Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA Adverse Events Reporting System.

ABSTRACT: Second primary malignancies were reported in 536 of 12 394 (4.3%) adverse event reports following chimeric antigen receptor T-cell therapies in the Food and Drug Administration Adverse Event Reporting System. Myeloid and T-cell neoplasms were disproportionately more frequently reported, warranting further follow-up.

Impact of Acute Coronary Syndrome on Clinical Outcomes in Patients With Thrombotic Thrombocytopenic Purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening clinical syndrome characterized by microangiopathy and a variable degree of end-organ ischemic damage. Cardiac involvement has been recognized as a major cause of mortality in these patients. In this study, we queried the National Inpatient Sample (NIS) for all patients hospitalized with thrombotic microangiopathy from 2002 to 2017, who also received plasma exchange (PLEX) during the same admission. A total of 6,214 patients with TTP were identified. We stratified patients based on whether or not they had acute coronary syndrome (ACS) during admission. ACS was documented in 6.3% of patients. Compared with patients without ACS, those with ACS were relatively older (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02-1.03) and had a relatively higher prevalence of heart failure (OR, 2.02; 95% CI, 1.53-2.67) and coronary artery disease (OR, 2.69; 95% CI, 2.03-3.57). Certain complications were more prevalent in the ACS group including acute cerebrovascular accident (OR, 3.33; 95% CI, 2.94-3.78), acute heart failure (OR, 1.91; 95% CI, 1.67-2.19), acute kidney injury (OR, 1.76; 95% CI, 1.59-1.95), cardiogenic shock (OR, 2.15; 95% CI, 1.72-2.69), and respiratory failure (OR, 1.48; 95% CI, 1.32-1.66). Despite wider utilization of therapeutic plasmapheresis and improved supportive management of patients with TTP, associated morbidity and mortality remain significant. We demonstrate from this large retrospective cohort that ACS is an independent predictor of higher morbidity and mortality in TTP patients.

Primary small cell neuroendocrine cancer of adrenal gland: a rare extrapulmonary small cell cancer.

Small cell cancer is an aggressive neoplasm of neuroendocrine origin that is most commonly found in the lungs. However, up to 5% of cases can be extrapulmonary. These have been reported to be located in the gastrointestinal and genitourinary systems and rarely in other locations. Only five prior cases of small cell cancer have been reported where the primary lesion is at the adrenal gland. Here we present the case of a female patient in her mid-50s who presented with right upper quadrant pain and was diagnosed with metastatic small cell carcinoma of the adrenal gland. The patient received palliative chemotherapy for her metastatic cancer and was ultimately admitted to hospice after progression of her disease. This case and the accompanying literature review highlight a rare manifestation of extrapulmonary small cell cancer.

Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia: a systematic review and meta-analysis.

Chimeric Antigen Receptor (CAR) T cell therapy is an effective treatment approach for patients with relapsed or refractory acute lymphoblastic leukemia (R/R B-ALL). However, identifying the factors that influence long-term response to this therapy is necessary to optimize patient selection and treatment allocation. We conducted a literature review and meta-analysis to investigate the use of autologous anti-CD19 CAR T cell therapy in both pediatric and adult patients with R/R B-ALL, using several databases including MEDLINE, Cochrane Central, ScienceDirect, Web of Science, Journals@Ovid, Embase, and clinicaltrial.gov. A total of 38 reports were analyzed, which enrolled 2134 patients. Time-to-event endpoints were estimated using reconstructed patient survival data. The study explored key modulators of response, including costimulatory domains, disease status, age, and lymphodepletion. The median overall survival and event-free survival were 36.2 months [95% CI 28.9, NR] and 13.3 months [95% CI 12.2, 17], respectively. The overall response rate was 76% [95% CI 71, 81]. The use of 4-1BB costimulatory domain in the CAR construct, administration of low-dose cyclophosphamide lymphodepletion, and pretreatment morphologic remission were associated with better overall survival, with hazard ratios of 0.72, 0.56, and 0.66, respectively. Morphologic remission and 4-1BB domain were associated with better event-free survival, with hazard ratios of 0.66 and 0.72, respectively. These findings suggest that CAR T cell therapy may offer long-term benefits to patients with R/R B-ALL. However, further research is needed to optimize patient selection and better understand the impact of various factors on the outcome of CAR T cell therapy.

The evolution of clinical outcomes in metastatic pancreatic adenocarcinoma: a 10-year experience at a tertiary referral center.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the US. Recent studies have demonstrated survival benefits for FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) and Gem/nab-P (gemcitabine/nab-paclitaxel) over gemcitabine. We aimed to evaluate the clinical outcomes of mPDAC before and after incorporating these newer regimens into the clinical practice. METHODS: A retrospective study of patients with mPDAC at our institution between 2009 and 2018, who were followed up until December 2019. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier survival analysis. Univariate and multivariable Cox regression analyses were used to explore predictors of survival. RESULTS: A total of 394 patients with mPDAC were included: 122 (31%) were diagnosed 2009-2013 and 272 (69%) 2014-2018. In 2009-2013 cohort vs. 2014-2018 cohort, the median OS and PFS were similar (4 vs. 3.6 months, P = 0.5) and (2.3 vs. 2.5 months, P = 0.41), respectively. Age, ECOG-PS >1, serum albumin, neutrophil-to-lymphocyte ratio, and platelets-to-lymphocyte ratio were independent predictors of better OS. CONCLUSIONS: In this study of real-world data, the median OS and PFS for all patients with mPDAC were equivalent before and after incorporating newer treatment regimens into the clinical practice.

Yersinia enterocolitica Prosthetic Joint Septic Arthritis Successfully Treated with Ceftriaxone.

Yersinia enterocolitica is a Gram-negative coccobacillus that is known to cause gastroenteritis and symptoms mimicking appendicitis or terminal ileitis. It is also one of the culprit infections implicated in causing reactive arthritis. Rarely, it can cause musculoskeletal infections including osteomyelitis, septic arthritis, and discitis. We describe the case of a 70-year-old female with multiple comorbidities who presented with left knee pain and swelling after recent gastroenteritis. She was found to have Yersinia enterocolitica septic arthritis in her left knee prosthetic joint. The patient underwent an exchange of her prosthetic material and was successfully treated with a six-week course of ceftriaxone. Our article aims to highlight a rare manifestation of Yersinia enterocolitica infection and to point out an important differential for reactive arthritis after Yersinia enterocolitica infection.

Outcomes of Richter's transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): an analysis of the SEER database.

Richter's transformation (RT) is a rare complication arising in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is associated with an overall dismal outcome. The rarity of this entity poses many challenges in understanding its biology and outcomes seen and the optimal treatment approach. We utilized the SEER (Surveillance, Epidemiology and End Results) database to identify patients diagnosed with CLL/SLL between 2000 and 2016 and subsequently had a diagnosis of diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL), thus capturing those who experienced an RT event. We compared the outcomes of those patients to those of patients in the database diagnosed with DLBCL without a preceding CLL/SLL diagnosis. We identified 530 patients who developed RT out of 74,116 patients diagnosed with CLL/SLL in the specified period. The median age at RT diagnosis was 66 years, and the median time from CLL/SLL diagnosis to RT development was roughly 4 years. Patients with RT had a dismal outcome with median overall survival of 10 months. We identified advanced Ann Arbor stage (III/IV) and prior treatment for CLL as predictors of worse outcome in patients with RT. Our study represents the largest dataset of patients with CLL/SLL and RT and adds to the existing literature indicating the poor outcomes for those patients.

Dysphagia Megalatriensis: An Uncommon Cause of Dysphagia.

Dysphagia megalatriensis is a rarely reported entity of cardiovascular dysphagia. Affected patients present with dysphagia to solid foods and regurgitation secondary to esophageal compression from an enlarged left atrium (LA). Here we report a case of a 68-year-old man with long standing atrial fibrillation who presented with chest pressure, bloating and dysphagia to solids. Esophagogastroduodenoscopy revealed a large area of extrinsic compression of the middle third of the esophagus that varied with cardiac contractions. Computerized tomography of the chest did not reveal any masses and transthoracic echocardiogram showed moderate LA enlargement. Based on those findings, a diagnosis of cardiac dysphagia was made. While severe LA enlargement is usually reported in cardiac dysphagia, our patient developed symptoms with moderate LA enlargement. Surgical intervention, dietary modifications, treatment of the underlying cause of LA enlargement and enteric tube feeding are available treatment options for cardiovascular dysphagia.

Impact of Body Mass Index on COVID-19-Related In-Hospital Outcomes and Mortality.

BACKGROUND: Given the high prevalence of obesity around the globe, patients with coronavirus disease 2019 (COVID-19) are at an increased risk of devastating complications. METHODS: A retrospective cohort study was performed to determine the association of basal metabolic index (body mass index (BMI)) with the need for invasive mechanical ventilation (IMV), dialysis, upgrade to an intensive care unit (ICU) and mortality. Independent t-test and multivariate logistic regression analysis were performed to calculate mean differences and adjusted odds ratios (aORs) with its 95% confidence interval (CI), respectively. RESULTS: A total of 176 consecutive patients with confirmed COVID-19 diagnosis were included. The mean age was 62.2 years, with 51% being male patients. The mean BMI for non-surviving patients was significantly higher compared to patients surviving on the seventh day of hospitalization (35 vs. 30 kg/m2, P = 0.022). Similarly, patients requiring IMV had a higher BMI (33 vs. 29, P = 0.002) compared to non-intubated patients. The unadjusted OR for patients with a higher BMI requiring IMV (56% vs. 28%, OR: 3.3, 95% CI: 1.6 - 7.0, P = 0.002) and upgrade to ICU (46% vs. 28%, OR; 2.2, 1.07 - 4.6, P = 0.04) were significantly higher compared to patients with a lower BMI. Similarly, patients with a higher BMI had higher in-hospital mortality (21% vs. 9%, OR: 3.2, 95% CI: 1.3 - 8.2, P = 0.01) compared to patients with a normal BMI. Despite a numerical advantage in the lower BMI group, there was no significant difference between the two groups in terms of the need for dialysis (5% vs. 13%, OR: 3.8, 13% vs. 4%, 1.1 - 14.1, P = 0.07). aORs controlled for baseline comorbidities and medications mirrored the overall results, except for the need to upgrade to ICU. CONCLUSIONS: In patients with confirmed COVID-19, morbid obesity serves as an independent risk factor of high in-hospital mortality and the need for IMV.

Differential Effects of Clinically Relevant N- versus C-Terminal Truncating CDKN1A Mutations on Cisplatin Sensitivity in Bladder Cancer.

Muscle-invasive bladder cancer (MIBC) frequently harbors mutations in the CDKN1A gene, which encodes the tumor suppressor protein p21, with the majority of alterations truncating the peptide. The effect of these mutations is poorly understood. We hypothesized that after DNA-damaging events, cells deficient in p21 would be unable to halt the cell cycle and efficiently repair DNA damage, thus proceeding down the apoptotic pathway. We used synthetic CRISPR guide RNAs to ablate the whole peptide (sg12, targeting the 12th amino acid) or the C-terminal proliferating cell nuclear antigen (PCNA)-binding domain (sg109) to mimic different p21-truncating mutations compared with a negative control (sgGFP) in bladder cancer cell lines. Loss of detectable p21 and a stable truncated p21 peptide were identified in sg12 and sg109 single-cell clones, respectively. We found that p21-deficient cells (sg12) were sensitized to cisplatin, while cells harboring distally truncated p21 (sg12 clones) demonstrated enhanced cisplatin resistance. p21-deficient sg12 clones demonstrated less repair of DNA-platinum adducts and increased γ-H2AX foci after cisplatin exposure, suggesting there was persistent DNA damage after p21 loss. p21-deficient sg12 clones were also unable to prevent the activation of CDK1 after DNA damage, and therefore, continued through the cell cycle, resulting in replication fork collapse, potentially explaining the observed cisplatin sensitization. sg109 clones were neither unable to sequester PCNA nor localize p21 to the nucleus after DNA damage, potentially explaining the chemoresistant phenotype. Our findings suggest that different CDKN1A truncations have different and perhaps disparate biology, and that there may be a duality of effect on cisplatin sensitivity depending on mutation context. IMPLICATIONS: Some truncating CDKN1A mutations generate a retained peptide that may have neomorphic functions and affect cisplatin sensitivity in patients with bladder cancer.

CYP2C19 genotype-guided antiplatelet therapy: promises and pitfalls.

Pharmacogenetic variants can alter the mechanism of action (pharmacodynamic gene variants) or kinetic processes such as absorption, distribution, metabolism and elimination (pharmacokinetic gene variants). Many initial successes in precision medicine occurred in the context of genes encoding the cytochromes P450 (CYP enzymes). CYP2C19 activates the antiplatelet drug clopidogrel, and polymorphisms in the CYP2C19 gene are known to alter the outcome for patients taking clopidogrel in the context of cardiovascular disease. CYP2C19 loss-of-function alleles are specifically associated with increased risk for coronary stent thrombosis and major adverse cardiovascular events in patients taking clopidogrel following percutaneous coronary intervention. We explore successes and challenges encountered as the clinical and scientific communities advance CYP2C19 genotyping in the context of routine patient care.

Pulmonary Adenocarcinoma Presenting as a Pineal Gland Mass With Obstructive Hydrocephalus.

Background: Adenocarcinoma is the most prevalent type of non-small cell carcinoma of the lungs. Patients with lung adenocarcinoma often present with cough, dyspnea, pain, and weight loss. They can also present with signs and symptoms of brain metastasis because the lungs are one of the most common origins of metastatic brain cancer. We describe a rare case of adenocarcinoma of the lungs presenting with pineal region metastasis. Case Report: A 61-year-old male presented to the emergency department with dizzy spells and gait disturbance. Magnetic resonance imaging of the brain demonstrated a solitary mass in the pineal region with marked obstructive hydrocephalus. A stereotactic biopsy was performed, and metastatic adenocarcinoma consistent with pulmonary origin was diagnosed. Computed tomography scan of the chest revealed a spiculated mass. The patient died shortly after the diagnosis was made. Conclusion: The pineal region is an unusual site for brain metastasis. Although such metastasis has rarely been described, it should be considered in the differential diagnosis of pineal region tumors, especially for patients with suggestive clinical or histopathologic features of primary malignancy elsewhere.

Utility of Endoscopic Ultrasound in the Work Up for Solitary Hepatobiliary Neuroendocrine Lesions.

A 43-year-old woman, with an unremarkable past medical history, presented with a three-week history of generalized itching, jaundice, and abdominal pain. Initial workup showed amorphous, regionally invasive, and obstructing soft tissue mass in the region of the hepatic hilum. The middle third of the main bile duct was subsequently found to harbor a polypoid mass on endoscopic retrograde cholangiopancreatograph. Biopsy revealed nests of neoplastic cells that was subsequently identified as well-differentiated neuroendocrine tumor. A search for a possible primary neuroendocrine tumor was performed and included imaging of the chest, abdomen, and pelvis, a colonoscopy, capsule endoscopy, and an octreotide scan; however, no primary tumor outside of the liver was identified. Surgical debulking was performed, during which intraoperative exploration and ultrasound failed to reveal any extra-hepatic tumor sanctuaries. A few months later, patient underwent endoscopic ultrasound (EUS) for evaluation of recurrent abdominal pain which revealed a small lesion in the pancreas. It was unclear, however, whether it was primary or a metastatic lesion. This case represents a diagnostic challenge and emphasizes the potential utility of EUS in the preoperative work up for any presumable primary hepatobiliary neuroendocrine tumor.

Toxicities of Immune Checkpoint Inhibitors: Itis-Ending Adverse Reactions and More.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer worldwide. Not long ago, before the introduction of ICIs, many cancers incurred a grave prognosis on patients due to the lack of effective therapies. For instance, patients with malignant melanoma survive longer and experience a better quality of life than ever before due to agents such as nivolumab and ipilimumab. Nevertheless, toxicities associated with the use of ICIs have been increasingly recognized in clinical trials as well as oncology practice. The widespread usage of ICIs and the expected addition of newer ICIs to the arsenal of medications to fight cancer raise awareness of the potential toxicities of these medications. Once these toxicities develop, immunosuppression with or without withholding immunotherapy is the standard of care. Because the long-term adverse effects of these toxicities and the impact of stopping therapy on survival are not well characterized, a joint decision by both the oncologist and the patient should be carried out if stopping therapy is being considered. Nevertheless, long-term data is necessary to guide such decisions. In this article, we will discuss common ICI's immune-related adverse events with a simplified approach to recognizing and managing these events.

Hypercalcaemia, renal dysfunction, anaemia and bone lesions (CRAB) do not always represent multiple myeloma: diffuse large B cell lymphoma presenting with CRAB symptoms in a 69-year-old man.

Hypercalcaemia, renal dysfunction, anaemia and bone lesions (CRAB) are a constellation of signs and symptoms that are collectively referred to as the CRAB features. When present together, multiple myeloma (MM) should be at the top of the differential diagnosis. We present a 69-year-old man who presented with severe body aches and bone pain in his ribs and pelvis, associated with fatigue and constipation. He was found to have hypercalcaemia, acute kidney injury, anaemia and numerous lytic lesion on chest imaging. Physical examination and imaging were unremarkable for any enlarged lymph nodes. The patient was initially suspected to have multiple myeloma, however, serum and urine protein electrophoresis, and serum free light chain assays were negative. The patient was ultimately diagnosed with diffuse large B cell lymphoma based on a bone marrow biopsy. This case highlights the fact that presence of hypercalcaemia, renal dysfunction, anaemia and bone lesions are not usually specific for MM.