Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. RESULTS: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CONCLUSION: CAR-T demonstrates clinical efficacy for patients with RT.

Novel chimeric antigen receptor targets and constructs for acute lymphoblastic leukemia: Moving beyond CD19.

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults with a poor prognosis with relapsed or refractory (R/R) B-cell lineage ALL (B-ALL). Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown excellent response rates in RR B-ALL, but most patients relapse due to poor persistence of CAR T-cell therapy or other tumor-associated escape mechanisms. In addition, anti-CD19 CAR T-cell therapy causes several serious side effects such as cytokine release syndrome and neurotoxicity. In this review, we will discuss novel CAR targets, CAR constructs, and various strategies to boost CARs for the treatment of RR B-ALL. In addition, we discuss a few novel strategies developed to reduce the side effects of CAR.

Venous Thromboembolism Risk Assessment in Hospitalized Cancer Patients: A Single Center Study.

This study aimed to identify predictors of venous thromboembolism (VTE) in hospitalized cancer patients and develop a predictive model using demographic, clinical, and laboratory data. Our analysis showed that patient groups categorized under a very high risk, and high risk, patients with low hemoglobin levels and renal disease were at a significantly increased risk of developing VTE. We developed a VTE risk-assessment model (RAM) with moderate discriminatory performance, high specificity, and negative predictive value, indicating its potential utility in identifying patients without VTE risk. However, the model's positive predictive value and sensitivity were low due to the low prevalence of VTE within the analyzed population. Future studies are needed to analyze additional predictive factors, and to validate the effectiveness of our VTE RAM to safely rule out VTE, compare it with other VTE RAMs in hospitalized cancer patients, and address any limitations of our study.

Bioinspired NiO Nanospheres: Exploring In Vitro Toxicity Using Bm-17 and L. rohita Liver Cells, DNA Degradation, Docking, and Proposed Vacuolization Mechanism.

The present work demonstrated a novel Cleome simplicifolia-mediated green fabrication of nickel oxide nanoparticles (NiO NPs) to explore in vitro toxicity in Bm-17 and Labeo rohita liver cells. As-fabricated bioinspired NiO NPs were characterized by several analytical techniques. X-ray diffraction (XRD) revealed a crystalline face-centered-cubic structure. Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible diffuse reflectance spectroscopy (UV-DRS), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS) confirmed NiO formation. The chemical composition was confirmed by energy-dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy. Brunauer-Emmett-Teller (BET) revealed the mesoporous nature. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed the formation of 97 nm diameter nanospheres formed due to the congregation of 10 nm size particles. Atomic force microscopy (AFM) revealed the nearly isotropic behavior of NiO NPs. Further, a molecular docking study was performed to explore their toxicity by binding with genetic molecules, and it was found that the docking energy was about -9.65284 kcal/mol. On evaluating the in vitro toxicity of NiO NPs for Bm-17 cells, the study showed that when cells were treated with a high concentration of NPs, cells were affected severely by toxicity, while at a lower concentration, cells were affected slightly. Further, on using 50 µg/mL, quick deaths of cells were observed due to the formation of more vacuoles in the cells. The DNA degradation study revealed that NiO NPs are significantly responsible for DNA degradation. For further confirmation, trypan blue assay was observed for cell viability, and morphological assessment was performed using inverted tissue culture microscopy. Further, the cytotoxicity of NiO NPs in L. rohita liver cells was studied. No toxicity was observed at 1 mg/L of NiO NPs; however, when the concentration was 30 and 90 mg/L, dark and shrank hepatic parenchyma was observed. Hence, the main cause of cell lysis is the increased vacuolization in the cells. Thus, the present study suggests that the cytotoxicity induced by NiO NPs could be used in anticancer drugs.

Mechanism of nanotoxicity in Chlorella vulgaris exposed to zinc and iron oxide.

Usage of nanoparticle in various products has increased tremendously in the recent past. Toxicity of these nanoparticles can have a huge impact on aquatic ecosystem. Algae are the ideal organism of the aquatic ecosystem to understand the toxicity impact of nanoparticles. The present study focuses on the toxicity evaluation of zinc oxide (ZnO) and iron oxide (Fe2O3) nanoparticles towards freshwater microalgae, Chlorella vulgaris. The dose dependent growth retardation in Chlorella vulgaris is observed under ZnO and Fe2O3 nanoparticles and nanoform attributed more toxicity than their bulk counterparts. The IC50 values of ZnO and Fe2O3 nanoparticles was reported at 0.258 mg L-1 and 12.99 mg L-1 whereas, for the bulk-form, it was 1.255 mgL-1 and 17.88 mg L-1, respectively. The significant decline in chlorophyll content and increase in proline content, activity of superoxide dismutase and catalase, indicated the stressful physiological state of microalgae. An increased lactate dehydrogenase level in treated samples suggested membrane disintegration by ZnO and Fe2O3 nanoparticles. Compound microscopy, scanning electron microscopy and transmission electron microscopy confirm cell entrapment, deposition of nanoparticles on the cell surface and disintegration of algal cell wall. Higher toxicity of nanoform in comparison to bulk chemistry is a point of concern.

Iatrogenic Severe Splenic Injury after Colonoscopy.

Colonoscopy is a low-risk procedure performed for screening and diagnostic purposes. About 15 million colonoscopies were carried out in the United States in 2012 with this number projected to increase. Injury to the spleen as a complication of colonoscopy is still a rather rare occurrence. We report a case of significant splenic injury, American Association of Surgery for Trauma (AAST) grade III with hemoperitoneum, in a patient following diagnostic colonoscopy, managed conservatively without the need for invasive or salvage surgical procedure.

Severe recurrent gastrointestinal bleeding following percutaneous endoscopic gastrostomy tube placement: a rare complication.

Severe bleeding requiring blood transfusions following endoscopic, percutaneous gastrostomy tube placement is a rare complication. We describe a case of severe recurrent haemorrhage with bright red blood from rectum from endoscopic, percutaneous gastrostomy tube placement, which ultimately required removal of the percutaneous endoscopic gastrostomy tube.

Overutilisation of imaging studies for diagnosis of pulmonary embolism: are we following the guidelines?

OBJECTIVE: To evaluate if imaging studies such as CT pulmonary angiography (CTPA) or ventilation-perfusion (V/Q) scan are ordered according to the current guidelines for the diagnosis of pulmonary embolism (PE). METHODS: We performed a retrospective observational cohort study in all adult patients who presented to the Sparrow Hospital Emergency Department from January 2014 to December 2016 and underwent CTPA or V/Q scan. We calculated the Wells' score retrospectively, and d-dimer values were used to determine if the imaging study was justified. RESULTS: A total of 8449 patients underwent CTPA (93%) or V/Q scan (7%), among which 142 (1.7%) patients were diagnosed with PE. The Wells' criteria showed low probabilities for PE in 96 % and intermediate or high probabilities in 4 % of total patients. Modified Wells' criteria demonstrated PE unlikely in 99.6 % and PE likely in 0.4 % of total patients. D-dimer was obtained in only 37 % of patients who were unlikely to have a PE or had a low score on Wells' criteria. Despite a low or unlikely Wells' criteria score and normal d-dimer levels, 260 patients underwent imaging studies, and none were diagnosed with PE. CONCLUSION: More than 99 % of CTPA or V/Q scans were negative in our study. This suggests extraordinary overutilisation of the imaging methods. D-dimer, recommended in patients with low to moderate risk, was ordered in only one-third of patients. Much greater emphasis of current guidelines is needed to avoid inappropriate utilisation of resources without missing diagnosis of PE.

Delayed Presentation of Isolated Adrenocorticotropin Insufficiency after Nivolumab Therapy for Advanced Non-small-cell lung carcinoma (NSCLC).

We describe a 73-year-old man who developed adrenal insufficiency 7 months after completing nivolumab therapy for advanced non-small cell lung cancer. He presented with non-specific symptoms of malaise and fatigue with an insidious 13.6 kilogram weight loss, prompting an evaluation for disease progression, which was negative. Subsequent evaluation revealed isolated adrenocorticotropin insufficiency as the aetiology, attributed to a delayed side effect of nivolumab therapy.

Spontaneous tumour lysis syndrome in small cell lung cancer: a rare phenomenon.

Tumour lysis syndrome (TLS) is an oncological emergency. It is caused by cellular death occurring secondary to cancer therapy or spontaneously in rapidly dividing tumours. More common in haematological malignancies, it has also been reported in solid tumours. Out of 14 cases of small cell lung cancer (SCLC) with TLS, only three cases of spontaneous TLS have been reported in literature to date. Here we report a case of SCLC presenting as a spontaneous TLS.

Angioimmunoblastic T-cell lymphoma: a rare subtype of peripheral T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of NHL and usually presents in the late stage due to the atypical laboratory findings. Immunohistochemistry of the lymph node in AITL is characterized by positive CD2, CD3, CD4, CD10, CXCL-13, PD1 often BCL-6 and CD20 positive. Meshworks of follicular dendritic cells are seen outside follicles with CD21 and CD23 stains. EBV can be often positive as well. Autologous transplantation should be offered in the first remission as poor outcome is reported with anthracycline-containing regimens.

Blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm is an aggressive neoplasm with a median survival of only a few months despite treatment. An exhaustive immunohistochemical workup is required to differentiate it from myeloid sarcoma and extranodal NK/T cell lymphoma. Treatment is with induction using a regimen utilized for leukemia. Allogeneic hematopoietic stem cell transplantation is recommended for those who achieve remission following induction.

CK 20-positive and CK 7-negative Merkel cell carcinoma of the cheek.

Merkel cell carcinomas (MCCs) are uncommon, highly malignant skin tumors that develop in sun-exposed areas of the skin. Most of the MCCs are CK 20-positive and CK 7-negative such as our case. About 80% of Merkel cell carcinoma is associated with Merkel cell polyomavirus.

Dieulafoy's Lesion In The Oesophagus: A Rare Cause Of Upper Gastrointestinal Bleeding.

A Dieulafoy's lesion is defined as a dilated, aberrant, submucosal artery that erodes overlying mucosa in the absence of an underlying ulcer, aneurysm or intrinsic mural abnormality. It is a rare cause of upper gastrointestinal (GI) bleed with a very high mortality rate if it goes unidentified. It is most commonly located in the lesser curvature of the stomach but is extremely rare in the oesophagus. We are reporting a 55-year-old man who had massive haematemesis. Emergent endoscopy showed Dieulafoy's lesion in the distal oesophagus. It was sclerosed using endoscopic therapy. Patient's symptoms of GI bleeding resolved, and he was discharged home in a stable manner. Although a Dieulafoy's lesion is exceedingly rare in the oesophagus, it is associated with a high mortality if undiscovered. Its amenability to life-saving endoscopic therapy prompts us to keep this as a possible differential diagnosis of an upper GI bleed.

Hepatotoxicity Associated With Vismodegib.

An 82-year-old Caucasian woman with a history of basal cell carcinoma on vismodegib presented with nausea, vomiting and intermittent abdominal pain. Laboratory results were remarkable for the elevation of liver enzymes. Endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiogram (PTC) did not show evidence of intrahepatic or extrahepatic obstruction of the biliary tract. During PTC external biliary catheter was placed; however, bilirubin continued to rise. Further, laboratory work-up and imaging studies ruled out other possible aetiologies for hepatotoxicity such as infections, autoimmune hepatitis and other drugs known to be hepatotoxic thus leaving vismodegib the most likely cause of hepatotoxicity.

Role Of Conservative Management In Emphysematous Gastritis.

Emphysematous gastritis (EG) is a rare disease of the stomach that is caused by gas-forming bacteria, and it can be lethal. There have been <70 reported cases in the English literature of this disease which carries a mortality rate up to 60%. Early recognition and treatment through conservative management have been a popular and successful choice in today's medicine. Studies have shown that surgical intervention does not confer a statistical benefit on mortality in this condition. We present another case of EG in a 33-year-old woman who was successfully managed conservatively.