immediate recognition. Reference #1: Kim JY, Lee SA, Hwang JJ, Park JB, Park SW, Kim YH, et al. Spontaneous lumbar artery rupture and massive retroperitoneal hematoma, successfully treated with arteriographic embolization. Pak J Med Sci. 2019;35(2):569-574. doi: https://doi.org/10.12669/pjms.35.2.639 (Literature review) Reference #2: Hwang NK, Rhee H, Kim IY, et al. Three cases of spontaneous lumbar artery rupture in hemodialysis patients. Hemodial Int 2017;21: E18-21 Reference #3: Sun, PL., Lee, YC. & Chiu, KC. Retroperitoneal hemorrhage caused by enoxaparin-induced spontaneous lumbar artery bleeding and treated by transcatheter arterial embolization: a case report. Cases Journal 2, 9375 (2009). https://doi.org/10.1186/1757-1626-2-9375 DISCLOSURES: No relevant relationships by Mohamad Al-Momani No relevant relationships by Rami Dalbah No relevant relationships by Mohammad Darweesh No relevant relationships by Ratib Mahfouz No relevant relationships by nizar obeidat No relevant relationships by Ahmad Othman
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Background: Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, has demonstrated clinical efficacy across patients with different tumor types, including clear cell renal cell carcinoma (ccRCC), when administered via IV infusion. As an alternative to IV infusion, subcutaneous (SC) administration alleviates the need for IV ports, thereby lowering the risk of associated complications such as infections and phlebitis. SC formulation also reduces the time for dose preparation and administration, which may decrease overall treatment burden and reduce patient time in the clinic, benefiting patients and healthcare providers and improving overall healthcare resource utilization. SC-administered NIVO consists of NIVO co-formulated with the recombinant human hyaluronidase PH20 enzyme (NIVO + rHuPH20), which aims to increase the dispersion and absorption of NIVO within the SC space. SC NIVO + rHuPH20 was shown to be safe and well tolerated in a phase 1/2 study, warranting further investigation (Lonardi S et al. J Clin Oncol 2021;39(suppl 15):2575). Methods: CheckMate 67T is a multicenter, randomized, open-label, phase 3 study that will evaluate the noninferiority of SC NIVO + rHuPH20 versus IV NIVO in patients with advanced or metastatic ccRCC who have progressed after receiving ≤ 2 prior systemic treatment regimens. Key inclusion criteria are age ≥ 18 years, histologically confirmed advanced or metastatic ccRCC, measurable disease by RECIST v1.1 within 28 days prior to randomization, and a Karnofsky performance status ≥ 70. Key exclusion criteria are untreated symptomatic metastases to the central nervous system, other malignancy, autoimmune diseases, HIV-positive status with AIDS-defining infection within past year or current CD4 count < 350 cells/μL, other serious or uncontrolled disorders including severe, acute SARS-CoV-2 infection, and prior treatment with immune checkpoint inhibitors, other T-cell-targeting antibody drugs, or live attenuated vaccines within 30 days of first study treatment. At least 454 eligible patients will be randomized to receive SC NIVO + rHuPH20 or IV NIVO. The primary objectives are to demonstrate pharmacokinetic (PK) noninferiority of SC NIVO versus IV NIVO, as measured by time-averaged serum concentration over the first 28 days (Cavgd28) and trough serum concentration at steady state (Cminss) (co-primary endpoints). Secondary endpoints include objective response rate by blinded independent central review, additional PK parameters, safety, efficacy, and immunogenicity of SC NIVO and IV NIVO. This study is currently enrolling patients globally.
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Background: Immune-mediated adverse events (irAEs) can be seen in patients (pts) receiving checkpoint inhibitors (CPI). It is unknown whether the immune response to vaccines against Sars-CoV-2 interacts with the immune activation from CPI therapy. In this retrospective study, we examined the incidence of severe irAEs in pts with renal cell carcinoma (RCC) who received vaccines against Sars-CoV-2 during the course of their CPI therapy. Methods: Following IRB approval, RCC pts who received any CPI treatment since FDA authorization of the first COVID-19 vaccine in March 2021 were identified via institutional electronic health record. Pts who received one or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (defined as one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation. Data was analyzed using descriptive statistics. Results: Sixty-five pts were included in our analysis with a median age of 66 years (IQR: 58.0, 73.0);80% pts were male. At the time of vaccination, 26 pts (40.0%) received CPI monotherapy, 12 pts (18.4%) received combination (combo) CPI therapy, and 27 pts (41.6%) received combo therapy with a tyrosine kinase inhibitor (TKI) and CPI. The type of vaccine received was Pfizer Bio-NTech in 30 pts (46.2%), Moderna in 33 pts (50.7%), and Johnson and Johnson in 2 pts (3.1%). Six pts received only one vaccination (9.2%), 18 pts received two vaccinations (27.7%), and 40 pts received 3 or more vaccinations (61.5%). Eleven pts (16.9%) experienced severe irAEs following vaccination. Rates of severe irAEs was 3.8% (1/26) with CPI monotherapy, 25% (3/12) with combo CPI, and 25.9% (7/27) with combo CPI and TKI. Severe irAEs occurred after the first vaccine dose in 4 pts (36.4%), second dose in 3 pts (27.3%), and third dose in 4 pts (36.4%) pts. The median time between CPI treatment and vaccination in this group was 11.0 days (IQR: 7.5-15.5). Hospitalization was required for 6 patients (54.5%). Ten pts (90.9%) required immunosuppressive therapy with a median steroid duration of 85.5 days (IQR 36.8, 176.0). Six pts (54.5%) discontinued CPI therapy following severe irAEs. Conclusions: In this retrospective study, the observed rate of severe irAEs in RCC patients who received CPI and COVID-19 vaccine concomitantly was similar to historical controls, suggesting that there is no definite increase in the incidence of severe irAEs in pts undergoing CPI therapy and receiving COVID-19 vaccination. Future confirmatory studies are warranted.
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CASE: A 30-year-old woman with a history of hypertension, obesity, and reactive airway disease presents with a two-month history of persistent cough, wheeze, and diaphoresis. At that time, chest x-ray and COVID-19 PCR were negative and pulmonary function tests were within normal limits. Her symptoms were managed with inhaled corticosteroid/long-acting muscarinic antagonist, albuterol, guaifenesin, and second-generation antihistamines. However, she continued to be symptomatic. Two months after these symptoms arose, she presented to the ED with a sixhour history of sudden onset right non-radiating flank pain. Her symptoms were associated with acute onset nausea, vomiting, urinary frequency, urgency, hesitancy, and burning;negative for hematuria. She was hemodynamically stable and physical exam was significant for right flank tenderness. Urinalysis showed proteinuria of 100 mg/dL and gross hematuria. Imaging of the abdomen demonstrated an enlarged right kidney with a large mass involving the cortex with mass effect on the liver. Urology performed a right radical nephrectomy with pathology positive for chromophobe renal cell carcinoma. Following surgery, the patient's original symptoms of cough, wheezing, and diaphoresis resolved. IMPACT/DISCUSSION: The typical symptomatic presentation of renal carcinoma with flank pain, abdominal mass, hematuria, and weight loss occurs in roughly 9% of cases and is indicative of advanced disease. Renal cell carcinoma is most commonly found incidentally on imaging studies, leading to improved outcomes due to early recognition. Young patients, however, are more likely to present symptomatically. Our patients' initial presentation of cough could be due to two different mechanisms. One possibility is chronic irritation of the diaphragm due to mass effect from the growing tumor. This mechanism is possible in our case as there was minor mass effect on the liver which could then disturb the diaphragm. A more likely mechanism is a paraneoplastic process. This has been demonstrated in prior cases with a chronic unremitting cough associated with diaphoresis, not improved with anti-tussives, and resolves upon removal of the mass. The cough has been shown to return with metastases. The proposed mechanism is tumor secretion of prostaglandins which enhance the cough reflex. Our case displays an uncommon symptomatic presentation of renal cell carcinoma in a young woman due to paraneoplastic cough stimulation. This demonstrates the importance of digging deeper when common symptoms such as cough are not successfully resolved with typical treatments. CONCLUSION: Most commonly renal cancer is diagnosed on incidental imaging allowing clinicians to make a diagnosis before symptoms arise. An unremitting cough may be an early warning sign of renal cell carcinoma before urinary symptoms begin, making early diagnosis more likely. Due to this, seemingly minor symptoms such as cough should be followed through to diagnosis as they can have significant consequences.
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Objective: To describe a case report of Cerebral Venous Sinus Thrombosis (CSVT) and bilateral thalamic infarcts following Pfizer-BioNTech mRNA vaccine in a patient with ulcerative colitis. Background: CSVT has been reported as a rare but life-threatening side effect from SARS-CoV2 vaccines. Although the incidence of developing CSVT is higher following administration of viral vector vaccines (Oxford-AstraZeneca and Johnson&Johnson), six cases of CSVT have been reported following administration of mRNA vaccines (Moderna and Pfizer- BioNTech).1,2,3 In these six cases, only two patients had risk factors (oral contraceptives use and undiagnosed renal cell carcinoma).1,2,3 Our patient was diagnosed with ulcerative colitis (UC) after her presentation with CSVT. Current literature suggests the risk of thromboembolism is twice as common in patients with UC in comparison to the general population. Design/Methods: N/A Results: A 22-year female developed headache, vomiting, and altered mental status after 14 days following administration of the first dose of Pfizer-BioNTech mRNA vaccine. MRI/MRV confirmed bilateral symmetric thalamic infarctions with straight and inferior sagittal sinus thrombosis. She did not have other risk factors such as the use of oral contraceptive pills or pregnancy. ESR/CRP elevated, but platelet count, INR were normal. Hypercoagulable workup was unrevealing. Treatment with therapeutic anticoagulation led to an improvement in symptoms within a week. As the patient previously had rare intermittent bloody diarrhea, further workup (CT abdomen and colonoscopy with biopsy) led to a diagnosis of ulcerative colitis. Conclusions: The temporal association demonstrated between the development of CSVT and the administration of Pfizer-BioNTech mRNA vaccine in the patient is likely a result of the combined hypercoagulability effect of the vaccine and Ulcerative colitis. Active surveillance and continuous pharmacovigilance are necessary to clarify this association. This might help to identify at-risk populations where prophylactic short-term anticoagulation can be used to prevent CVST.
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Paraneoplastic syndromes (PNS) are rare and can be challenging to diagnose and treat. The uniqueness of PNS lies in the complexity of presentation, the importance of early diagnosis, and the role of multidisciplinary care in managing those patients to mitigate long-term neurologic complications. We describe a patient with metastatic renal cell carcinoma who presented with a complex constellation of neurological symptoms (progressive global ataxia and sensory changes) that did not resolve following nephrectomy. While complete resolution of symptoms was not achieved, he did have stabilization of his neurologic decline with the initiation of cancer-directed therapies.
ABSTRACT
INTRODUCTION: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor used to treat metastatic renal cell carcinoma (mRCC). Patients on sunitinib do require regular in-person appointments to monitor for adverse events (AEs). Given the Covid-19 pandemic, regular in-person visits expose patients to an increased risk of infection in addition to potentially preventable travel costs. This study investigated the feasibility of implementing a remote monitoring strategy for patients being treated with sunitinib for mRCC by examining the time trends of AEs. MATERIALS AND METHODS: In this retrospective chart review of patients with a diagnosis of mRCC, 167 patients received sunitinib during their treatment. The time between initiation of treatment and the first AE was recorded. The AEs were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Survival analysis was used to calculate the time-to-AE. RESULTS: Of the 167 patients identified, 145 experienced an AE (86.8%). Hypertension was the most common AE with 80% of AEs were ≤ Grade 2. Incidence of AE dropped by 91% after 3 months follow up and a further 36% after 6 months. The cumulative incidence of AEs were 87.8%, 94.6% and 98.0%, at 3, 6 and 9 months respectively. The severity of AEs observed were 39.3%, 38.6%, 20.7%, 1.4%,0% of Grade 1-5 events respectively. A trend of grade migration to less severe grades was also shown over time, with percentage of Grade ≥ 3 toxicity dropping from 22% between 0-3 months to 14% beyond 6 months follow up. CONCLUSIONS: The role of remote monitoring for mRCC patients on sunitinib remains relevant now with new waves of the Covid-19 pandemic, triggered by novel variants. The majority of AEs observed were of low severity ≤ Grade 2, with a trend of reduced AE frequency and severity most prevalent beyond 3 months of follow up. This data appears to support the implementation of a remote monitoring strategy 3 months after initiation of treatment.