Metabolic dysfunction-associated fatty liver disease and heavy alcohol consumption increase mortality:A nationwide study.

BACKGROUND: The effects of excessive alcohol consumption on the prognosis of metabolic dysfunction-associated fatty liver disease (MAFLD) remain unclear. We investigated all-cause and cause-specific mortality according to the amount of alcohol consumed by Asian individuals with MAFLD. METHODS: This nationwide retrospective study included 996,508 adults aged 40-79 years who underwent health check-ups between 2009 and 2012. Participants were categorized by the alcohol consumption-non-alcohol, moderate alcohol, and heavy alcohol group (≥ 30 g/day for men, ≥ 20 g/day for women) and by the combination of the presence or absence of MAFLD. Hepatic steatosis was defined as the fatty liver index ≥ 30. Cox analyses were used to analyze the association between alcohol consumption and MAFLD and all-cause and cause-specific mortality. RESULTS: MAFLD significantly increased all-cause, liver-, and cancer-related mortality. Individuals with both MAFLD and heavy alcohol consumption expressed the highest mortality risk in liver-related mortality compared to non-MAFLD and non-alcohol group (adjusted hazard ratio (HR), 9.8; 95% confidence interval (CI), 8.20-12.29). Regardless of MAFLD, heavy alcohol consumption increased the risk of liver- and cancer-related mortality. CONCLUSIONS: MAFLD and heavy alcohol consumption increased all-cause, liver-, and cancer-related mortality. Heavy alcohol consumption and MAFLD synergistically increase liver-related mortality.

Novel Personalized Cancer Vaccine Using Tumor Extracellular Vesicles with Attenuated Tumorigenicity and Enhanced Immunogenicity.

Cancer vaccines offer a promising avenue in cancer immunotherapy by inducing systemic, tumor-specific immune responses. Tumor extracellular vesicles (TEVs) are nanoparticles naturally laden with tumor antigens, making them appealing for vaccine development. However, their inherent malignant properties from the original tumor cells limit their direct therapeutic use. This study introduces a novel approach to repurpose TEVs as potent personalized cancer vaccines. The study shows that inhibition of both YAP and autophagy not only diminishes the malignancy-associated traits of TEVs but also enhances their immunogenic attributes by enriching their load of tumor antigens and adjuvants. These revamped TEVs, termed attenuated yet immunogenically potentiated TEVs (AI-TEVs), showcase potential in inhibiting tumor growth, both as a preventive measure and a possible treatment for recurrent cancers. They prompt a tumor-specific and enduring immune memory. In addition, by showing that AI-TEVs can counteract cancer growth in a personalized vaccine approach, a potential strategy is presented for developing postoperative cancer immunotherapy that's enduring and tailored to individual patients.

Association between total cholesterol levels and all-cause mortality among newly diagnosed patients with cancer.

We aimed to determine the association between cholesterol values and the risk of all-cause mortality in newly diagnosed patients with cancer in a large-scale longitudinal cohort. Newly diagnosed patients with cancer were reviewed retrospectively. Cox proportional hazards regression models determined the association between baseline levels of total cholesterol (TC), triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and the risk of all-cause mortality. A restricted cubic spline curve was used to identify the association between total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol with the risk of death on a continuous scale and to present the lowest values of lipid measurements associated with death. The median follow-up duration of the study was 5.77 years. Of the 59,217 patients with cancer, 12,624 patients were expired. The multivariable adjusted hazard ratio (aHR) for all-cause mortality in patients with cancer with 1st-5th (≤ 97 mg/dL) and 96th-100th (> 233 mg/dL) in TC levels was 1.54 (95% CI 1.43-1.66) and 1.28 (95% CI 1.16-1.41), respectively, compared to 61st-80th (172-196 mg/dL). The TC level associated with the lowest mortality risk in the multivariable model was 181 mg/dL. In comparison with LDL-C levels in the 61st-80th (115-136 mg/dL), the multivariable aHR for all-cause mortality in cancer patients with LDL-C levels in the 1st-5th (≤ 57 mg/dL) and 96th-100th (> 167 mg/dL) was 1.38 (95% CI 1.14-1.68) and 0.94 (95% CI 0.69-1.28), respectively. The 142 mg/dL of LDL cholesterol showed the lowest mortality risk. We demonstrated a U-shaped relationship between TC levels at baseline and risk of mortality in newly diagnosed patients with cancer. Low LDL levels corresponded to an increased risk of all-cause death.

Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a phase I/II open-label multicenter study.

Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twice-daily and intravenous romidepsin administered on days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose escalation determined the maximum tolerated dose (MTD)/optimal doses of tenalisib and romidepsin. The phase II/dose expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose escalation, no dose-limiting toxicity was identified. Hence, the recommended doses for dose expansion were tenalisib 800 mg twice daily orally, and romidepsin 14 mg/m2 intravenous. Overall treatment-emergent adverse events of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related grade ≥3 treatment-emergent adverse events. The overall objective response rate in evaluable patients was 63.0% (peripheral TCL: 75% and cutaneous TCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Co-administration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL (clinicaltrials gov. Identifier: NCT03770000).

Association between lipid variability and the risk of mortality in cancer patients not receiving lipid-lowering agents.

Aim: We investigated the association between total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride (TG) variability and cancer patient mortality risk. Methods: We retrospectively analyzed 42,539 cancer patients who were not receiving lipid-lowering agents and who had at least three TC measurements within 2 years of their initial cancer diagnosis. Using a multivariable Cox regression model, the risk of mortality was evaluated. Results: In multivariable analysis, Q2 (adjusted hazard ratio [aHR]: 1.32, 95% confidence interval (CI): 1.24-1.41), Q3 (aHR: 1.66, 95% CI: 1.56-1.76), and Q4 (aHR: 1.96, 95% CI: 1.84-2.08) of coefficient of variation (CV) in TC were significantly associated with mortality risk compared to Q1, showing a linear association between higher TC variability and mortality (P for trend<0.001). Q2 (aHR: 1.34, 95% CI: 1.06-1.77), Q3 (aHR: 1.40, 95% CI: 1.06-1.85), and Q4 (aHR: 1.50, 95% CI: 1.14-1.97) were all significantly associated with a higher risk of death compared to Q1 in multivariable Cox regression for the association between CV in LDL and all-cause mortality (P for trend=0.005). Conclusion: In cancer patients who do not receive lipid-lowering agents, high variability in total cholesterol and LDL cholesterol levels was found to pose significant role in mortality risk.

Bone-modifying agents for non-small-cell lung cancer patients with bone metastases during the era of immune checkpoint inhibitors: A narrative review.

During the course of lung cancer progression, bone metastases occur in about 40% of patients. Common complications associated with bone metastases in lung cancer patients include musculoskeletal pain, pathologic fractures, spinal cord compression, and hypercalcemia. We discuss the efficacy of bone-modifying agents (BMAs) in reducing skeletal-related events (SREs) and improving cancer-related outcomes, particularly in patients with stage IV non-small-cell lung cancer with bone metastases. In addition, the combined effects of BMAs with radiotherapy or immunotherapy in reducing SREs in patients with lung cancer and bone metastases are explored.

Harnessing Oncolytic Extracellular Vesicles for Tumor Cell-Preferential Cytoplasmic Delivery of Misfolded Proteins for Cancer Immunotherapy.

In this study, extracellular vesicles (EVs) are reimagined as more than just a cellular waste disposal system and are repurposed for cancer immunotherapy. Potent oncolytic EVs (bRSVF-EVs) loaded with misfolded proteins (MPs) are engineered, which are typically considered cellular debris. By impairing lysosomal function using bafilomycin A1 and expressing the respiratory syncytial virus F protein, a viral fusogen, MPs are successfully loaded into the EVs expressing RSVF. bRSVF-EVs preferentially transplant a xenogeneic antigen onto cancer cell membranes in a nucleolin-dependent manner, triggering an innate immune response. Furthermore, bRSVF-EV-mediated direct delivery of MPs into the cancer cell cytoplasm initiates endoplasmic reticulum stress and immunogenic cell death (ICD). This mechanism of action leads to substantial antitumor immune responses in murine tumor models. Importantly, when combined with PD-1 blockade, bRSVF-EV treatment elicits robust antitumor immunity, resulting in prolonged survival and complete remission in some cases. Overall, the findings demonstrate that utilizing tumor-targeting oncolytic EVs for direct cytoplasmic delivery of MPs to induce ICD in cancer cells represents a promising approach for enhancing durable antitumor immunity.

EBV-positive PCNSL in older patients: incidence, characteristics, tumor pathology, and outcomes across a large multicenter cohort.

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

Endolysosomal impairment by binding of amyloid beta or MAPT/Tau to V-ATPase and rescue via the HYAL-CD44 axis in Alzheimer disease.

Impaired activities and abnormally enlarged structures of endolysosomes are frequently observed in Alzheimer disease (AD) brains. However, little is known about whether and how endolysosomal dysregulation is triggered and associated with AD. Here, we show that vacuolar ATPase (V-ATPase) is a hub that mediates proteopathy of oligomeric amyloid beta (Aß) and hyperphosphorylated MAPT/Tau (p-MAPT/Tau). Endolysosomal integrity was largely destroyed in Aß-overloaded or p-MAPT/Tau-positive neurons in culture and AD brains, which was a necessary step for triggering neurotoxicity, and treatments with acidic nanoparticles or endocytosis inhibitors rescued the endolysosomal impairment and neurotoxicity. Interestingly, we found that the lumenal ATP6V0C and cytosolic ATP6V1B2 subunits of the V-ATPase complex bound to the internalized Aß and cytosolic PHF-1-reactive MAPT/Tau, respectively. Their interactions disrupted V-ATPase activity and accompanying endolysosomal activity in vitro and induced neurodegeneration. Using a genome-wide functional screen, we isolated a suppressor, HYAL (hyaluronidase), which reversed the endolysosomal dysfunction and proteopathy and alleviated the memory impairment in 3xTg-AD mice. Further, we found that its metabolite hyaluronic acid (HA) and HA receptor CD44 attenuated neurotoxicity in affected neurons via V-ATPase. We propose that endolysosomal V-ATPase is a bona fide proteotoxic receptor that binds to pathogenic proteins and deteriorates endolysosomal function in AD, leading to neurodegeneration in proteopathy.Abbreviations: AAV, adeno-associated virus; Aß, amyloid beta; AD, Alzheimer disease; APP, amyloid beta precursor protein; ATP6V0C, ATPase H+ transporting V0 subunit c; ATP6V1A, ATPase H+ transporting V1 subunit A; ATP6V1B2, ATPase H+ transporting V1 subunit B2; CD44.Fc, CD44-mouse immunoglobulin Fc fusion construct; Co-IP, co-immunoprecipitation; CTSD, cathepsin D; HA, hyaluronic acid; HMWHA, high-molecular-weight hyaluronic acid; HYAL, hyaluronidase; i.c.v, intracerebroventricular; LMWHA, low-molecular-weight hyaluronic acid; NPs, nanoparticles; p-MAPT/Tau, hyperphosphorylated microtubule associated protein tau; PI3K, phosphoinositide 3-kinase; V-ATPase, vacuolar-type H+-translocating ATPase; WT, wild-type.

The association between clinical parameters and resectability in stage III non-small cell lung cancer, and a combination of N2 lymph node burden and lung immune prognostic index score as a potential biomarker.

Background: Surgery is important treatment option for stage III non-small cell lung cancer (NSCLC) because of its curative potential. We investigated the characteristics of resectable patients, and compared the outcomes according to treatment modalities. Methods: Among 1,092 patients with NSCLC diagnosed between 2008 to 2020 from 7 university hospitals of Catholic Medical Center, we retrospectively analyzed 252 patients with clinical or pathological stage III. We compared survival outcomes among the groups according to resectability, first-line treatments, and the lung immune prognostic index (LIPI) score. Clinical N2 subgroup was analyzed using multi-parameter scoring system. Results: The resectable group consisted of less smokers, showed better pulmonary function and lower inflammatory markers, and tended to be diagnosed as earlier cancer stage than the unresectable group. The resectable group showed better progression-free survival (PFS) and overall survival (OS) than the unresectable group (P<0.001 and P<0.001, respectively). Regarding the first-line treatment, surgery showed the longest median PFS (33.70 months) and the highest 12-month OS rate (91.6%) than the other treatment modalities. OS was significantly different depending on the LIPI score in whole population, as well as in the unresectable group (P=0.004 and P=0.003, respectively). LIPI 0 group exhibited better OS than LIPI 1 and 2 in both populations. Eastern Cooperative Oncology Group (ECOG) 2-4, LIPI 1-2, and first-line treatment were independent prognostic factors for OS. Smoking, forced expiratory volume in the first second (FEV1) and more advanced cancer stage were associated with unresectability. In subgroup analysis of N2 disease, we attempted to create new scoring system combining lymph node (LN) status and LIPI score. This scoring system showed significant association with OS. Conclusions: The patients with resectable stage III NSCLC showed better PFS and OS than the patients with unresectable tumor. LIPI score exhibited possibility to be used as potential biomarker in stage III NSCLC. The multi-parameter scoring system using LN status and LIPI score was predictive of OS in the N2 subgroup.

Protein-based nanocages for vaccine development.

Protein nanocages have attracted considerable attention in various fields of nanomedicine due to their intrinsic properties, including biocompatibility, biodegradability, high structural stability, and ease of modification of their surfaces and inner cavities. In vaccine development, these protein nanocages are suited for efficient targeting to and retention in the lymph nodes and can enhance immunogenicity through various mechanisms, including excellent uptake by antigen-presenting cells and crosslinking with multiple B cell receptors. This review highlights the superiority of protein nanocages as antigen delivery carriers based on their physiological and immunological properties such as biodistribution, immunogenicity, stability, and multifunctionality. With a focus on design, we discuss the utilization and efficacy of protein nanocages such as virus-like particles, caged proteins, and artificial caged proteins against cancer and infectious diseases such as coronavirus disease 2019 (COVID-19). In addition, we summarize available knowledge on the protein nanocages that are currently used in clinical trials and provide a general outlook on conventional distribution techniques and hurdles faced, particularly for therapeutic cancer vaccines.

Additive interaction of diabetes mellitus and chronic kidney disease in cancer patient mortality risk.

We investigated the additive interaction of diabetes mellitus (DM) and chronic kidney disease (CKD) on the risk of mortality in cancer patients and evaluated the impact of diabetic kidney disease (DKD) on mortality in cancer patients with DM. We retrospectively analyzed 101,684 cancer patients. A multivariable Cox regression model was used for assessing mortality risk. Relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI) were used to evaluate the additive interactive effect. The adjusted hazard ratio (aHR, 95%CI) for mortality was significant for those with CKD alone (1.53, 1.39-1.68), DM alone (1.25, 1.2-1.3), and both CKD and DM (1.99, 1.84-2.17) compared to non-CKD and non-DM cancer patients. The additive interaction between CKD and DM was significant (RERI 0.22[95%CI = 0.01-0.42], AP 0.11[0.01-0.21], SI 1.28[1.01-1.62]). Among cancer patients with DM, the presence of DKD raised the aHR for mortality (1.55, 95%CI = 1.33-1.81) compared to those without DKD. Coexistence of DM and CKD at the time of cancer diagnosis was significantly associated with an increased risk of mortality, and their interaction exerted an additive interactive effect on mortality. DKD was significantly associated with an increased risk of mortality in cancer patients with DM.

Iatrogenic Immunodeficiency Associated Lymphoproliferative Disorder in a Patient With Inflammatory Bowel Disease.

Primary colorectal lymphoma is incredibly rare and cases of iatrogenic immunodeficiency associated lymphoproliferative disorder (IILPD) isolated to colorectal area are even more uncommon. Immunodeficiency associated lymphoproliferative disorders can occur in association with primary immune disorders such as inflammatory bowel diseases (IBDs) which are often treated with various immunomodulatory drugs. Of the immunomodulatory drugs, thiopurines, in particular, are known to have a significantly increased relative risk for development of IILPDs. Here we present the case of a 43-year-old Caucasian man with a 22-year history of IBD treated with longstanding immunomodulatory therapy who presented with severe rectal pain and drainage. He underwent an examination under anesthesia with rigid proctoscopy and biopsies were taken of a hard exophytic appearing tissue along the posterior wall of the rectosigmoid junction. Pathological investigation of the samples revealed IILPD. He underwent treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and achieved complete remission. Literature demonstrates that the use of immunomodulators such as azathioprine has been shown to significantly improve the quality of life in patients with IBD. However, while the absolute risk of lymphoma for any given patient remains quite low, the relative risk of lymphoma in patients who are actively treated with thiopurines is moderate. Therefore, the decision to proceed with thiopurine treatment, especially in the setting of long-term therapy, requires extensive discussion and patient education of the risks/benefits along with closer monitoring of new or uncharacteristic symptoms.

Clinical Course of Small Subepithelial Tumors of the Small Bowel Detected on CT.

Purpose: This study aimed to evaluate the natural growth of subepithelial tumors of the small bowel detected on CT. Materials and Methods: Consecutive patients who were suspected of having subepithelial tumors of the small bowel between January 2005 and December 2020 were reviewed. Eligible patients with suspected small (< 30 mm) subepithelial tumors on at least two CT evaluations were included in the analysis. The patients' data on demographic characteristics, tumoral characteristics, and tumoral size changes during the follow-up were collected. Results: This study included 64 patients with suspected small subepithelial tumors (n = 64) of the small bowel. After a median follow-up of 15.8 months, the diameter and volume growth rates were 0.02 mm/month and 1.5 mm3/month, respectively. A significant correlation was observed between the initial size and the growth rate of the small bowel subepithelial tumors. The group of large-sized tumors (initial diameter ≥ 10 mm) tended to show lobulated contours, heterogeneous enhancement, and necrotic changes more frequently than the group of small-sized tumors (initial diameter < 10 mm). Conclusion: Small bowel subepithelial tumors measuring less than 10 mm grew more slowly than those measuring 10-30 mm.

The influence of parent and peer disapproval on youth marijuana use mediated by youth risk perception: Focusing on the state comparison.

BACKGROUND: The prevention of youth marijuana use has become a national priority in the United States. This study examined the influence of parent and peer disapproval on youth marijuana use, mediated by youth risk perception. Because the legal status of marijuana use can influence individual perceptions of the drug, this study investigated differences in the mediating mechanism between youth living in states with medical marijuana legalization (MML) and those living in non-MML states. METHODS: The 2019 National Survey of Drug Use and Health was used with a youth population aged 12-17 years (N = 2293). Structural equation modeling and bias-corrected bootstrapping were used to examine hypothesized path models and to evaluate the mediating effect of youth risk perception. RESULT: Findings demonstrated that parent and peer disapproval significantly increased youth risk perception of marijuana and reduced youth marijuana use. Second, youth risk perception significantly mediated the association between parent and peer disapproval and youth marijuana use. Third, parent disapproval had a more significant direct effect on youth marijuana use, while peer disapproval had a more significant indirect effect on youth marijuana use via youth risk perception. Finally, the results showed a similar pattern in the mechanism between youths living in MML states compared with those in non-MML states in terms of significance and direction. CONCLUSION: The findings suggested a need for improvements in marijuana related policies for both MML and non-MML states. Moreover, parent and peer focused strategies for education and prevention concerning marijuana use among youth are emphasized.

Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study.

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23-7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03-8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17-37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15-12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.

Immune checkpoint inhibitor-related interstitial lung disease in patients with advanced non-small cell lung cancer: systematic review of characteristics, incidence, risk factors, and management.

Background: Immune checkpoint inhibitors (ICIs) are widely used in cancers with or without other treatments. Immune-related adverse events (irAEs) have been reported as side effects of ICIs and involve various organs. Pneumonitis, which is also called ICI-related interstitial lung disease (ILD), is one of the life-threatening adverse events. In this report, we reviewed the safety of ICIs and risk factors for ICI-related ILD in non-small cell lung cancer (NSCLC) patients. Methods: Databases (The National Center for Biotechnology Information, PubMed, Cochrane Library, Google Scholar, and Embase) were searched for the literature on pulmonary adverse events and immunotherapy following PRISMA guidelines. All studies published in English between January 2016 and June 2021 were included. Results: One-hundred twenty-five articles were included at final. Pre-existing ILD as well as asthma and chronic obstructive lung disease (COPD) were associated with high risk for the development of ICI-related ILD, however, it did not affect the prognosis. The treatment of ICI-related ILD is different according to the severity grades, which includes discontinuation of ICI, corticosteroids, and for steroid-refractory ILD, other immunosuppressants. Rechallenging of ICI should be carefully considered in selected patients. Discussion: Patients with pre-existing lung disease and poor lung function need more attention for the development of ICI-related ILD. It is necessary to be aware of clinical manifestation of ICI-related ILD with prompt management.

An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma.

Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n = 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio = 0.16; 95% CI, 0.04-0.71; P = .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered.