Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.

AIMS: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. METHODS AND RESULTS: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. CONCLUSION: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update.

Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaw (MRONJ) were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007 and 2009. The position papers were developed by a special committee appointed by the board and composed of clinicians with extensive experience in caring for these patients and basic science researchers. The knowledge base and experience in addressing MRONJ has expanded, necessitating modifications and refinements to the previous position paper. This special committee met in September 2013 to appraise the current literature and revise the guidelines as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis, staging, and management strategies and highlights current research status. The AAOMS considers it vitally important that this information be disseminated to other relevant health care professionals and organizations.

A case of malignant transformation of a serous borderline ovarian tumor effectively treated with BRAF/MEK inhibitor combination.

We describe a patient diagnosed with a metastatic adenocarcinoma of Müllerian origin, harboring a BRAF V600E mutation, ten years after being treated for a serous borderline tumor (SBOT). While BRAF mutations in the setting of SBOTs are common, they have been typically associated with a low chance of transformation or recurrence. The therapeutic approach, which combined hormone inhibition with receptor tyrosine kinase inhibitors (dabrafenib and trametinib), has demonstrated notable and enduring efficacy. This is clinically evidenced through serial PET-CT scans with sustained responses and extended progression-free survival, and serologically confirmed by monitoring CA-125 levels. This case demonstrates the critical role of early next-generation sequencing in detecting actionable molecular changes in rare cancers and possible metastases. It provides valuable insights into treating uncommon Müllerian adenocarcinomas and underscores the importance of targeted therapies in achieving long-lasting treatment outcomes.

Bisphosphonate-related osteonecrosis of the jaw: diagnosis, prevention, and management.

Bisphosphonate therapy has been considered standard therapy in the management and care of cancer patients with metastatic bone disease and patients with osteoporosis. The efficacy of these drugs is due to their ability to inhibit osteoclast-mediated bone resorption. However, the postmarketing experience with intravenous and, to a much lesser extent, oral bisphosphonates has raised concerns about potential side effects related to profound bone remodeling inhibition and osteonecrosis isolated to the jaws. We review the risk factors, incidence, pathogenesis, prevention strategies, and management of this new complication.

Electrocardiographic manifestations of COVID-19: Effect on cardiac activation and repolarization.

BACKGROUND: Prolonged QT intervals are reported in patients with COVID-19. Additionally, virus particles in heart tissue and abnormal troponin levels have been reported. Consequently, we hypothesize that cardiac electrophysiologic abnormalities may be associated with COVID-19. METHODS: This is a retrospective study between March 15th, 2020 and May 30th, 2020 of 828 patients with COVID-19 and baseline ECG. Corrected QT (QTc) and QRS intervals were measured from ECGs performed prior to intervention or administration of QT prolonging drugs. QTc and QRS intervals were evaluated as a function of disease severity (patients admitted versus discharged; inpatients admitted to medical unit vs ICU) and cardiac involvement (troponin elevation >0.03 ng/ml, elevated B-natriuretic peptide (BNP) or NT pro-BNP >500 pg/ml). Multivariable analysis was used to test for significance. Odds ratios for predictors of disease severity and mortality were generated. FINDINGS: Baseline QTc of inpatients was prolonged compared to patients discharged (450.1±30.2 versus 423.4±21.7  msec, p<0.0001) and relative to a control group of patients with influenza (p=0.006). Inpatients with abnormal cardiac biomarkers had prolonged QTc and QRS compared to those with normal levels (troponin - QTc: 460.9±34.6 versus 445.3±26.6  msec, p<0.0001, QRS: 98.7±24.6 vs 90.5±16.9  msec, p<0.0001; BNP - QTc: 465.9±33.0 versus 446.0±26.2  msec, p<0.0001, QRS: 103.6±25.3 versus 90.6±17.6 msec, p<0.0001). Findings were confirmed with multivariable analysis (all p<0.05). QTc prolongation independently predicted mortality (8.3% increase in mortality for every 10  msec increase in QTc; OR 1.083, CI [1.002, 1.171], p=0.04). INTERPRETATION: QRS and QTc intervals are early markers for COVID-19 disease progression and mortality. ECG, a readily accessible tool, identifies cardiac involvement and may be used to predict disease course. FUNDING: St. Francis Foundation.

Tracheostomy during SARS-CoV-2 pandemic: Recommendations from the New York Head and Neck Society.

The rapid spread of SARS-CoV-2 in 2019 and 2020 has resulted in a worldwide pandemic characterized by severe pulmonary inflammation, effusions, and rapid respiratory compromise. The result of this pandemic is a large and increasing number of patients requiring endotracheal intubation and prolonged ventilator support. The rapid rise in endotracheal intubations coupled with prolonged ventilation requirements will certainly lead to an increase in tracheostomy procedures in the coming weeks and months. Performing tracheostomy in the setting of active SARS-CoV-2, when necessary, poses a unique situation, with unique risks and benefits for both the patient and the health care providers. The New York Head and Neck Society has collaborated on this document to provide guidance on the performance of tracheostomies during the SARS-CoV-2 pandemic.

EGFR expression in gallbladder carcinoma in North America.

BACKGROUND: Increased epidermal growth factor receptor (EGF receptor) expression has been noted in various cancers and has become a useful target for therapeutic interventions. Small studies from Asia and Australia have demonstrated EGFR over-expression in gallbladder cancer. We sought to evaluate the expression of EGFR in a series of 16 gallbladder cancer patients from North America. METHODS: Using tumor registry data, we identified 16 patients diagnosed with gall bladder carcinoma at our medical center between the years of 1998 and 2005. We performed a retrospective review of these patients' charts, obtained cell blocks from pathology archives and stained for EGFR and Her2/neu. RESULTS: Fifteen of sixteen patients were noted to over-express EGFR. Three were determined 1+, nine were 2+ and three were 3+. Eight patients had poorly differentiated adenocarcinoma, six had moderately differentiated and two had well-differentiated tumors. In this small series, there was a trend toward shorter survival and more poorly differentiated tumors in patients with greater intensity of EGFR expression. One patient was EGFR negative but 3+ for erb-2/Her 2-neu expression. No patient co-expressed EGFR and Her-2-neu. Median survival of patients in this series was 17 months. CONCLUSION: In view of our observations confirming the over-expression of EGFR in our patient population in North America, and the recent success of EGFR targeted therapies in other solid tumors that over-express EGFR, it may now be appropriate to evaluate agents targeting this pathway either as single agents or in combination with standard chemotherapy.

Safety profile of intravenous bisphosphonates.

Because of their proven efficacy, intravenous bisphosphonates play an important role in reducing the risk of skeletal-related events including pathologic fractures, spinal cord compression, and palliative radiotherapy to bone in patients with malignant bone lesions. Overall, intravenous bisphosphonates have an acceptable safety profile and are commonly associated with transient and manageable flu-like symptoms after initial infusions. In addition, bisphosphonates have dose- and infusion rate-dependent effects on renal function that can be proactively managed in patients with reduced creatinine clearance rates by following recommended dosing guidelines. Recently, there have been reports of osteonecrosis of the jaw (ONJ) in patients with advanced cancer receiving complex chemotherapeutic treatment regimens and supportive care with bisphosphonates. ONJ prevention and management recommendations have been developed that may reduce the risk of ONJ and the impact of ONJ on quality of life. Moreover, bisphosphonate therapy has resulted in considerable clinical benefits in patients with malignant bone disease; therefore, the potential for adverse events such as ONJ must be placed into context with these meaningful benefits.

Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: An objective response rate of 11% was reported in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with 500 mg daily gefitinib although the recommended dose in lung cancer is 250 mg. This study evaluated the efficacy and toxicity of 250 mg daily gefitinib in patients with recurrent and/or metastatic SCCHN. EXPERIMENTAL DESIGN: Phase II trial with objective response rate as the primary end point. Measurements of quality of life and levels of serum vascular endothelial growth factor and transforming growth factor-alpha were assessed before and during therapy. RESULTS: In 70 patients, 1 (1.4%) partial response was observed. Median progression-free survival and overall survival were 1.8 and 5.5 months, respectively. Quality of life scores improved transiently during the first weeks of therapy before returning to baseline. Median vascular endothelial growth factor and transforming growth factor-alpha levels were above the normal range but were not predictive of outcome. Four patients experienced grade 3 drug-related adverse events. Rash of any grade was observed in 64% of subjects. Correlation between disease control (partial response + stable disease), progression-free survival, and overall survival and grade of cutaneous toxicity was observed (P = 0.001, 0.001, and 0.008 respectively). CONCLUSIONS: Gefitinib monotherapy at 250 mg in recurrent and/or metastatic SCCHN seems to have less activity than was previously observed for 500 mg daily. A dose-response relationship may exist for this agent in SCCHN and grade of cutaneous toxicity attributable to gefitinib is a clinical predictor of better outcome.

Orbital lymphomas: a clinicopathologic study of a rare disease.

OBJECTIVE: To evaluate the clinicopathologic features and prognosis of patients with orbital lymphomas. METHODS: Clinical and pathologic data of 35 patients with biopsy-proven orbital lymphoma diagnosed at a tertiary care hospital from 1992 to 2001 were reviewed. Lymphomas were divided into low-grade and high-grade lymphomas. Survival of patients was compared according to age, gender, disease site, extent of disease, tumor grade, and treatment modality by using log rank test. RESULTS: Median patient age was 75 years (23-94) and the male-to-female ratio was 1:2.9. Twenty-three patients (66%) were diagnosed with low-grade lymphoma, and 12 patients (34%) were found to have high-grade lymphoma. Among low-grade lymphomas, marginal zone lymphoma (n=6), follicle center cell lymphoma (n= 6), and small lymphocytic lymphoma (n=5) were common entities, whereas diffuse large cell B-cell lymphoma (n=5) was the most common entity in patients with high-grade lymphoma. Disease was clinically localized in 74% of patients at the time of diagnosis. Radiation alone or with chemotherapy was the primary treatment modality in 83% of patients. All except one patient had an objective response to therapy. Over the median follow-up period of 47 months (range, 1.5-141 months), disease recurred in 37% patients who achieved a complete response. The estimated 5- and 10-year survival rates were 64% and 42%, respectively. Overall, 13 (37%) patients died, 6 with high-grade and 7 with low-grade lymphoma. No clinical variable was found to be prognostically significant with respect to survival. CONCLUSIONS: Orbital lymphoma is a disease of the elderly with a female preponderance. It tends to be localized to the orbit at the time of diagnosis and responds well to local or systemic therapy.

Antiresorptive Therapies for the Treatment of Malignant Osteolytic Bone Disease.

Osteolytic bone disease contributes to morbidity and mortality. Antiresorptive therapies reduce the morbidity of metastatic bone disease and alter the natural progression of malignant bone pathophysiology. Several trials showed improvement in quality of life, delay of skeletal-related events, and improvement in bone pain with these agents. Evolving data suggest a role of improvement in morbidity related to other cancer therapies that have potential side effects. Early indication shows they may alter survival in a subset of patients. This article reviews data confirming the efficacy of antiresorptive agents and discusses preliminary data on preventative therapy.

Randomized Multicenter Phase II Study of Modified Docetaxel, Cisplatin, and Fluorouracil (DCF) Versus DCF Plus Growth Factor Support in Patients With Metastatic Gastric Adenocarcinoma: A Study of the US Gastric Cancer Consortium.

PURPOSE: Docetaxel, cisplatin, and fluorouracil (DCF) is a standard first-line three-drug chemotherapy regimen for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and is associated with significant toxicity. We examined the safety and efficacy of a modified DCF (mDCF) regimen in a randomized multicenter phase II study. PATIENTS AND METHODS: Previously untreated patients with metastatic gastric or GEJ adenocarcinoma were randomly assigned to receive either mDCF (fluorouracil 2,000 mg/m2 intravenously [IV] over 48 hours, docetaxel 40 mg/m2 IV on day 1, cisplatin 40 mg/m2 IV on day 3, every 2 weeks) or parent DCF (docetaxel 75 mg/m2, cisplatin 75 mg/m2, and fluorouracil 750 mg/m2 IV over 5 days with granulocyte colony-stimulating factor, every 3 weeks). The study had 90% power to differentiate between 6-month progression-free survival of 26% and 43%, with type I and II error rates of 10% each. An early stopping rule for toxicity was included, defined as grade 3 to 4 adverse event rate > 70% in the first 3 months. RESULTS: From November 2006 to June 2010, 85 evaluable patients were enrolled (male, n = 61; female, n = 24; median age, 58 years; Karnofsky performance status, 90%; GEJ, n = 28; gastric, 57). mDCF (n = 54) toxicity rates included 54% grade 3 to 4 toxicity (22% hospitalized) within the first 3 months and 76% grade 3 to 4 toxicity over the course of treatment. The DCF arm (n = 31) closed early because of toxicity, with rates of 71% grade 3 to 4 toxicity (52% hospitalized) within 3 months and 90% grade 3 to 4 toxicity over the course of treatment. Six-month PFS was 63% (95% CI, 48% to 75%) for mDCF and 53% (95% CI, 34% to 69%) for DCF. Median overall survival was improved for mDCF (18.8 v 12.6 months; P = .007). CONCLUSION: mDCF is less toxic than parent DCF, even when supported with growth factors, and is associated with improved efficacy. mDCF should be considered a standard first-line option for patients with metastatic gastric or GEJ adenocarcinoma.

The role of monoclonal antibodies in stem cell transplantation.

Monoclonal antibodies directed at the lymphoid antigens have become established treatments for hematological malignancies either alone or in combination with chemotherapy. However, their incorporation in the transplant setting remains investigational. This review focuses on the currently available data for in vitro and in vivo purging with these antibodies as well as their role in modulating graft-versus-host disease (GVHD).

Clinical staging and prognostic markers in chronic lymphocytic leukemia.

In this article we provide a brief review of the two staging systems in chronic lymphocytic leukemia, and we discuss the more recently identified, new prognostic markers that are of interest to clinicians and researchers in this field.

Gemcitabine-induced pulmonary toxicity: case report and review of the literature.

Gemcitabine is a pyrimidine analog with a similar chemical structure and mechanism of action, as cytarabine. It has been shown to be a highly active agent for non-small cell lung cancer, pancreatic cancer, urothelial cancer, breast cancer and ovarian cancer. Gemcitabine is relatively well tolerated and myelosuppression is the dose-limiting toxicity. Pulmonary toxicity with gemcitabine is relatively uncommon, but a well recognized entity, associated with significant morbidity and mortality. A high index of suspicion, early diagnosis and timely intervention with oxygen supplementation, steroids, and diuretics is necessary to manage patients with this complication.

F-18 FDG versus Ga-67 for detecting splenic involvement in Hodgkin's disease.

PURPOSE: The objectives of this investigation were to characterize splenic uptake patterns of F-18 fluorodeoxyglucose (FDG) and Ga-67 in newly diagnosed Hodgkin's disease, to correlate these uptake patterns with the presence or absence of splenic disease, and to compare the accuracy of these two studies for detecting splenic disease. METHODS: FDG positron emission tomography and Ga-67 whole-body and SPECT imaging were performed in 32 patients with previously untreated Hodgkin's disease. Two readers, blinded to clinical information and final diagnoses, independently reviewed the study results. For both FDG and Ga-67, the intensity of splenic uptake was compared with the intensity of hepatic uptake and graded as follows: 0, less than liver uptake; 1, equal to liver uptake; and 2, greater than liver uptake. Differences in interpretation were resolved by consensus. RESULTS: Twelve (38%) of 32 patients had splenic disease. Using splenic uptake greater than hepatic uptake as the criterion for a positive study, the sensitivity, specificity, and accuracy of FDG were 92%, 100%, and 97%, respectively. Using splenic uptake at least as intense as hepatic uptake as the criterion for a positive study, the sensitivity specificity, and accuracy of Ga-67 were 50%, 95%, and 78%, respectively. The differences in sensitivity and accuracy of FDG and Ga-67 were significant (P = 0.04, and 0.03, respectively). CONCLUSION: In newly diagnosed Hodgkin's disease, FDG accurately diagnoses splenic involvement and is significantly more sensitive and accurate than Ga-67 for this purpose.

Utility of immunocytochemistry in diagnosing leptomeningeal metastases from an intrahepatic cholangiocarcinoma.

Isolated spinal leptomeningeal metastases (LMM) without brain metastases are infrequent, accounting for about 1% of all solid tumors. In LMM, cerebrospinal fluid (CSF) analyses are mostly abnormal. Demonstrations of intrathecal tumor markers are highly suggestive, but only a positive cytology is diagnostic. The initial CSF cytology can give a false negative result in up to 40-50% of patients with pathologically proven LMM on autopsy. We report a case of intrahepatic cholangiocarcinoma with spinal LMM confirmed using cytokeratin7 and pancytokeratin (AE1/AE3) immunocytochemical studies on paucicellular cerebrospinal fluid cytospin preparation. Given the paucicellularity of the smears and difficult morphologic categorization, immunocytochemistry is vital for confirmatory diagnosis and can help reduce false negative results. To the best of our knowledge this is the first case report of cytologically confirmed LMM from an intrahepatic cholangiocarcinoma while the patient was undergoing treatment.

Renal Medullary Carcinoma Masquerading as Bilateral Breast Carcinoma Category: Case Report.

Metastatic disease to the breast accounts for less than 1% of all breast carcinoma. Here we describe an unusual case of a 34-year-old black female with history of sickle cell trait who presented to her gynecologist with bilateral palpable breast masses. Based on initial workup including pathology results from biopsies of both breast masses, she was diagnosed with bilateral breast cancer. However further radiographic imaging revealed a large right kidney mass suspicious for primary renal neoplasm along with lung and bone lesions. This prompted re-review of the initial breast pathology. Sickled erythrocytes were identified and results of an additional immunohistochemical panel revealed positive expression of PAX 8, vimentin, Oct3/4, and loss of INI1, confirming the diagnosis of metastatic renal medullary carcinoma. We discuss the importance of considering renal medullary carcinoma in the differential diagnosis when evaluating young patients with sickle cell hemoglobinopathies who present with aggressive metastatic disease.