Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Classical Hodgkin Lymphoma Across the United States.

BACKGROUND: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). PATIENTS/METHODS: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. RESULTS: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). CONCLUSION: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.

Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium.

PURPOSE: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS. CONCLUSION: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease.

Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD-CD38hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation.

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome-heat shock protein 70 (HSP70) signaling axis is triggered by CD8+ T cell cytotoxicity and contributes to the development of adaptive resistance to anti-programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti-PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti-PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti-PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti-PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.

Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events.

The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs.

Meta-Analysis of the Role of Intermittent Pneumatic Compression of the Lower Limbs to Prevent Venous Thromboembolism in Critically Ill Patients.

Critically ill patients (patients treated in a medical or surgical intensive care unit) are at high risk of venous thromboembolism (VTE) development (deep vein thrombosis [DVT] and/or pulmonary embolism). Multiple thromboprophylaxis strategies have been used for the prevention of VTE in this population with various outcomes. Therefore, we aimed to evaluate the efficacy of intermittent pneumatic compression (IPC) prophylaxis in the lower limb compared with no treatment, anticoagulant use, or their combinations in reducing risk. A comprehensive electronic database search was conducted for all randomized clinical trials (RCTs) comparing the clinical outcomes of IPC versus anticoagulants or no treatment or their combinations for the prevention of VTE for critically ill patients. The primary outcome was VTE. The secondary outcome was DVT. We performed a Bayesian network meta-analysis to calculate odds ratios (ORs) and 95% credible intervals (CrIs). We included 5 RCTs with 3133 total patients, represented by a mean age of 49.61 ± 18 years, while 60.28% were male. There was a significant reduction of the primary outcome (incidence of VTE events) when no treatment was compared with IPC (OR = 0.36; 95% CrI = 0.18-0.71), anticoagulation alone (OR = 0.30; 95% CrI = 0.12-0.68), or anticoagulation with IPC (OR = 0.34; 95% CrI = 0.13-0.81). In addition, there was a significant reduction in DVT when no treatment was compared with IPC (OR = 0.45; 95% CrI = 0.21-0.9), anticoagulation alone (OR = 0.16; 95% CrI = 0.03-0.66), or anticoagulation with IPC (OR = 0.18; 95% CrI = 0.03-0.84). However, there were no significant differences between other comparisons (IPC vs anticoagulation alone, anticoagulation alone vs anticoagulation with IPC, or anticoagulation with IPC vs IPC alone) regarding VTE or DVT incidence. Among critically ill patients, IPC alone, anticoagulation alone, and IPC with anticoagulation were associated with a significant reduction of VTE and DVT incidence compared with no treatment. However, there was no significant difference between these modalities when compared together. Therefore, further larger studies comparing those different thromboprophylaxis modalities and their combinations are needed to provide more robust results for future clinical recommendations.

Meta-analysis and systematic review of randomized controlled trials assessing the role of thromboprophylaxis after vascular surgery.

BACKGROUND: Venous thromboembolism (VTE) is a well-known complication associated with surgical procedures. The implementation of thromboprophylaxis in this population has become a vital aspect of perioperative care to decrease VTE-associated morbidity and mortality risk. However, data assessing the role of thromboprophylaxis for patients undergoing vascular surgery are sparse. Assessing the role of thromboprophylaxis by low-molecular-weight heparin or unfractionated heparin in vascular surgery. METHODS: We searched MEDLINE, Embase, and the Cochrane Collaboration Central Register of Controlled Trials from inception until December 2020, for randomized controlled trials assessing the role of thromboprophylaxis in vascular surgery. RESULTS: Eight randomized controlled trials met inclusion criteria, including 3130 patients, with a mean age of 55.35 years and 45% were females. Compared with placebo, anticoagulant use was associated with a decrease in deep venous thrombosis (DVT) (risk ratio [RR], 0.34; 95% confidence interval [CI], 0.11-1.05; P = .06; I2 = 68%) and pulmonary embolism (PE) (RR, 0.17; 95% CI, 0.02-1.22; P = .08; I2 = 41%), but this trend did not attain statistical significance. There was no difference for bleeding outcomes between anticoagulants and placebo (RR, 0.90; 95% CI, 0.05-15.01; P = .94; I2 = 76%). There was no significant difference in outcomes when low-molecular-weight heparin was compared directly with unfractionated heparin. In a sensitivity analysis, anticoagulant use was associated with a significant decrease in DVT or PE in patients undergoing venous surgeries, but was not associated with a significant decrease in DVT or PE in patients undergoing arterial surgeries, although this analysis was limited by the small number of studies in each group. CONCLUSIONS: Among patients undergoing vascular surgery, thromboprophylaxis with anticoagulants showed a trend toward a lesser incidence of VTE when compared with placebo, although this difference was not statistically significant. Bleeding outcomes were comparable between both treatment groups.

Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.

The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.

When Variants Collide: An Unusual Presentation of Metastatic Gastric Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm.

Gastrointestinal neuroendocrine neoplasms were recently reclassified into the 2019 World Health Organization schema into well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Among these, gastric MiNENs are exceedingly rare and often metastasize quickly without diagnostic clues. We present a refractory gastric MiNEN with unique presenting features. This case highlights the clinical spectrum of these tumors, the importance of accurate histochemical interpretation, and clinical management in the absence of formalized guidelines. Future therapies looking at novel targets and palliative symptom relief are needed.

Human Immunodeficiency Virus (HIV) Masquerading as Myopathy and Rhabdomyolysis.

Human immunodeficiency virus (HIV) characteristically presents as a mononucleosis-like prodrome; rhabdomyolysis as a sole manifestation remains a rare finding from infection to seroconversion. A young male with a vague sexual history presented with myopathy progressing rapidly to rhabdomyolysis and renal failure. Acute HIV rarely presents with classic features, and rhabdomyolysis seems to manifest more in younger patients. Our case also demonstrates the importance of keeping a strong suspicion for HIV in the right setting despite false-negative results in the pre-seroconversion phase. The variability in HIV presentation and stigma of sexual history taking represents a diagnostic challenge. The astute clinician must be privy to these peculiarities to formulate a prompt diagnosis.

Thromboprophylaxis for orthopedic surgery; An updated meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) is a serious complication of orthopedic surgery. Low molecular weight heparin (LMWH) has been the standard of care for thromboprophylaxis in this population. However, direct oral anticoagulants (DOACs) are increasingly being used as alternatives. OBJECTIVE: To assess the efficacy and safety of DOACs versus LMWH for thromboprophylaxis in orthopedic surgery. METHODS: We searched MEDLINE, Embase, and the Cochrane Collaboration Central Register of Controlled Trials from inception until April 2020, for randomized controlled trials (RCTs) comparing DOACs with LMWH for thromboprophylaxis in orthopedic surgery. RESULTS: Twenty-five RCTs met inclusion criteria, including 40,438 patients, with a mean age of 68 years and 50% were males. Compared to LMWH, DOACs were associated with a significant reduction of major VTE; defined as the composite events of proximal deep vein thrombosis (DVT), pulmonary embolism (PE), and VTE-related mortality (RR 0.33; 95% CI: 0.20-0.53; P<0.01), and total DVT (RR: 0.59; 95% CI: 0.48-0.73; P<0.01), but not PE (RR 0.81; 95% CI: 0.49-1.34; P=0.42). There was no statistically significant difference between both groups on the incidence of major bleeding (RR 0.99; 95% CI: 0.77-1.27; P=0.92), clinically relevant non-major bleeding (RR 1.04; 95% CI: 0.92-1.17; P=0.52), all-cause mortality (RR 1.06; 95% CI: 0.64-1.76; P=0.83), VTE-related mortality (RR 0.84; 95% CI: 0.40-1.74; P=0.64) and bleeding-related mortality (RR 1.24; 95% CI: 0.30-5.18; P=0.77). CONCLUSION: For patients undergoing orthopedic surgery, thromboprophylaxis with DOACs is associated with a significant reduction of major VTE and DVT, compared to LMWH. Safety outcomes were not significantly different between both treatment groups.

Acute Esophageal Necrosis (Gurvits Syndrome) Presenting as Globus and Altered Phonation.

BACKGROUND Acute esophageal necrosis (AEN), also known as black esophagus or Gurvits syndrome, is an infrequently seen clinical condition distinguishable by a visually striking endoscopic appearance of necrotic esophageal mucosa that involves the distal esophagus with proximal extensions ending at the gastroesophageal junction. Since its early recognition pathologically in the 1960s and endoscopically in the 1990s, AEN, despite its rarity, is being increasingly recognized as a demonstratable cause of upper gastrointestinal bleeding. Cases of pan-esophageal necrosis are sparsely reported, leaving management guidance to isolated case reports. CASE REPORT An 80-year-old female smoker with advanced chronic obstructive pulmonary disease presented with signs and symptoms of acute pharyngitis and globus sensation that had been evolving over the preceding weeks. An esophagogastroduodenoscopy revealed circumferential necrotic mucosa encircling the entire lumen of the esophagus. The patient was made nil-per-os and started on high-dose anti-reflux therapy with adequate hemodynamic resuscitation. CONCLUSIONS AEN is multifactorial but primarily a combination of decreased tissue perfusion and a massive influx of gastric contents in settings of impaired local defense barriers. Despite its dramatic presentation, the majority of cases resolve with conservative medical management, foregoing surgical interventions.

A Case of an IgG4-Related Disease Mimicking Malignancy and Resolving With Steroids.

A 77-year-old African American female was referred to oncology for evaluation of an adrenal fossa mass detected on computed tomography scan of the abdomen and pelvis (CT-scan A/P) that was ordered as a work-up for painless hematuria. Further evaluation by positron emission tomography (PET) scan showed hypermetabolic masses in the left suprarenal and right iliac region. The biopsy of the right iliac mass was consistent with IgG4-related disease (IgG4RD). It was supported by an elevated serum IgG4 level. She was treated with prednisone with a good response.

Understanding the means of communication between nurses and resident physicians in the modern world: A community-based university hospital survey results.

In a hospital setting, nurses and physicians are the two main caregivers for admitted patients. Their communication is an important driver of positive teamwork and ensures proper patient safety and a high level of patient care. In a hospital with a large internal medicine residency program, where the main communication between nurses and residents is by phone calls, the excess number of phone calls received, especially for non-urgent patient-related matters, can be disruptive and cause fatigue and burnout. Alternative means of communication have been reported, namely using the electronic medical records to try and create new means of communication and to decrease the burden of direct communication for non-urgent matters. This manuscript describes the results of a survey administered in an attempt to understand the communication between residents and nurses in the setting of a new communication tool created within the electronic medical records.

Direct oral anticoagulant versus low-molecular-weight heparin for treatment of venous thromboembolism in cancer patients: An updated meta-analysis of randomized controlled trials.

BACKGROUND: Cancer associated venous thromboembolism (VTE) results in significant morbidity and mortality. Low molecular weight heparin (LMWH) has been standard of care for treatment of cancer-associated VTE, however direct oral anticoagulants (DOACs) are emerging as alternative treatment options. OBJECTIVE: To compare the benefits and harms of DOACs versus LMWH for treatment of VTE in cancer. DATA SOURCES: MEDLINE, Embase, and the Cochrane Collaboration Central Register of Controlled Trials from inception to April 2020. STUDY SELECTION: Randomized controlled trials (RCT) comparing DOACs with LMWH for treatment of VTE in cancer patients. DATA SYNTHESIS: Four good-quality RCTs, met inclusion criteria. Compared with LMWH, DOACs were associated with lower rates of VTE recurrence (RR 0.62; 95% CI: 0.44-0.87; P = 0.006), and DVT recurrence (RR 0.61; 95% CI: 0.4-0.94; P = 0.02) but not PE recurrence (RR 0.73; 95% CI: 0.51-1.04; P = 0.08), in cancer patients. However, the risk of clinically relevant non-major bleeding (CRNMB) (RR 1.58; 95% CI: 1.11-2.24; P = 0.01), and major bleeding in gastrointestinal cancer (RR 2.55; 95% CI 1.24-5.27, P = 0.01), were higher with DOACs. The risk of overall major bleeding (RR 1.33; 95% CI: 0.84-2.1; P = 0.22), all-cause mortality (RR 0.99; 95% CI: 0.84-1.17; P = 0.92), VTE-related mortality (RR: 1; 95% CI: 0.29-3.44; P = 1) and bleeding-related mortality (RR: 0.71; 95% CI: 0.17-2.91; P = 0.63), were similar in both treatment groups. CONCLUSION: Among cancer patients with VTE, treatment with DOACs is associated with a significant reduction of VTE and DVT recurrence, compared to LMWH. These benefits were offset by an increased risk of CRNMB, and major bleeding in gastrointestinal cancer.

Severe primary refractory thrombotic thrombocytopenic purpura (TTP) in the post plasma exchange (PEX) and rituximab era.

Acute acquired thrombotic thrombocytopenic purpura (TTP) requires prompt recognition and initiation of plasma exchange (PEX) therapy and immunosuppression. When PEX fails, mortality nears 100%, making finding an effective treatment crucial. Primary refractory TTP occurs when initial therapies fail or if exacerbations occur during PEX therapy, both signifying the need for treatment intensification to achieve clinical remission. Rituximab helps treat most of the refractory TTP cases, except those that are severely refractory. A paucity of studies guiding severely refractory TTP makes management arbitrary and individualised, highlighting the value of isolated reports. We present an extremely rare case of primary refractory TTP with an insufficient platelet response to numerous types of treatments, including emerging therapies such as caplacizumab, on the background of repeated PEX and immunosuppressive therapies.