Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas.

The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

Early bladder dysfunction after vesicovaginal fistula repair: A prospective comparative analysis of transvaginal, open, and laparoscopic abdominal approaches.

INTRODUCTION: We aim to compare the clinical and urodynamic profile of lower urinary tract symptoms (LUTS) in patients undergoing laparoscopic, open transabdominal, and laparoscopic transabdominal vesicovaginal fistulae (VVF) repair at 3 months of repair, that is, in early postoperative period. MATERIALS AND METHODS: Fifty-one consecutive patients with endoscopically confirmed VVF were enrolled in our study over 2 years. Malignant fistulae, radiation-induced, and complex fistulae were excluded after cross-sectional imaging. All patients underwent a postoperative assessment for the success of the repair. Then at 3 months, they completed the American Urological Association Symptom Score questionnaire and underwent a dual channel pressure-flow urodynamic study. The results of transvaginal, laparoscopic, and open transabdominal repairs were compared. RESULTS: All patients belonged to the Indian Caucasian race. The mean age was 35.43 ± 6.63 years. Thirty-two patients had supratrigonal and 19 had trigonal fistulae. Laparoscopic transabdominal repair was done in 15 patients, open transabdominal repair in 22 patients, and transvaginal repair in 14 patients. Forty-six patients reported some LUTS at a median follow-up of 5.83 ± 2.37 months postoperatively. Only 18 (35.2%) of these patients had moderate to severe symptoms The postoperative bladder dysfunction rates in open transabdominal, transvaginal and laparoscopic transabdominal groups were 36.4%, 28.6%, and 20%, respectively. Twenty-seven patients (52.9%) had some urodynamic abnormality, that is, small capacity (5), high voiding pressures (14), genuine stress incontinence (3), and poor compliance (3). Bladder capacity was a significant predictor of bladder dysfunction in our patients. CONCLUSIONS: In our study, all three surgical approaches were associated with bladder dysfunction, however, it was the least in the laparoscopic transabdominal approach. Postoperative bladder capacity is a significant predictor of bladder dysfunction.

Global treatment of haemorrhoids-A worldwide snapshot audit conducted by the International Society of University Colon and Rectal Surgeons.

AIM: There is no universally accepted treatment consensus for haemorrhoids, and thus, management has been individualized all over the world. This study was conducted to assess a global view of how surgeons manage haemorrhoids. METHODS: The research panel of the International Society of University Colon and Rectal Surgeons (ISUCRS) developed a voluntary, anonymous questionnaire evaluating surgeons' experience, volume and treatment approaches to haemorrhoids. The 44 multiple-choice questionnaire was available for one month via the ISUCRS email database and the social media platforms Viber and WhatsApp. RESULTS: The survey was completed by 1005 surgeons from 103 countries; 931 (92.6%) were in active practice, 819 (81.5%) were between 30 and 60 years of age, and 822 (81.8%) were male. Detailed patient history (92.9%), perineal inspection (91.2%), and digital rectal examination (91.1%) were the most common assessment methods. For internal haemorrhoids, 924 (91.9%) of participants graded them I-IV, with the degree of haemorrhoids being the most important factor considered to determine the treatment approach (76.3%). The most common nonprocedural/conservative treatment consisted of increased daily fibre intake (86.9%), increased water intake (82.7%), and normalization of bowel habits/toilet training (74.4%). Conservative treatment was the first-line treatment for symptomatic first (92.5%), second (72.4%) and third (47.3%) degree haemorrhoids; however, surgery was the first-line treatment for symptomatic fourth degree haemorrhoids (77.6%). Rubber band ligation was the second-line treatment in first (50.7%) and second (47.2%) degree haemorrhoids, whereas surgery was the second-line treatment in third (82.9%) and fourth (16.7%) degree symptomatic haemorrhoids. Rubber band ligation was performed in the office by 645(64.2%) of the participants. The most common surgical procedure performed for haemorrhoids was an excisional haemorrhoidectomy for both internal (87.1%) and external (89.7%) haemorrhoids - with 716 (71.2%) of participants removing 1, 2 or 3 sectors as necessary. CONCLUSION: Although there is no global haemorrhoidal treatment consensus, there are many practice similarities among the different cultures, resources, volume and experience of surgeons around the world. With additional studies, a consensus statement could potentially be developed.

Probing the Formation of Dark Interlayer Excitons via Ultrafast Photocurrent.

Optically dark excitons determine a wide range of properties of photoexcited semiconductors yet are hard to access via conventional time-resolved spectroscopies. Here, we develop a time-resolved ultrafast photocurrent technique (trPC) to probe the formation dynamics of optically dark excitons. The nonlinear nature of the trPC makes it particularly sensitive to the formation of excitons occurring at the femtosecond time scale after the excitation. As a proof of principle, we extract the interlayer exciton formation time of 0.4 ps at 160 µJ/cm2 fluence in a MoS2/MoSe2 heterostructure and show that this time decreases with fluence. In addition, our approach provides access to the dynamics of carriers and their interlayer transport. Overall, our work establishes trPC as a technique to study dark excitons in various systems that are hard to probe by other approaches.

Clinico-pathological characteristics of obstructing colorectal cancer and its management outcomes at a tertiary referral center of Eastern Nepal.

BACKGROUND: The aim of this study is to explore the treatment strategies being followed for patients with obstructing colorectal cancer (OCRC) at our institute and to know the management outcomes. METHODS: This study included 28 patients who were diagnosed with obstructing colorectal cancer (OCRC) either preoperatively or intraoperatively over a period of 5 years. RESULTS: Most were in the younger age group with mean age of 49.78 ± 15.96 years with 1/4th of the patients being younger than 40. There was no difference in incidence of OCRC among genders. It was found to be common in rural areas of the eastern Nepal, 16(57%) patients from such areas. 21.4% patients had complete bowel obstruction at presentation. The investigating modalities used were abdominal X-ray, ultrasonoghraphy of abdomen/pelvis, abdominal CT-scan, colonoscopy, serum CEA, punch biopsy and Faecal occult blood test. The anatomical shift to the right was observed with 54% lesions in the proximal colon. Majority were in advanced stage (stage 3:53.6%, stage 4:32.1%) with histologically adenocarcinoma (100%) and a higher incidence of synchronous lesion (28.6%). Patients averaged 13.82 days in the hospital with post-operative mortality rate of 3.6%. The 1-year and 2-years disease free survivals were 89.3% and 82.1% while overall survivals were 92.8% and 82.1% respectively. CONCLUSION: In developing countries like ours, relatively younger patients present to health center with obstructive colorectal cancer with anatomical shift to the right sided lesions. The treatments provided at our center and their outcomes are not inferior to that of the developed world.

Spin/Valley Coupled Dynamics of Electrons and Holes at the MoS2-MoSe2 Interface.

The coupled spin and valley degrees of freedom in transition metal dichalcogenides (TMDs) are considered a promising platform for information processing. Here, we use a TMD heterostructure MoS2-MoSe2 to study optical pumping of spin/valley polarized carriers across the interface and to elucidate the mechanisms governing their subsequent relaxation. By applying time-resolved Kerr and reflectivity spectroscopies, we find that the photoexcited carriers conserve their spin for both tunneling directions across the interface. Following this, we measure dramatically different spin/valley depolarization rates for electrons and holes, ∼30 and <1 ns-1, respectively, and show that this difference relates to the disparity in the spin-orbit splitting in conduction and valence bands of TMDs. Our work provides insights into the spin/valley dynamics of photoexcited carriers unaffected by complex excitonic processes and establishes TMD heterostructures as generators of spin currents in spin/valleytronic devices.

Outcomes of primary and secondary prophylaxis of chemotherapy-induced and febrile neutropenia in bendamustine plus rituximab regimens in patients with lymphoma and chronic lymphocytic leukemia: real-world, single-center experience.

PURPOSE: To examine the outcomes associated with granulocyte colony stimulating factors (G-CSFs) administered as primary versus secondary prophylaxis in setting of bendamustine plus rituximab (BR) regimens. METHODS: Eighty-five patients who underwent treatment for non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) with BR at the University of Arizona Cancer Center from November 2013 to June 2019 were evaluated through retrospective chart review. Patients were stratified into two groups: those who were given G-CSF for primary prophylaxis (n = 47) and for secondary prophylaxis (n = 38). G-CSF-included filgrastim or pegfilgrastim. The primary endpoints were incidence of febrile neutropenia and grade 3 or 4 neutropenia. RESULTS: Same-day G-CSF compared with next-day G-CSF was the most common G-CSF dosing method utilized in primary and secondary prophylaxis (94% and 100%), respectively. Primary and secondary prophylaxis groups were similar on baseline characteristics (p > 0.05); the primary outcome of FN (p > 0.05); all secondary outcomes (p > 0.05) except for a higher frequency of dose delays in secondary (40%) vs primary prophylaxis patients (13%; p = 0.01), and mean absolute neutrophil counts (ANC) in cycles 1 through 5. With higher ANC levels observed during all cycles in the primary prophylaxis group compared with secondary prophylaxis. CONCLUSIONS: In this single-center retrospective study, BR-treated lymphoma and CLL patients receiving primary versus secondary with G-CSF showed similar outcomes except, notably, for chemotherapy dose delays that may put secondary patients at risk for poor treatment outcomes. Further research is needed to evaluate the impact of primary versus secondary prophylaxis on treatment outcomes.

Treating Diffuse Large B Cell Lymphoma in the Very Old or Frail Patients.

OPINION STATEMENT: R-CHOP has been the standard of care for diffuse large B cell lymphoma (DLBCL), curing approximately 60% of patients for more than 2 decades. However, the optimal treatment of patients who are too frail to tolerate this regimen and/or are not candidates for anthracycline therapy continues to be debated. MInT and GELA trials established addition of rituximab to CHOP in DLBCL but excluded patients older than 80 years. Multiple regimens have been tried with varying success in the very elderly, including R-mini-CHOP, R-mini CEOP, R-split CHOP, pre-phase strategies, and R-GCVP. However, there has not been a randomized trial among these strategies. Although addition of novel agents including ibrutinib, brentuximab vedotin, lenalidomide, and many others on the horizon holds promise in this population, none have been tested in a randomized setting or have results awaited. There is also a lack of a validated and easy to use clinical tool in this population to predict patients who will not tolerate R-CHOP. Identifying patients who will not tolerate R-CHOP early with the help of tools like CGA, along with integrating biology-based treatment (ibrutinib, lenalidomide in activated B cell type DLBCL) is being investigated in this population.

Effect of Geometry on Electrokinetic Characterization of Solid Surfaces.

An analytical approach is presented to describe pressure-driven streaming current (Istr) and streaming potential (Ustr) generation in geometrically complex samples, for which the classical Helmholtz-Smoluchowski (H-S) equation is known to be inaccurate. The new approach is valid under the same prerequisite conditions that are used for the development of the H-S equation, that is, the electrical double layers (EDLs) are sufficiently thin and surface conductivity and electroviscous effects are negligible. The analytical methodology is developed using linear velocity profiles to describe liquid flow inside of EDLs and using simplifying approximations to describe macroscopic flow. At first, a general expression is obtained to describe the Istr generated in different cross sections of an arbitrarily shaped sample. Thereafter, assuming that the generated Ustr varies only along the pressure-gradient direction, an expression describing the variation of generated Ustr along the sample length is obtained. These expressions describing Istr and Ustr generation constitute the theoretical foundation of this work, which is first applied to a set of three nonuniform cross-sectional capillaries and thereafter to a square array of cylindrical fibers (model porous media) for both parallel and transverse fiber orientation cases. Although analytical solutions cannot be obtained for real porous substrates because of their random structure, the new theory provides useful insights into the effect of important factors such as fiber orientation, sample porosity, and sample dimensions. The solutions obtained for the model porous media are used to device strategies for more accurate zeta potential determination of porous fiber plugs. The new approach could be thus useful in resolving the long-standing problem of sample geometry dependence of zeta potential measurements.

Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance.

Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy.

Limited Stage Aggressive Non-Hodgkin Lymphoma: What Is Optimal Therapy?

OPINION STATEMENT: The seminal SWOG trial S8736 trial established the success of a short course of chemotherapy followed by involved field radiation in treating limited stage aggressive NHL lymphoma. Addition of rituximab offered a surprisingly modest improvement in this disease subset. Radioimmunotherapy could hold a slight advantage over rituximab, but that should be investigated in a randomized trial setting. The role of radiation therapy continues to be widely debated, with interpretation complicated by different trial populations, methods of assessing risk, as well as by differences in timing and dose of radiation. Prolonged course of chemotherapy followed by radiation is certainly not justified in all patients with limited stage disease. Three to four cycles of R-CHOP followed closely by IFRT/ISRT, or six cycles of R-CHOP chemoimmunotherapy (based on the MInT trial) are acceptable options. PET/CT scans may further limit radiation to minority of patients who have residual PET-positive masses. PET/CT-directed treatment strategy is being tested in a US intergroup trial. There is evidence that localized DLBCL has a different biology as compared to advanced stage disease. This relates to propensity of limited stage disease to be proportionately more germinal center B-cell like (GCB) and to have late relapses beyond 5 years. Both biology and imaging need to be integrated in the study of limited stage disease without presumption that it should be approached the same as advanced stage disease.

Cardiovascular adverse effects of targeted antiangiogenic drugs: mechanisms and management.

Anticancer treatment has evolved enormously over the last decade. Drugs targeting receptor tyrosine kinases, VEGFR and EGFR have changed the treatment landscape of certain cancers and have shifted the theme of anticancer therapy toward personalized care. However, these newer agents also come with unique side-effect profiles not seen with conventional chemotherapy including serious cardiovascular adverse effects. Hence, meticulous understanding of the adverse effects is crucial in maximizing clinical benefits and minimizing detrimental effects of these newer drugs. We have reviewed the cardiovascular adverse effects of anti-VEGF therapy in this article.

A comparative study on effects of defect closure versus non-closure in laparoscopic totally extraperitoneal repair of direct inguinal hernia.

Introduction: Totally extraperitoneal (TEP) and transabdominal preperitoneal (TAPP) repair are the principal techniques in laparoscopic hernia repair. Seroma formation and pain are frequent complications of moderate-large size laparoscopic direct inguinal hernia mesh repair. This study was conducted to evaluate the feasibility of defect closure in moderate-large direct inguinal hernias and its effect on various outcomes. Method: This is a prospective cohort study from September 2020 to August 2021, where a total of 88 patients with uncomplicated direct inguinal hernia (M3 or more) were enrolled in the study and divided into two equal groups of TEP defect closure and non-closure, and various outcome measures were noted. Results: The majority of patients were male (94.31%), with a mean age range of 18-85 years, and had right-sided inguinal hernia (46.5%). Seroma formation at 10th POD in the defect closure and non-closure were 24% and 33% (p value: 0.225), which reduced to 11% and 18%, respectively, at 1 month (p value: 1.000). All seromas resolved within 6 months. Pain in VAS at 10th POD in the defect closure and non-closure were 1.55±0.571 and 1.38±0.527, respectively (p value: 0.121), which gradually decreased to 1.20±0.524 and 1.16±0.420 at a 6-month interval (p value: 0.689). The mean operative time in the bilateral and unilateral defect closure groups was 72.3±4.1 and 56.5±4.3 min, respectively, whereas that in the bilateral and unilateral defect non-closure groups was 62.3±3.7 and 45.7±3.6 min, respectively. Conclusion: The defect closure was found to have higher pain and less seroma formation at various intervals of time following TEP for moderate-large direct inguinal hernia. Although these findings were statistically insignificant, they may be clinically significant, and further studies with a larger sample size are suggested.

Malignant rectal GIST managed with chemotherapy (Imatinib Mesylate): A case report and a comprehensive review.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors involving the gastrointestinal tract, arising from the interstitial cells of Cajal. GIST comprises about 1% of all GI tumors. Rectal GISTs are rare and comprise of approximately 5% of all GISTs and only 0.1% of rectal tumors are found to be GISTs. Rectal GISTs may be diagnosed incidentally or present with symptoms, including defecation problems, bleeding, and/or pain. We report a case of a 46-year-old male with rectal GIST metastasized to the liver and bilateral lung parenchyma managed by Imatinib Mesylate (IM) regimen. Rectal GIST although being rare, must be considered as a differential diagnosis in a patient presenting with defecatory problems with bleeding.

Acute intestinal obstruction secondary to ingested foreign body in an adult with autism spectrum disorder: A rare case report and review of literature.

Key Clinical Message: Foreign body ingestion is common in pediatric age group however can be found in any age group with intellectual disability and neurodevelopmental delay. There is usually a delay in presentation and interventions following foreign body ingestion in patients with neurodevelopmental delay, leading to increased morbidity, mortality, and complications owing to inability of such patients giving relevant history. Most ingested foreign bodies naturally pass through the digestive tract without untoward effects. Only a few patients may require surgical interventions. Principle of management should be to reduce anxiety among patients and their visitors. Speedy recovery is enhanced so that they can return to their familiar environment soon. Abstract: Foreign body ingestion is common in pediatric populations and may be found in any age group with intellectual disability and neurodevelopmental delay. As the patient cannot give a clear and relevant history, there is usually a delay in presentation and interventions following foreign body ingestion in patients with neurodevelopmental delay, leading to increased morbidity, mortality, and complications. Most foreign bodies pass through the digestive system without any complications, and very few require surgical intervention. The goal should be to reduce anxiety among patients and their visitors and to enhance speedy recovery so that they can return to their familiar environment soon. Here we report a case of Acute intestinal obstruction secondary to ingestion of the head portion of a doll which was managed with emergency laparotomy with enterotomy and removal of foreign body in a 16 years female with Autism Spectrum Disorder.

Traumatic Abdominal wall hernia with ileal perforation following blunt trauma abdomen: A rare case report and review of literature.

Blunt trauma abdomen with abdominal wall herniation with bowel perforation is an acute emergency condition. Road traffic accidents causing blunt trauma are common in a youngster like in our case. Once the patient is resuscitated, ultrasonography and Computed tomography must be done. Early surgical exploration with mesh or primary repair of the defect is the mainstay of management. We have a case of a 25-year-old male with blunt trauma abdomen and anterior wall hernia following a road traffic accident who was managed with emergency exploratory laparotomy as computed tomography suggested anterior abdominal wall herniation of bowel content.

Safety and efficacy of parsaclisib in combination with rituximab, bendamustine + rituximab, or ibrutinib in patients with previously treated B-cell lymphoma: analysis of a phase 1 dose-finding study (CITADEL­112).

Parsaclisib, a potent and highly selective phosphoinositide 3-kinase δ inhibitor, has shown clinical activity in relapsed/refractory (R/R) B-cell lymphoma. The phase 1 CITADEL-112 (NCT03424122) study assessed safety and efficacy of parsaclisib in combination with investigator choice standard of care (SOC; rituximab [Treatment A], rituximab plus bendamustine [Treatment B], or ibrutinib [Treatment C]) in 50 patients with R/R B-cell lymphoma. The most common treatment-emergent adverse events included neutropenia (62.5%, 50.0%, and 50.0% of patients in Treatments A, B, and C, respectively); diarrhea (37.5%) and anemia (31.3%) in Treatment A; abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Treatment B; and increased alanine and aspartate aminotransferase (each 37.5%) in Treatment C. Objective responses were observed in 13 patients (81.3%) in Treatment A, 10 (55.6%) in Treatment B, and 8 (50.0%) in Treatment C. Parsaclisib combined with SOC therapies had an expected safety profile and promising efficacy in patients with R/R B-cell lymphomas.

Strain fingerprinting of exciton valley character in 2D semiconductors.

Intervalley excitons with electron and hole wavefunctions residing in different valleys determine the long-range transport and dynamics observed in many semiconductors. However, these excitons with vanishing oscillator strength do not directly couple to light and, hence, remain largely unstudied. Here, we develop a simple nanomechanical technique to control the energy hierarchy of valleys via their contrasting response to mechanical strain. We use our technique to discover previously inaccessible intervalley excitons associated with K, Γ, or Q valleys in prototypical 2D semiconductors WSe2 and WS2. We also demonstrate a new brightening mechanism, rendering an otherwise "dark" intervalley exciton visible via strain-controlled hybridization with an intravalley exciton. Moreover, we classify various localized excitons from their distinct strain response and achieve large tuning of their energy. Overall, our valley engineering approach establishes a new way to identify intervalley excitons and control their interactions in a diverse class of 2D systems.

Household and plot-level survey data on adoption, outcomes, and perceptions of early sown wheat and zero tillage in Northwest India.

This study collected evidence on the use of early sown wheat varieties and complementary zero tillage technologies in Northwest India. Detailed information on farmers' knowledge, adoption decisions, personal experience, and perceptions of early sown wheat and zero tillage technologies were collected at the household level using different survey tools. Additional information on agricultural practices during the Rabi Season 2021/22 were collected at the plot level and geocoded. Overall, the dataset comprises responses from 1206 wheat farmers in 70 villages across 7 districts in Punjab and Haryana that were collected between September and October 2022. The villages were selected using stratified random sampling based on a sampling frame of 1722 communities that had been identified as predominantly wheat growing areas based on remote-sensing data from satellite images. The dataset provides rich information that may be used for assessing the diffusion and impact of recently developed wheat varieties designed for early sowing, identifying barriers to the wider adoption of these technologies, and informing policy making aimed at improving adoption and usage decisions of agricultural innovations.

Utilising anterolateral bladder flap to create a continent cutaneous diversion in a patient with pelvic fracture urethral injury.

A male child in the first decade of life presented to us with a history of a pelvic fracture and urethral injury resulting from a road traffic accident 4 months prior. He had previously undergone an exploratory laparotomy and suprapubic cystostomy at another medical centre. He was circumcised and exhibited a substantial urethral defect on the retrograde urethrogram, as well as on the micturating cystourethrogram. Following a careful assessment of the patient's and caregivers' expectations, a continent cutaneous catheterisable channel was planned. This procedure involved the use of an anterolateral bladder flap, and continence was achieved through the creation of a Nissen-type seromuscular invagination. Three months postoperatively, the child remains continent, can easily catheterise the stoma and has resumed his education.