Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma.

BACKGROUND: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause. RESULTS: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation. CONCLUSIONS: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.).

Role of Continuous Drainage of Tense Ascites in Peritoneal Dialysis: Mehandru/Masud Technique.

Insertion of a peritoneal dialysis (PD) catheter in end-stage renal disease (ESRD) patients with cirrhosis and tense ascites remains a challenge for nephrologists. Ascitic fluid leak at the surgical site, a common postoperative occurrence, leads to the disqualification of many patients who could be otherwise great candidates for PD. The ascitic fluid leak has been described to occur during or immediately after surgery even after the entire volume of ascitic fluid has been drained. In this study, we report a case study of three patients with ESRD, liver cirrhosis, and tense ascites on hemodialysis. The patients required super large volume paracentesis (SLVP), draining 9,000 - 15,000 cc of ascitic fluid twice weekly in an interventional radiology setup. Besides ascitic fluid drainage, the patients needed in-center hemodialysis (ICHD) 3 days a week, leading to their engagement in procedures 5 days a week. In addition, intradialytic symptomatic hypotension, hypoalbuminemia, and other adverse effects of hemodialysis lead to their poor lifestyle. To improve their lifestyle, all patients desired to switch to PD from ICHD. Upon the PD catheter insertion and drainage of the entire ascitic fluid, leaks developed at the insertion site within a few hours. To overcome these leaks, PD catheters of all three patients were attached via a transfer set to a bag for continuous drainage of ascitic fluid for about 2 weeks. No leak or complication was noted, leading to complete healing of insertion site. We recommend, for the patients with tense ascites requiring SLVP, approximately 2 weeks of healing period continuously be performed till initiation of PD training,.

Dentistry and Bioterrorism: A Legitimate Threat.

Bioterrorism involves the deliberate release of harmful biological agents, such as bacteria and viruses, aimed at causing mass casualties within a population. Often referred to as "poor man's nuclear weapons," chemical and biological weapons pose a significant threat due to their potential for mass destruction. Detecting and preventing bioterrorist attacks is challenging, making them one of the most feared scenarios. Dentistry plays a crucial role in responding to bioterrorism and other catastrophic events, leveraging its personnel and facilities effectively. This paper explores the signs and symptoms of biological agents used in mass destruction, as well as the oral and dental manifestations of both naturally occurring and bioengineered infectious agents. Furthermore, the article stresses the importance of countermeasures against bioterrorism, including deterrence, prevention, surveillance, medical management, and training. Emphasis is placed on implementing surveillance systems, bolstering medical readiness, and conducting training programs to effectively detect, assess, and respond to bioterrorism threats. Ultimately, the article underscores the critical role of dentists and healthcare professionals in collaborative efforts to mitigate the impacts of bioterrorism through proactive measures.

Hyperviscosity Syndrome in Undifferentiated Connective Tissue Disease: A Diagnostic and Therapeutic Challenge.

Hyperviscosity is an uncommon manifestation of various underlying diseases. Rapid diagnosis and management of the underlying disease is crucial to prevent significant complications, including hypertension, cerebral vascular accidents, pulmonary embolism, bowel ischemia, and ophthalmologic pathologies. Although the acute management of complications arising from hyperviscosity is relatively straightforward, identifying and treating the underlying cause can prove difficult. This case highlights the difficulties of establishing a diagnosis and initiating appropriate management for a patient with hyperviscosity syndrome in a suspected rheumatologic disorder.

The impact of race and ethnicity on diffuse large B-cell lymphoma outcomes within the veterans health administration (VHA).

We performed a retrospective chart review of 6266 randomly selected DLBCL patients treated in the VHA nationwide between 1/1/2011 and 12/31/2021. The 3178 patients who met inclusion criteria were predominantly male (97%) and white (75%). Median age of diagnosis for Black patients was 63 years vs 69 years for the entire cohort (p < 0.001). However, patients in each race/ethnicity subgroup presented with similar rates of stage I/II and III/IV disease, IPI score, cell of origin and HIT status. Outcomes analysis revealed similar treatment, response rates, median overall survival, and 1-, 3-, and 5-year survival across all subgroups. Hispanic patients had a 21% lower risk of death (HR = 0.79) than white patients, and Black patients had no significant difference in survival (HR = 0.98). This large retrospective study shows that when standard of care therapy is given within an equal access system, short-term treatment and survival outcomes are the same for all races.

Dosimetric comparison between carotid-sparing IMRT and 3DCRT in early glottic cancer patients treated with definitive radiation therapy.

BACKGROUND: The purpose of this study was to evaluate the dosimetric benefits of carotid-sparing IMRT (intensity-modulated radiation therapy) over 3DCRT (three-dimensional conformal radiation therapy) in early glottic cancer patients. MATERIAL AND METHODS: Ten patients with histologically proven early-stage squamous cell cancer of glottis (T1N0), treated with definitive radiotherapy, were selected retrospectively for the dosimetric analysis. Patients were originally treated with 3DCRT technique. For comparison purpose, IMRT plans were generated for each patient. Dosimetric comparison was done between two techniques (IMRT and 3DCRT) in terms of PTV (planning target volume) coverage, HI (homogeneity index), CI (conformity index), and doses to right carotid artery, left carotid artery, and spinal cord. RESULTS: V95% for the PTV was higher in IMRT plans (98.26%) as compared to 3DCRT plans (95.12%) (P-value <0.001), whereas V105% for PTV was significantly higher in 3DCRT plans (16.77%) as compared to IMRT plans (0.32%) (P-value 0.11). In terms of both HI and CI, IMRT plans showed better conformity as compared to 3DCRT plans, with statistically significant difference. Both right and left carotid arteries' average mean and maximum doses were significantly lower in IMRT plans as compared to 3DCRT plans (P-value <0.001). IMRT plans resulted in significant carotid-sparing as compared to 3DCRT plans in terms of V35 and V50 (P-value <0.001). CONCLUSION: Carotid-sparing IMRT resulted in better PTV coverage and lower carotid artery dose as compared to 3DCRT in early glottic cancer patients.

Comparative Analysis of VMAT and IMRT Techniques: Evaluation of Dose Constraints and Bone Marrow Sparing in Cervical Cancer Patients Undergoing Chemoradiotherapy.

BACKGROUND: Carcinoma of the cervix is a globally significant cause of morbidity and mortality among women. Concurrent chemoradiotherapy, a standard approach for locally advanced cervical cancer, invariably involves pelvic irradiation. Although this strategy is effective, it inevitably affects the pelvic bone marrow, a crucial hematopoietic site, and leads to hematological toxicity The potential of IMRT to spare bone marrow in pelvic irradiation settings has been an area of significant interest, with the aim to mitigate the hematological toxicity associated with pelvic radiotherapy. Radiotherapy techniques have evolved in terms of conformity and normal tissue sparing. Our study intends to explore the use of BM sparing techniques among patients of carcinoma cervix. PATIENTS AND METHODS: Twenty patients of carcinoma cervix FIGO Stage IIIB treated with concurrent chemoradiotherapy were selected for this study. The external contour of bones was delineated on planning CT as a surrogate for BM. We generated three plans on a single patient:1. without BM as the dose constraint, namely N-IMRT plan; 2. with BM constraint, namely BMS-IMRT plan; 3. VMAT plan in which BM constraint was given. The dose volume histogram (DVH) for planning target volume (PTV) and organs at risk (OAR) were analyzed. BM parameters: V10, V20, V30, V40, mean, maximum and minimum dose were compared.  Results: PTV coverage was comparable in all techniques. VMAT plans resulted in superior BM sparing compared with N-IMRT plan (P-<0.001) and BMS-IMRT plan (P-<0.001, 0.021 and 0.001 respectively for V20, V30 and V40). VMAT plans had better CI compared with BMS-IMRT (P-0.002) and N-IMRT (P-0.001) plans. CONCLUSION: Our study adds to the growing evidence that VMAT might be the preferred technique for patients with carcinoma of the cervix undergoing concurrent chemoradiotherapy, as it provides comparable target coverage and better sparing of bone marrow compared to IMRT.

Classical Hematology Referrals at an National Cancer Institute-Designated Cancer Center: Lessons Learned.

PURPOSE: To understand the spectrum and volume of classical hematology (CH) referrals to hematology clinics at a National Cancer Institute (NCI)-designated cancer center (CC) to plan for the delivery of effective and equitable care for this population. METHODS: One referral office at the Academic CC located in Bexar County, TX, handles all adult hematology referrals. From October 1, 2021, to September 30, 2022, all nonmalignant hematology (MH) referrals were triaged daily to define the category of CH problem. Declined referrals (confirmed at triage that no CH problem was evident) are included as part of this analysis. Electronic consultation (opinion rendered without patient seen) at our CC is available and is not part of this analysis. RESULTS: One thousand nine hundred forty-five CH referrals were received in the 12-month period. Seventy-six referrals (3.9%) were declined. During the study period, there were 2,289 medical oncology referrals and 779 referrals for MH. CH referrals therefore comprise 39% of all hematology-oncology referrals and 71% of all hematology referrals at the CC. Anemia and thrombotic disorders were the most common categories of the accepted CH referrals at 487 (26%) and 393 (21%), respectively. Video visits were used for 447 of all CH referrals (23%), and the rest were in person. CONCLUSION: Nearly 40% of all referrals to hematology and medical oncology at our NCI-designated CC are for CH. Effective management of the CH population of patients will allow ideal care for CH problems and also allow cancer-focused care to improve.

The Impact of Time From Diagnosis to Initiation of Chemotherapy on Survival of Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma in the Veterans Health Administration.

INTRODUCTION: Our retrospective study evaluates the impact of time from diagnosis to treatment (TDT) on outcomes of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated within the Veterans Health Administration (VHA). METHODS: VHA patients diagnosed with DLBCL between 2011 and 2019 were included, while those with primary central nervous system lymphoma were excluded. The median overall survival and progression-free survival were estimated with the Kaplan-Meier method. Univariate, bivariate, and multivariable analyses were performed using the Cox proportional hazards model. The odds ratio for refractory outcomes was calculated using logistic regression. RESULTS: A total of 2448 patients were included. The median time from diagnosis to treatment of the cohort was 19 days. When comparing median progression-free survival, median overall survival, and the 2-year overall survival between the group that started treatment within 1 week and each of the other groups individually, there was a significant difference favoring improved survival in all groups with a TDT longer than 1 week (P < .0001). These patients also had a lower odds ratio for refractory outcomes. On multivariable analysis, TDT remained an independent prognostic factor. CONCLUSION: Our study shows that a TDT equal to or less than 1 week is associated with adverse clinical factors, worse outcomes, and response in DLBCL, even after adjusting for multiple known poor prognostic factors. This was the first time that response to first-line therapy was correlated to time to treatment. Our findings support ongoing efforts to improve currently standardized prognostic tools and the incorporation of TDT into clinical trials to avoid selection bias.

Advancing Inclusive Research (AIR) Site Alliance: Facilitating the inclusion of historically underrepresented people in oncology and ophthalmology clinical research.

BACKGROUND: The Advancing Inclusive Research (AIR) Site Alliance is composed of clinical research centers that partner with Genentech, a biotechnology company, to advance the representation of diverse patient populations in its oncology and ophthalmology clinical trials, test recruitment, and retention approaches and establish best practices to leverage across the industry to achieve health equity. METHODS: Through a data-driven selection process, Genentech identified 6 oncology and 3 ophthalmology partners that focus on reaching historically underrepresented patients in clinical trials and worked collaboratively to share knowledge and explore original ways of increasing clinical study access for every patient, including sites co-creation of a Protocol Entry Criteria Guideline with inclusion principles. RESULTS: For patients, three publicly available educational videos about clinical trials were created in multiple languages. The AIR Site Alliance has also defined invoiceable services for sites to enhance patient support; this has been built into the new study budget templates for sustainability. For healthcare professionals (HCPs), the first-of-its-kind AIR Educational Program was developed to focus on identifying and addressing bias and engaging historically underrepresented patient populations in trials. The sites also co-created videos for HCPs and patients on why advancing inclusive research matters. Over 16 regional health equity symposia have been delivered for patients, HCPs, and community leaders. CONCLUSIONS: This AIR Site Alliance is a model for other site alliances, including Kenya, South Africa, the United Kingdom, and Canada. Such alliances will build a robust and sustainable research ecosystem that includes diverse patient groups and encourages change across the healthcare system.

Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity.

Nonalcoholic fatty liver disease (NAFLD) is prevalent in the majority of individuals with obesity, but in a subset of these individuals, it progresses to nonalcoholic steatohepatitis (0NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of patients with NAFLD remain unclear. Here, we report that NAD(P)H oxidase 4 (NOX4) and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH and fibrosis. Mitochondria-derived ROS activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signaling, and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high-fat diet-fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation, and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH and fibrosis in mice fed a NASH-promoting diet. Thus, mitochondria- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and progression to NASH and fibrosis in obesity.

Plasmablastic Lymphoma: Past, Present, and Future.

Plasmablastic Lymphoma is a rare large B-cell lymphoma with unique immunohistochemical and morphological features. It was most commonly associated with HIV infection; however, it's now seen in other immunosuppressed states like autoimmune conditions, post-transplant settings, and even in elderly immunocompetent individuals. Although rare, it is an aggressive lymphoma with unfavorable outcomes. The aim of this manuscript is to have an in-depth review of the current knowledge of epidemiology, pathophysiology, prognostic markers, and treatment approaches currently in use and in clinical trials for this challenging disease.

Nematic Phase of Polar Unsymmetrical Bent-Core Molecules.

In liquid crystalline systems, the presence of polar groups at lateral or terminal positions is fundamentally and technologically important. Bent-core nematics composed of polar molecules with short rigid cores usually exhibit highly disordered mesomorphism with some ordered clusters that favourably nucleate within. Herein, we have systematically designed and synthesized two new series of highly polar bent-core compounds comprised of two unsymmetrical wings, highly electronegative -CN and -NO2 groups at one end, and flexible alkyl chains at the other end. All the compounds showed a wide range of nematic phases composed of cybotactic clusters of smectic-type (Ncyb ). The birefringent microscopic textures of the nematic phase were accompanied by dark regions. Further, the cybotactic clustering in the nematic phase was characterized via temperature-dependent XRD studies and dielectric spectroscopy. Besides, the birefringence measurements demonstrated the ordering of the molecules in the cybotactic clusters upon lowering the temperature. DFT calculations illustrated the favourable antiparallel arrangement of these polar bent-core molecules as it minimizes the large net dipole moment of the system.

Contrast-enhanced computed tomography abdomen versus diagnostic laparoscopy-based management in patients with penetrating abdominal trauma: a randomised controlled trial.

PURPOSE: Penetrating abdominal trauma was traditionally managed by mandatory exploration, which led to high rates of non-therapeutic surgery and prolonged hospital stay. Diagnostic laparoscopy (DL) is a less-invasive alternative; however, it requires general anaesthesia and carries a potential risk of iatrogenic injuries. Contrast-enhanced computed tomography (CECT)-guided selective non-operative management (SNOM) may avoid surgery altogether, but there is apprehension of missed injury. Randomised trials comparing these two modalities are lacking. This study is aimed at comparing outcomes of these two management approaches. METHODS: Hemodynamically stable patients with penetrating trauma to anterior abdominal wall were randomised in 1:1 ratio to DL or CECT-based management. Primary outcome was length of hospital stay (LOS). Secondary outcomes were rate of non-therapeutic surgery, complications, and length of intensive care unit (ICU) stay. RESULTS: There were 52 patients in DL group and 54 patients in CECT group. Mean LOS was comparable (3 vs 3.5 days; p = 0.423). Rate of non-therapeutic surgery was significantly lower in CECT group (65.4 vs 17.4%, p = 0.0001). Rate of complications and length of ICU stay were similar. Selective non-operative management based on CECT findings was successful in 93.8% of patients; 2 patients had delayed surgery. CONCLUSION: In patients with penetrating trauma to anterior abdominal wall, DL and CECT-based management led to comparable hospital stay. Significant reduction in non-therapeutic surgery could be achieved using a CECT-based approach. TRIAL REGISTRATION: Clinical trials registry-India (CTRI/2019/04/018721, REF/2019/01/023400).

Blunt Trauma to Brachiocephalic Artery: Presentation and Management.

Isolated innominate artery injury is very rare and accounts for less than 3% of recognized arterial injuries. Surgical exploration of the artery, especially at the origin of the artery from the arch of the aorta, is surgically challenging. Due to its rarity, any 1 surgeon's experience in dealing with innominate artery injury is bound to be limited. We report 2 cases of innominate artery injury post-blunt chest trauma. Both patients underwent thoracotomy and innominate artery Dacron graft repair and both had an uneventful postoperative course.

Hypermetabolic lymphadenopathy following the administration of COVID-19 vaccine and immunotherapy in a lung cancer patient: a case report.

BACKGROUND: Given the current climate of the pandemic, lung cancer patients are especially vulnerable to complications from severe acute respiratory syndrome coronavirus 2 infection. As a high-risk population group, these patients are strongly advised to receive coronavirus disease 2019 vaccination in accordance with Center for Disease Control and Prevention guidelines to minimize morbidity and mortality. In recent years, immunotherapy has taken a preeminent role in the treatment of non-small cell lung cancer with dramatic improvement in overall survival. Reactive lymphadenopathy following the administration of a coronavirus disease 2019 vaccination can confound the radiographic interpretation of positron emission tomography-computed tomography or computed tomography scans from lung cancer patients receiving immunotherapy. CASE PRESENTATION: Here, we present a case of a 61-year-old Caucasian female and former smoker who developed cervical, hilar, supraclavicular, mediastinal, and left retroauricular lymphadenopathy following her coronavirus disease 2019 booster vaccination. At the time, she had been receiving long-term immunotherapy for the treatment of advanced lung adenocarcinoma. Biopsy was pursued owing to concerns of treatment failure and confirmed recurrent malignancy. CONCLUSION: This case report highlights the importance of lymph node biopsies in lung cancer patients who present with contralateral lymphadenopathy following coronavirus disease 2019 vaccination to rule out tumor recurrence in this deserving patient population.

Promising antimalarials targeting apicoplast DNA polymerase from Plasmodium falciparum.

Malaria is caused by the parasite Plasmodium falciparum, which contains an essential non-photosynthetic plastid called the apicoplast. A single DNA polymerase, apPOL, is targeted to the apicoplast, where it replicates and repairs the genome. apPOL has no direct orthologs in mammals and is considered a promising drug target for the treatment and/or prevention of malaria. We previously reported screening the Malaria Box to identify MMV666123 as an inhibitor of apPOL. Herein we extend our studies and report structure-activity relationships for MMV666123 and identify key structural motifs necessary for inhibition. Although attempts to crystallize apPOL with the inhibitor were not fruitful, kinetic analysis and crystal structure determinations of WT and mutant apo-enzymes, facilitated model building and provided insights into the putative inhibitor binding site. Our results validate apPOL as an antimalarial target and provide an avenue for the design of high potency, specific inhibitors of apPOL and other A-family DNA polymerases.

The long-term sustainability of a respiratory culture nudge.

Resource-intensive interventions and education are susceptible to a lack of long-term sustainability and regression to the mean. The respiratory culture nudge changed reporting to "Commensal Respiratory Flora only: No S. aureus/MRSA or P. aeruginosa." This study demonstrated sustained reduction in broad-spectrum antibiotic duration and long-term sustainability 3 years after implementation.