The Equipoise Between the Treatment of Glioblastoma and the Risk of Secondary Acute Myelogenous Leukemia: An Illustrative Case Report.

We present a case report of a 56-year-old woman who was diagnosed with biopsy-proven left thalamic glioblastoma multiforme (GBM). She was treated with standard concurrent chemotherapy and radiation, as well as a 2-year period of adjuvant temozolomide. She relapsed 2 ½ years after starting her initial therapy and was treated with bevacizumab and lomustine, but she relapsed. She was then placed on a phase 1/2 clinical trial that included KHK2455 and mogamulizumab-kpkc individually and in combination for almost 4 years. She had a rapid demise due to the development of a neutropenic pneumonia and treatment-induced acute myeloid leukemia (AML) and elected for hospice care.

Hairy Cell Leukemia: Where Are We in 2023?

PURPOSE OF REVIEW: This article summarizes the current state of knowledge of hairy cell leukemia (HCL) regarding presentation, diagnosis, therapy, and monitoring, including perspectives on emergent therapies. RECENT FINDINGS: Over the past decade, there has been enormous progress in the understanding of the biology of HCL which has led to the development of novel therapeutic strategies. The maturation of data regarding existing management strategies has also lent considerable insight into therapeutic outcomes and prognosis of patients treated with chemo- or chemoimmunotherapy. Purine nucleoside analogs remain the cornerstone of treatment, and the addition of rituximab has deepened and prolonged responses in the upfront and relapsed setting. Targeted therapies now have a more defined role in the management of HCL, with BRAF inhibitors now having a potential in the first-line setting in selected cases as well as in relapse. Next-generation sequencing for the identification of targetable mutations, evaluation of measurable residual disease, and risk stratification continue to be areas of active investigation. Recent advances in HCL have led to more effective therapeutics in the upfront and relapsed setting. Future efforts will focus on identifying patients with high-risk disease who require intensified regimens. Multicenter collaborations are the key to improving overall survival and quality of life in this rare disease.

Outcomes of responders to PD-1/PD-L1 inhibitors who discontinue therapy after sustained disease control.

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). METHODS: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center (UNMCCC) between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD, PR, CR)] were selected and outcomes reviewed from their electronic health records. RESULTS: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head & neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n = 14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n = 20, non-cancer related surgery, n = 1) (non-irAE group, n = 21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 9 of 14 (64%) patients continued to show SDC. Only 5 of 14 (36%) patients in this group experienced progression of disease (PD), with 1 of 2 patients achieving DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. CONCLUSIONS: We demonstrate that 22 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 25 (71%) remain in DC. Future prospective malignancy-specific trials are warranted to evaluate optimal treatment duration.

Nephrotoxicity in the Age of Immune Checkpoint Inhibitors: Mechanisms, Diagnosis, and Management.

Immune checkpoint inhibitors (ICI) revolutionized cancer therapy by augmenting anti-tumor immunity via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). However, this breakthrough is accompanied by immune-related adverse effects (irAEs), including renal complications. ICI-related nephritis involves complex mechanisms like auto-reactive T cells, auto-antibodies, reactivation of drug-specific T cells, and cytokine-driven inflammation culminating in AKI. ICI-AKI typically manifests weeks to months into treatment, often with other irAEs. Timely detection relies on monitoring creatinine levels and urine characteristics. Biomarkers, like soluble interleukin-2 receptor (sIL-2R) and urine cytokine levels, provide non-invasive insights, while renal biopsy remains the gold standard for confirmation. Management of ICI-AKI requires a balance between discontinuing ICI therapy and prompt immunosuppressive intervention, typically with corticosteroids. Some cases permit ICI therapy resumption, but varying renal recovery rates highlight the importance of vigilant monitoring and effective therapy. Beyond its clinical implications, the potential of irAEs to predict positive treatment responses in certain cancers raises intriguing questions. Data on nephritis-treatment response links are limited, and ongoing research explores this complex interaction. In summary, ICI therapy's transformative impact on cancer treatment is counterbalanced by irAEs, including nephritis. Early recognition and management are vital, with ongoing research refining diagnostic and treatment strategies.

The Cook Score: A Novel Assessment for the Prediction of Liver-Associated Clinical Events in a Diverse Population.

BACKGROUND AND AIMS: Transient elastography (TE) provides accurate quantification of liver fibrosis. Its usefulness could be significantly amplified in terms of predicting liver-associated clinical events (LACE). Our aim was to create a model that accurately predicts LACE by combining the information provided by TE with other variables in patients with chronic liver disease (CLD). METHODS: We retrospectively reviewed the electronic medical records of patients who underwent liver elastography, at John H. Stroger Hospital in Cook County, Chicago, IL. The incidences of LACE were documented including decompensation of CLD, new hepatocellular carcinoma, and liver-associated mortality. Significant predicting factors were identified through a forward stepwise Cox regression model. We used the beta-coefficients of these risk factors to construct the Cook Score for prediction of LACE. Receiver-operating characteristic (ROC) curves were plotted for Cook Score to evaluate its efficiency in prediction, in comparison with MELD-Na Score and FIB-4 Score. RESULTS: A total of 3097 patients underwent liver elastography at our institution. Eighty-eight LACE were identified. Age (hazard ratio (HR) 1.04, p = 0.002), aspartate aminotransferase to alanine aminotransferase ratio (HR 2.61, p < 0.001), platelet count (HR 0.98, p < 0.001), international normalized ration (INR) (HR 17.80, p < 0.001), and liver stiffness measurement (HR1.04, p < 0.001) were identified as significant predictors. The Cook Score was constructed with two optimal cut-off points to stratify patients into low-, intermediate-, and high-risk groups for LACE. The Cook Score proved superior than MELD-Na Score and FIB4 Score in predicting LACE with an area under curve of 0.828. CONCLUSION: This novel score based on a large robust sample would provide accurate prediction of prognosis in patients with chronic liver disease and guide individualized surveillance strategy once validated with future studies.

Reactivation of Pulmonary Tuberculosis During Treatment of Chronic Myelomonocytic Leukemia.

A 76-year-old woman from a tuberculosis (TB) endemic region with chronic myelomonocytic leukemia (CMML) on Azacitidine presented with a non-productive cough. A CT scan of the chest revealed a lobulated opacity in the right upper lobe and antibiotic therapy was initiated for a potential bacterial pneumonia. However, a high suspicion for pulmonary TB remained given her nation of origin, immunosuppression, and imaging findings. Three sputum and bronchoalveolar lavage (BAL) acid-fast bacilli (AFB) smears with PCR testing for Mycobacterium tuberculosis were negative, as were examinations for other potential fungal or bacterial etiologies of the patient's symptoms and imaging findings. While awaiting final TB culture results from BAL, her CMML underwent a transformation to acute myeloid leukemia (AML). Given the urgent need for initiation of chemotherapy, empiric treatment for TB was commenced while awaiting the final TB culture. Within 48-hours of initiating therapy for TB, the patient's fevers subsided. One week after discharge our team was notified of a positive M. tuberculosis culture from BAL. We suspect that our patient had a latent TB infection which reactivated due to her CMML. This case highlights the importance of maintaining a high clinical suspicion for TB in high-risk patients, even in the case of initially negative laboratory examinations. Further, it demonstrates the importance of screening and treating latent TB in patients with leukemias.

Merkel Cell Carcinoma With Isolated Pancreatic Metastasis.

Merkel cell carcinoma (MCC) is a highly aggressive cutaneous neuroendocrine carcinoma, frequently associated with distant metastasis. However, recurrence of MCC manifesting with only pancreatic involvement is exceedingly rare. A 53-year-old man presented to our institution with abdominal discomfort 3 months after initial resection of chest wall MCC. Imaging revealed lesions in the pancreas and peripancreatic lymph nodes. Pathology obtained through endoscopic ultrasound confirmed recurrence of MCC. He underwent chemotherapy with cisplatin and etoposide, resulting in a complete resolution of the pancreatic lesions. Unfortunately, he passed away from sudden cardiac arrest while being in remission from MCC. Immunohistochemistry is crucial in differentiating MCC from primary pancreatic glandular and neuroendocrine tumors. While there are no definitive guidelines in the management of pancreatic lesions associated with MCC, checkpoint inhibitor immunotherapy is increasingly being used.

Heparin-Induced Thrombocytopenia in COVID-19.

COVID-19 (coronavirus disease-2019) infection is a highly prothrombotic state, resulting from a dysregulation of the coagulation cascade. Therefore, thromboprophylaxis is strongly recommended in these patients, with some experts even advocating for therapeutic dosing to prevent thromboembolic events. Heparin-induced thrombocytopenia (HIT) is a well-known complication of heparin therapy. In this article, we report a case of HIT in a patient with COVID-19. A 63-year-old male presented with 1 week of dry cough and diarrhea. He had a positive nasopharyngeal COVID-19 reverse-transcriptase-polymerase chain reaction. On admission, the platelet count and liver function tests were within normal limits. During his hospitalization, he developed a right femoral deep venous thrombosis and was started on therapeutic anticoagulation. Due to worsening respiratory failure, he was intubated and mechanically ventilated. Between days 11 and 12 of hospitalization, platelet count dropped from 304 000 to 96 000 cells/µL. He had a high pretest probability for HIT with a 4T score of 6 and a positive anti-PF4/heparin antibody. Heparin drip was discontinued and was switched to argatroban. The serotonin release assay eventually returned positive, which confirmed the diagnosis of HIT. We also discuss potential overdiagnosis of HIT in COVID-19 through 4 cases with false-positive HIT antibodies.

Tumor Lysis Syndrome in a Patient With Gastric Adenocarcinoma.

Tumor lysis syndrome (TLS) is a severe metabolic complication that usually occurs in patients with aggressive tumors who undergo treatment with chemotherapy. Traditionally, it was mainly associated with hematologic malignancies. However, over the past 4 decades, there have been increasing reports of TLS in solid tumors. We report a case of TLS in a patient with gastric cancer, as a complication of FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy. Our patient was a 48-year-old man with metastatic gastric adenocarcinoma who presented with altered mental status and slurred speech. On examination, he was confused and disoriented, but the rest of his examination, including vitals, was unremarkable. Laboratory findings on admission were significant for an elevated uric acid of 14.5 mg/dL, creatinine of 4.1 mg/dL, and phosphorus of 6.9 mg/dL. He had received his first cycle of FOLFOX chemotherapy 4 days prior to admission. The constellation of electrolyte abnormalities and the temporal relationship to chemotherapy led to the diagnosis of chemotherapy-induced TLS. He was treated with aggressive fluid repletion and rasburicase, following which the electrolyte derangements resolved, and he improved clinically. This case highlights the importance of early recognition of TLS in patients with gastric cancer. Initiation of early treatment can reduce the high morbidity and mortality associated with this oncologic emergency.

Gut derived-endotoxin contributes to inflammation in severe ischemic acute kidney injury.

BACKGROUND: Recent researches indicate that the intestinal consequences of renal ischemia reperfusion (IR) would predispose to the translocation of gut-derived endotoxin. Here, we designed experiments to test the hypothesis that the gut-derived endotoxin has a potential role in mediating local inflammatory processes in the acutely injured kidney. METHODS: Rats were performed sham or renal IR surgery (60 min of bilateral renal ischemia, then 24 h of reperfusion) (n = 5). The intestinal structural and mucosa permeability were evaluated. Serum endotoxin and bacterial load in liver and mesenteric lymph nodes (MLN) were measured. Separate groups were pretreated with oral norfloxacin 20 mg/kg/day or saline for 4 weeks and divided into sham plus saline, sham plus norfloxacin, renal IR plus saline and renal IR plus norfloxacin group. Serum biochemistry and endotoxin were determined. Kidney pathological changes were scored. Protein or mRNA expression of toll-like receptor 4 (TLR4) and proinflammatory mediators were measured in kidney homogenate. RESULTS: Renal IR led to marked intestinal integrity disruption and increase in intestinal permeability. These are accompanied by low grade of endotoxemia as well as increased bacterial load in liver and MLN. The group pretreated with norfloxacin showed significant attenuation of the increase in serum urea, ALAT, ASAT and endotoxin. The increased renal protein or mRNA of TLR4 and proinflammatory mediators (IL-6 and MCP-1) in the unpretreated animals was significantly attenuated in the norfloxacin-pretreated animals. However, norfloxacin pretreatment did not produce any protective effects on renal tubular integrity. CONCLUSIONS: Our results show for the first time that gut-derived endotoxin, resulting from an increased intestinal permeability after severe renal IR, subsequently amplifies intrarenal inflammatory response by activation renal TLR4 signaling. Our study results do not establish that antibiotic administration was effective in improving the overall renal outcome. However, our findings may be the first step to understanding how to tailor therapies to mitigate intrarenal inflammation in select groups of patients.