Search

Background: The objective of this study was to investigate the expression levels and biological significance of CKS2 in Burkitt cell lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Additionally, the potential synergistic anti-tumor effects of CKS2 knockdown in combination with etoposide in BL and DLBCL were explored for the first time., Methods: Bioinformatics analysis was utilized to explore the transcriptional levels, prognostic value, and gene function enrichment of CKS2 in BL and DLBCL. Specific shRNA sequences were designed to target CKS2 for the purpose of constructing a lentiviral expression vector, and therapeutic effects were assessed through analyses of cell proliferation, cell cycle distribution, and cell apoptosis., Results: First, the study examined the increased transcriptional and protein levels of CKS2 in BL and DLBCL through analysis of various databases and immunohistochemistry tests. Elevated CKS2 expression was found to be correlated with a worse prognosis in BL and DLBCL patients, as evidenced by data from the TCGA and GEO databases. Enrichment analysis indicated that CKS2 functions were primarily linked to protein kinase regulatory activity, G1/S phase transition of the cell cycle, and the p53 signaling pathway, among others. Second, stable suppression of CKS2 gene expression in Raji and SUDHL6 cells using shRNA resulted in a significant inhibition of cell proliferation. Moreover, CKS2-shRNA induced G0/G1 cell cycle arrest and apoptosis by activating the p53 signaling pathway in Raji and SUDHL6 cells. Third, the combined treatment of CKS2-shRNA and etoposide exhibited a synergistic effect on the proliferation and apoptosis of Raji and SUDHL6 cells., Conclusions: Our findings suggest that CKS2 may play a critical role in the progression of BL and DLBCL and provide evidence for the potential therapeutic application of combining CKS2-shRNA and etoposide agents in the treatment of BL and DLBCL., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Exploration of novel combination mode of pyrotinib and chemotherapy for heavily pretreated HER2-positive metastatic breast cancer (MBC) and how to balance survival benefits and compliance are still urgent problems in clinical practice. The current single-arm prospective phase II study aimed to evaluate the efficacy and safety of pyrotinib in combination with metronomic oral etoposide in heavily pretreated HER2-positive MBC., Methods: HER2-positive MBC patients previously treated with trastuzumab were enrolled to receive oral pyrotinib 400 mg per day and metronomic oral etoposide 50 mg per day d1-21 every 28 days, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and safety., Results: 22 patients were enrolled with a median of 4 prior treatment regimens for MBC. During the follow-up of 20 evaluable patients, the median PFS was 9.0 months (95% CI, 7.6-10.4 months), and the median OS was 27.0 months (95%CI, 20.9-33.1 months). The ORR was 30% (6/20), the DCR was 80% (16/20), and the CBR was 65% (13/20). The most common grade 3 adverse events (AEs) included nausea (15%), vomiting (15%), diarrhea (5%), anemia (5%), and peripheral neuropathy (5%). No grade 4 or lethal AEs were observed., Conclusion: The combination of pyrotinib with metronomic oral etoposide has achieved promising clinical benefits in heavily pretreated HER2-positive MBC, with acceptable and manageable toxicity., Trial Registration: Registry number: NCT03923179. Registered April 18, 2019., (© 2024. The Author(s).)

Choriocarcinoma is characterized as the most aggressive malignant alternation of gestational trophoblastic neoplasm; however, this illness is a curable malignancy. Although a rarity, this disease affects a female patient's life and causes a fatal condition. Choriocarcinoma is a life-threatening disease since it is initially insidious and can rapidly lead to masive hemorrhage, even death. Choriocarcinoma should be suspected in childbearing-age women with the high-risk scores according to FIGO. The study aims to report a severe case of widespread metastatic choriocarcinoma to optimize the treatment with multiagent chemotherapy and a multidisciplinary cooperation at our center. A G1P0 20-year-old woman was referred to the hospital for suspicion of metastatic choriocarcinoma after self-stopping chemotherapy because of the COVID-19 pandemic. During hospitalization, the tumor metastasized and presented profuse intraabdominal hemorrhage. The patient underwent immediate surgical intervention to control bleeding, and a definitive diagnosis was accurately established by the histopathological examination. After surgery, the EMA/CO regimen was administered as the first line of treatment, despite the patient being in a coma and requiring a ventilator machine. After 6 cycles of the EMA/CO regimen, her serum β-hCG level decreased to 8 mUI/mL, however, her β-hCG concentration was not down to a negative value. Thus, the patient received paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE regimen) for complete remission following 2 cycles. The delays in choriocarcinoma treatment are prognostic factors for worse outcomes, whereas chemotherapy may be considered a suitable treatment even in a patient's coma, thus improving a prognosis substantially.

Rationale: Gastric large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive neuroendocrine carcinoma that arises from the stomach and with high malignancy. Patients with gastric LCNEC usually have a poor prognosis. The standard treatment plan has not been established and its curative effect is poor. The present study described 2 cases diagnosed with gastric LCNEC and reviewed in depth the literature to improve our understanding more about this uncommon tumor and further to provide more experience to diagnose and treat this disease., Patient Concerns: The present study reported 2 cases of gastric LCNEC in male patients aged 51 and 73 years old, respectively. Both patients had epigastric discomfort, pain, acid reflux and heartburn. The medical history was unremarkable., Diagnoses: The ulcerative lesion located at gastric was examined in the 2 patients by taking the esophagogastroduodenoscopy (EGO), computed tomography (CT) and digital gastrointestinal radiography (GI), that both were suspected gastric malignancy. Endoscopic biopsies of the tumor led to the initial diagnosis of gastric cancer. Postoperative pathological and immunohistochemical examinations of the surgical specimens confirmed that 1 case had mixed adeno-neuroendocrine carcinoma (MANEC) and the other had LCNEC., Interventions: Both patients underwent surgical resection and received etoposide-cisplatin combination chemotherapy following surgery., Outcomes: The operation was successful. Both patients had uneventful recoveries following surgery, and had been followed-up regularly. The general condition was satisfactory, and no tumor metastasis was observed at present., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The prognosis of high-risk neuroblastomas (NB) that are resistant to first-line induction chemotherapy is relatively poor. This study explored the mechanism of resistance to first-line chemotherapeutics mediated by TXNDC17 and its potential solutions in NB., Methods: The genetic and clinical data of patients with NB were obtained from the Therapeutically Applicable Research to Generate Effective Treatments dataset. TXNDC17 and BECN1 expressions in NB cells were up- and downregulated by transfection with plasmids and shRNA, respectively. Autophagy-related proteins were detected by western blot. Cell viability was determined using cell proliferation and toxicity experiments. Apoptotic cells were detected using flow cytometry., Results: Overall, 1076 pediatric and adolescent patients with NB were enrolled in this study. The 10-year overall survival (OS) rates and event-free survival (EFS) rates for the patients with a mutation of BECN1 were 37.4 ± 9.1% and 34.5 ± 8.8%, respectively. For patients with a mutation of TXNDC17, the 10-year OS and EFS were 41.4 ± 5.9% and 24.3 ± 5.1%, respectively, which were significantly lower than those in the unaltered group. The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance., Conclusions: Acquired resistance to first-line chemotherapeutics was associated with autophagy mediated by BECN1 and regulated by TXNDC17, which can be reversed by SAHA., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 ., (© 2024. The Author(s).)

This single-arm confirmatory study (JCOG1305) aimed to evaluate the utility of interim positron emission tomography (iPET)-guided therapy for newly diagnosed advanced-stage classic Hodgkin lymphoma (cHL). Patients aged 16-60 years with cHL received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and then underwent an iPET scan (PET2), which was centrally reviewed using a five-point Deauville scale. PET2-negative patients continued an additional four cycles of ABVD, whereas PET2-positive patients switched to six cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). The co-primary endpoints were 2-year progression-free survival (PFS) among all eligible and PET2-positive patients. Ninety-three patients were enrolled between January 2016 and December 2019. One patient was ineligible because of a diagnostic error. The median age of the 92 eligible patients was 35 (interquartile range, 28-48) years. Forty (43%) patients had stage III disease, and 43 (47%) had stage IV disease. The remaining nine (10%) patients had stage IIB disease with risk factors. Nineteen PET2-positive (21%) patients received eBEACOPP, 18 completed six cycles of eBEACOPP, 73 PET2-negative (79%) patients continued ABVD, and 70 completed an additional four cycles of ABVD. With a median follow-up period of 41.1 months, the 2-year PFS of 92 eligible patients and 19 PET2-positive patients were 84.8% (80% confidence interval [CI], 79.2-88.9) and 84.2% (80% CI, 69.7-92.1), respectively. Both primary endpoints were met at the prespecified threshold. This study demonstrates that iPET-guided therapy is a useful treatment option for younger patients with newly diagnosed advanced-stage cHL. Registration number: jRCTs031180218., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDC/ASCT) has been useful in relapsed or refractory classic Hodgkin lymphoma (RRcHL). Furthermore, a ranimustine, cytarabine, etoposide, and cyclophosphamide (MCVAC) conditioning regimen has been effective in diffuse large B-cell lymphoma. However, limited data are available regarding this conditioning regimen for cHL. In this study, we investigated the efficacy and toxicity of MCVAC for RRcHL. We retrospectively analyzed 10 patients with RRcHL who underwent ASCT preceded by the MCVAC conditioning regimen between January 2009 and December 2021 at our institution. A total of 10 patients (median [range] age, 36 [23-64] years), including 5 (50%) men and 5 (50%) women, were treated with the MCVAC regimen followed by ASCT. The median follow-up duration of the 10 patients was 25.0 months. The 36-month PFS and OS rates were 43.8% (95% CI, 11.9%-72.6%) and 64.0% (95% CI, 22.6%-87.5%), respectively. Two patients died because of treatment-related factors, and one patient died because of disease progression. Based on our findings, recognizing the risk factors for adverse events (AEs) associated with this treatment, MCVAC may be a valid treatment option for the management of RRcHL.

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome with an abnormal activation of the immune system and is associated with a high mortality even with treatment. We present a case of a woman in her mid-50s who developed HLH triggered by miliary tuberculosis (TB) while receiving a tumour necrosis factor alpha inhibitor.The patient was admitted with a high fever and respiratory pain. Her condition deteriorated despite empirical treatment. Diagnosis of HLH was established based on clinical presentation, H-score and HLH-04 criteria. Concurrently, miliary TB was identified as the trigger. She was treated with anti-tuberculous therapy and HLH-directed treatment with dexamethasone, etoposide and anakinra. Initial improvement was observed, leading to the withholding of HLH-orientated treatment. However, several relapses occurred, necessitating prolonged HLH treatment.A literature review corroborated the importance of combined anti-tuberculous and immunosuppressive therapy for managing HLH. This case underscores the necessity of timely and comprehensive management of HLH-oriented treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Peripheral T-cell lymphomas (PTCLs) have a poor prognosis with current treatments. High-dose chemotherapy followed by autologous hematopoietic cell transplant (AHCT) is used as a consolidation strategy after achieving clinical remission with first-line therapy, as well as in chemotherapy-sensitive relapse if allogeneic transplant is not an option. CD25 is a targetable protein often highly expressed in PTCLs. In this phase 1 clinical trial, we tested the addition of β-emitting 90yttrium (90Y)-labeled chimeric anti-CD25 basiliximab (aTac) to BEAM (carmustine, etoposide, cytarabine, and melphalan) as conditioning for AHCT for patients with PTCL. Twenty-three AHCT-eligible patients were enrolled, and 20 received therapeutic 90Y-aTac-BEAM AHCT. Radiation doses of 0.4, 0.5, and 0.6 mCi/kg were tested. With no observed dose-limiting toxicities, 0.6 mCi/kg was deemed the recommended phase 2 dose. The most prevalent adverse effect, grade 2 mucositis, was experienced by 80% of patients. As of this report, 6 (30%) of the treated patients had died, 5 due to progressive disease and 1 due to multiple organ failure (median time of death, 17 months [range, 9-21]) after AHCT. Median follow-up was 24 months (range, 9-26) overall and 24 months (range, 13-26) for surviving patients. For patients who received therapeutic 90Y-aTac-BEAM AHCT, the 2-year progression-free and overall survival were 59% (95% confidence interval [CI], 34-77) and 68% (95% CI, 42-84), respectively. 90Y-aTac-BEAM appears to be safe as an AHCT conditioning regimen for PTCL, with no increased toxicity over the toxicities historically seen with BEAM alone in this patient population. This trial was registered at www.ClinicalTrials.gov as #NCT02342782., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Hyperleukocytosis in pediatric acute myeloid leukemia (AML) is associated with severe complications and an inferior outcome. We report results on patients with hyperleukocytosis included in the NOPHO-DBH AML 2012 study. We recommended immediate initiation of full-dose chemotherapy (etoposide monotherapy for 5 days as part of the first course), avoiding leukapheresis and prephase chemotherapy. Of 714 patients included in the NOPHO-DBH AML 2012 study, 122 (17.1%) had hyperleukocytosis, and 111 were treated according to the recommendations with etoposide upfront without preceding leukapheresis or prephase chemotherapy. The first dose was applied the same day as the AML diagnosis or the day after in 94%. Etoposide was administered via peripheral veins in 37% of patients without major complications. After initiation of etoposide the white blood cell counts on days 2-5 were 69%, 36%, 17% and 8%, respectively, of the pre-treatment level. On day 3, 81% of patients had a white blood cell count <100 x109/L. Five-year event-free and overall survival rates for all patients with hyperleukocytosis were 52.9% (95% confidence interval [95% CI]: 44.4-63.0) and 74.1% (95% CI: 66.4-82.6), compared to 64.9% (95% CI: 60.9-69.1) and 78.9% (95% CI: 75.4-82.4) for patients without hyperleukocytosis (P<0.001 for event-free survival, P=0.1 overall survival). Six-week early mortality was 4.1% for all patients with hyperleukocytosis (2.7% for the 111 patients treated with etoposide upfront). We conclude that management of hyperleukocytosis in pediatric AML with immediate etoposide monotherapy without leukapheresis or prephase chemotherapy is feasible, safe and effective. The reduction in white blood cell count during the first days is comparable to the reported results of leukapheresis, and outcomes seem at least equivalent to therapies including leukapheresis. Based on our results, we advocate abandoning leukapheresis for hyperleukocytosis in pediatric AML. Instead, it is crucial to start induction chemotherapy as early as possible.

Objective: The prognosis of extra-nodal NK/T cell lymphoma (ENKTL) is poor, and the optimal therapy remains controversial. This study aims to evaluate the safety and efficacy of a new combined modality therapy., Methods: Phase-2 study of pegaspargase, etoposide and gemcitabine (PEG) combined with involved field radiation therapy (IFRT) in newly-diagnosed patients with early-stage ENKTL. Patients received 4 course of PEG followed by IFRT. The primary endpoints were complete response (CR), partial response (PR), and objective response rate (ORR) after IFRT. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events., Results: 34 consecutive patients with Ann Arbor stage I/II were enrolled. 3 patients progressed on PEG, while the remaining 31 received IFRT. The ORR was 88.2% (30/34), included 28 (82.4%) complete and 2 (5.8%) partial responses. With a median follow-up of 56.0 months (Interquartile Range [IQR], 36.0-66.9 months), the estimated 5-year PFS and OS were 87.4% (95% Confidence Interval [CI],69.5%-94.8%) and 97.1% (95%CI, 80.1%-99.6%), respectively. Most adverse events were hematological and easily managed., Conclusions: PEG followed by IFRT is a safe and effective initial therapy for early-stage ENKTL, demonstrating impressive PFS and OS rates. This promising approach warrants further validation in a randomized controlled trial (Registered at Clinicaltrials.gov NCT02705508). Trial registration: ClinicalTrials.gov identifier: NCT02705508.

Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is rare and is associated with poor prognosis. However, the standard treatment protocols for patients with SCLC transformation remain unknown. Here, we report the case of a patient with advanced EGFR exon 19 deletion (19del) NSCLC who underwent SCLC transformation during targeted therapy. Biopsies and genetic testing were performed to adjust treatment regimens accordingly. The patient responded favorably to a combined treatment regimen comprising etoposide plus cisplatin chemotherapy and adebrelimab plus osimertinib. This case highlights the critical importance of acknowledging tumor heterogeneity in clinical decision-making and identifying potentially effective treatment options for patients with SCLC transformation. Additionally, we reviewed cases of the transformation of NSCLC to SCLC from 2017 to 2023., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Luan, Zhang, Wang, Guo, Lv, Qiu and Zhao.)

Background: Autologous stem cell transplantation (ASCT) is a pivotal treatment for lymphoma patients. The BeEAM regimen (Bendamustine, Etoposide, Cytarabine, Melphalan) traditionally relies on cryopreservation, whereas the CEM regimen (Carboplatin, Etoposide, Melphalan) has been optimized for short-duration administration without the need for cryopreservation. This study rigorously compares the clinical and safety profiles of the BeEAM and CEM regimens., Methods: A controlled, randomized clinical trial was conducted with 58 lymphoma patients undergoing ASCT at the International Medical Center (IMC) in Cairo, Egypt. Patients were randomly assigned to either the BeEAM (n = 29) or CEM (n = 29) regimen, with an 18-month follow-up period. Clinical and safety outcomes were meticulously compared, focusing on time to engraftment for neutrophils and platelets, side effects, length of hospitalization, transplant-related mortality (TRM), and survival rates., Results: The findings demonstrate a significant advantage for the CEM regimen. Neutrophil recovery was markedly faster in the CEM group, averaging 8.5 days compared to 14.5 days in the BeEAM group (p < 0.0001). Platelet recovery was similarly expedited, with 11 days in the CEM group versus 23 days in the BeEAM group (p < 0.0001). Hospitalization duration was substantially shorter for CEM patients, averaging 18.5 days compared to 30 days for those on BeEAM (p < 0.0001). Furthermore, overall survival (OS) was significantly higher in the CEM group at 96.55% (95% CI: 84.91-99.44%) compared to 79.31% (95% CI: 63.11-89.75%) in the BeEAM group (p = 0.049). Progression-free survival (PFS) was also notably superior in the CEM group, at 86.21% (95% CI: 86.14-86.28%) versus 62.07% (95% CI: 61.94-62.20%) in the BeEAM group (p = 0.036)., Conclusion: The CEM regimen might demonstrate superiority over the BeEAM regimen, with faster neutrophil and platelet recovery, reduced hospitalization time, and significantly improved overall and progression-free survival rates. Future studies with longer duration and larger sample sizes are warranted., Trial Registration: This study is registered on ClinicalTrials.gov under the registration number NCT05813132 ( https://clinicaltrials.gov/ct2/show/NCT05813132 ). (The first submitted registration date: is March 16, 2023)., (© 2024. The Author(s).)

The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m 2 /d iv on days 1-3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H 0 50%, H 1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile., (© 2024. The Author(s).)

Rationale: Neuroendocrine neoplasms (NENs) originating from neuroendocrine cells occur in the thyroid, respiratory, and digestive systems, with Gallbladder Neuroendocrine Carcinoma (GB-NEC) accounting for only 0.5% of all NENs and 2.1% of gallbladder cancers. Due to its rarity, little is known about GB-NEC's clinical presentation and treatment., Patient Concerns: We report a case of a 52-year-old male presenting with acute upper right abdominal pain, leading to further investigation., Diagnoses: Initial diagnostic workup, including abdominal ultrasound and contrast-enhanced CT, suggested gallbladder malignancy. Post-surgical pathology confirmed GB-NEC, with immunohistochemistry supporting the diagnosis., Interventions: The patient underwent radical cholecystectomy, followed by etoposide plus cisplatin chemotherapy. After disease progression indicated by CT, the patient received additional cycles of chemotherapy with cisplatin and irinotecan, plus targeted therapy with anlotinib and immunotherapy with paimiplimab., Outcomes: The patient showed a partial response to initial treatment. Subsequent liver biopsy confirmed NEC, consistent with small cell carcinoma. With continued treatment, the patient maintains a good survival status., Lessons: GB-NEC is associated with poor prognosis, emphasizing the importance of early detection and multimodal treatment strategies. Our case underlines the potential benefit of a comprehensive treatment plan, including aggressive surgery and chemotherapy, with further research needed to standardize treatment for this rare condition., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The current treatment regimens for Hodgkin's lymphoma (HL) are associated with high incidences of adverse events., Purpose: This study aimed to compare the efficacy and safety of doxorubicin + bleomycin + vincristine + dacarbazine (ABVD) and standard bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone (BEACOPP) chemotherapy in the treatment of advanced stage HL., Methods: This multicenter, randomized, parallel, open, positive control noninferiority trial was conducted from 2016 to 2019 and comprised 93 subjects who were randomized in a 1:1 ratio between the treatment (BEACOPP; n = 44) and control (ABVD; n = 49) groups., Results: The primary efficacy endpoint of this trial was the objective response rate (ORR) after eight cycles of chemotherapy, which was 100.00% (36/36) in the treatment group and 95.74% (45/49) in the control group. The incidence of adverse reactions was 100% in both groups. Significant differences (P < 0.05) in the incidences of grade 3 (39/44 [88.64%] vs. 23/49 [46.94%]) and grade 4 (27/44 [61.36%] vs. 8/49 [16.94%]) adverse events were observed between the treatment and control groups, respectively. However, most of these reactions were manageable, with no serious consequences, and were reversible after discontinuation of the treatment., Conclusion: Both regimens had a similar ORR and were associated with a high number of adverse events. The ABVD regimen was better tolerated and safer than the standard BEACOPP regimen. This study indicates that the standard BEACOPP regimen may be considered as a treatment option for patients with advanced HL., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

Introduction : Small-cell lung cancer (SCLC) is an aggressive form of cancer with a poor prognosis. The two-year survival rate is 8% of all cases. Case presentation : We present the case of a male patient who was 50 years old at the time of diagnosis in May 2022. He was diagnosed with extensive-stage small-cell lung cancer, treated with immunotherapy in combination with chemotherapy (Durvalumab in combination with Etoposide plus Carboplatin) as a first-line treatment, followed by maintenance immunotherapy. In December 2023, a PET-CT scan revealed progressive disease with multiple metastases. Chemotherapy was reinitiated with Etoposide plus Cisplatin in January 2024. After two cycles of chemotherapy, the patient developed post-chemotherapy anemia, for which treatment with Epoetinum alpha was initiated. Chemotherapy was continued for another five cycles, until May 2024, with the maintenance of hemoglobin at a level within 9.9 mg/dL-11 mg/dL. Upon assessment at the end of May 2024, the patient presented an ECOG = 2 performance status, with a moderate general state, moderate-intensity fatigue, no pain, no anxiety or depression and no dyspnea. Discussions, Literature Review and Conclusions : Reinitiating chemotherapy after the failure of maintenance immunotherapy may be an option in patients with SCLC. Epoetinum allows oncological treatment by preventing chemotherapy-induced anemia.

Background: Autologous stem cell transplantation (ASCT) is a potentially curative strategy for relapse or refractory(r/r) aggressive lymphoma. However, a proportion of lymphoma patients who are at high risk of mobilization failure fail to mobilize stem cells and cannot proceed to ASCT. The aim of this study is to explore the efficacy and safety of Etoposide combined with Cytarabine (EA) plus G-CSF mobilization in poor mobilizers (PMs) with r/r aggressive lymphoma., Methods: This retrospective study analyzed the outcomes of chemo-mobilization based on EA (Etoposide 0.1 g/m2, qd d1~3; AraC 0.5 g/m2, q12h d1~3) in 98 patients with r/r aggressive lymphoma. Of these, 39 patients met the criteria for predicted PMs as proposed by the Gruppo Italiano Trapianto di Midollo Osseo working group., Results: Of the 39 PMs, 38(97.4%) patents harvested adequate mobilization (≥2×10 6 CD34+ cells/kg), while 31(79.5%) patients achieved optimal mobilization (≥5×10 6 CD34+ cells/kg). Overall, the mean number of CD34+ cells/kg collected was 17.99(range: 1.08~83.07) ×10 6 with an average of 1.4 apheresis sessions, and the number was 15.86(range: 0.37~83.07) ×10 6 for the first apheresis, respectively. A single apheresis procedure was sufficient to reach the target yield of adequate mobilization in 35(89.7%) PMs, while 76.9% of PMs achieved optimal collection within two apheresis sessions. We observed acceptable hematological toxicity and antibiotic usage exposure in 26 patients with a mean duration of 3.6 days. No grade 4 infection or mobilization-related mortality was recorded. Most patients underwent ASCT and achieved successful hematopoietic recovery with prompt engraftment duration, except for one NK/T-cell lymphoma patient who succumbed to severe septicemia after receiving conditioning chemotherapy., Conclusion: Our findings indicate that EA plus G-CSF is an effective and tolerable CD34+ stem cell mobilization strategy for patients with r/r lymphoma, including those predicted to be PMs. This regimen could be an option for patients with r/r lymphoma, particularly those undergoing mobilization for salvage ASCT therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu, Li, Yuan, Chen, Lin, Guo and Li.)

Background: Diagnosing non-gestational uterine choriocarcinoma in children is challenging because of its rarity and nonspecific imaging findings. Herein, we report a case of non-gestational uterine choriocarcinoma in a child, which was unexpectedly found during exploratory laparotomy and confirmed by histopathological findings. However, the tumor did not respond to chemotherapy., Case Presentation: A 4-year-old Indonesian female patient was brought into the emergency unit with chief complaint of vaginal bleeding. She had suffered from vaginal spotting 4 months before being admitted to the hospital. Physical examination revealed a distended abdomen in the left lumbar region and a palpable fixed mass with a smooth surface. Abdominal computed tomography scans revealed a large mass (10 × 6 × 12 cm) with fluid density and calcification. Thus, we suspected left ovarian teratoma. The patient's luteinizing hormone, follicle-stimulating hormone, and lactate dehydrogenase levels were 25.2 mIU/ml, 0.1 mIU/ml, and 406 U/l, respectively. According to the clinical and radiological findings, we decided to perform an exploratory laparotomy and found a tumor originating from the uterus, not the ovarium. We did not observe liver nodules and any enlargement of abdominal lymph nodes. Subsequently, we performed hysterectomy. The histopathological findings supported the diagnosis of choriocarcinoma. The patient was discharged uneventfully on postoperative day 5. Thereafter, the patient underwent nine cycles of chemotherapy, including carboplatin (600 mg/m 2 IV), etoposide (120 mg/m 2 IV), and bleomycin (15 mg/m 2 IV). However, on the basis of the clinical findings of a palpable mass and partial intestinal obstruction, the tumor relapsed soon after the ninth cycle of chemotherapy. Currently, the patient is undergoing chemotherapy again., Conclusions: Although pure non-gestational uterine choriocarcinoma is rare, it should be considered as one of the differential diagnoses for intraabdominal tumors in a child, so as to better guide and counsel families regarding the surgical plan and prognosis, respectively. In the present case, the patient's response to chemotherapy was poor, implying that the treatment of non-gestational choriocarcinoma is still challenging, particularly in the pediatric population., (© 2024. The Author(s).)

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition that can be either familial or acquired and, if untreated, frequently results in multiorgan failure and death. Treatment of HLH typically requires a combination of glucocorticoids and cytotoxic chemotherapy. We describe the case of a woman who presented with signs and symptoms concerning for HLH who was later found to have a primary central nervous system (CNS) diffuse large B-cell lymphoma. Her HLH symptoms were successfully treated with high doses of dexamethasone, and her primary CNS lymphoma was treated with high-dose methotrexate and rituximab. This is a rare case of HLH secondary to primary CNS lymphoma where HLH was controlled with steroids alone and did not require the use of an etoposide-based regimen or cyclophosphamide, doxorubicin, vincristine and prednisone., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH., Methods: An open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators., Results: A total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment., Conclusion: The addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hu, Wang and Wang.)

Transfusion-dependent thalassemia (TDT) is often accompanied by complications related to iron overload and the development of malignant solid tumors or hematological malignancies. The occurrence of Neuroendocrine carcinoma, specifically in the respiratory tract, is very rare, with a prevalence of approximately 25%. Therefore, this study presented a case of a 42-year-old male with a beta-thalassemia major at 28 years, complaining of shortness of breath. This case was reported due to its rarity in providing information about solid tumors in thalassemia patients. The physical examination revealed several symptoms, including tachycardia, tachypnea, anemia, icteric sclera, elevated jugular venous pressure, coarse wet Ronchi in the medial to basal areas of both lungs, hepatomegaly, and splenomegaly (Schuffner 4). The patient regularly received blood transfusions and iron chelation therapy. A thoracic CT scan showed a lung mass and a biopsy of the mass revealed Pulmonary Neuroendocrine Carcinoma with high-grade proliferation and, large cell type. The patient also passed through cisplatin-etoposide chemotherapy for 6 cycles every 21 days. There is almost no data on pulmonary neuroendocrine carcinoma in thalassemia patients, so it is hoped that this case report can provide information about malignant solid tumors that can occur in thalassemia patients.

Purpose: Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need., Experimental Design: Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed., Results: 42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups., Conclusions: In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients., Competing Interests: Competing interests: GP reports Advisory Boards/Honoraria/Speakers’ fee/Consultant by Amgen, AstraZeneca, BMS, Eli Lilly, Jansenn, MSD, Novartis, Pfizer, Roche, and unconditioned research support by AstraZeneca, Roche, MSD. VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Novartis, Roche and Zentiva; personal fees for expert testimony for Eli Lilly., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent years, lesbian, gay, bisexual, and transgender (LGBT) populations have been gaining acceptance in society. However, very few cases of malignancy in the LGBT population have been reported thus far. We herein report a transgender woman receiving estrogen supplementation who developed primary mediastinal large B-cell lymphoma (PMBCL) and was treated with dose-adjusted EPOCH-rituximab (DA-EPOCH-R) therapy. The patient achieved complete remission after the sixth course of DA-EPOCH-R therapy. To help this LGBT patient continue receiving chemotherapy smoothly on admission, adjusting the hospital environment, such as the allocation of rooms, was essential.

Adebrelimab, a novel anti-PD-L1 antibody, has been approved by the National Medical Products Administration of China as an intravenous infusion for use in combination with carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer in 2023. A two-compartment model with empirical time-varying CL for adebrelimab was established based on data from 263 patients receiving body weight-based doses from two clinical studies. Significant covariate effects of baseline body weight, albumin levels, tumor size, neutrophil counts, and presence of anti-drug antibodies were identified on CL of debrelimab, none of which were clinically significant or warranted dose adjustment. The degree of decrease in CL was higher in patients who responded to treatment with adebrelimab than in non-responders. Adebrelimab exposures (AUC, C trough , or C max ) were not identified as a statistically significant factor related to efficacy or safety endpoint in the exposure-response analysis. Distribution of simulated exposure metrics from the flat dose regimen (1200 mg q3w) was similar to the marketed weight-based dosing regimen (20 mg/kg q3w), supporting the alternative flat dose regimen in the clinic., (© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest nongynecological symptoms owing to distant metastases. The incidence of choriocarcinoma after a term pregnancy is really rare (1/160,000 pregnancies)., Case Presentation: We report a case of a 20-year-old Iranian woman, gravida 2 para 1 live 1 abortion 1, who was referred to our gynecology department with sudden onset dyspnea and pain in the left hemithorax the day after her labor. The index pregnancy was without any complications. After the initial workup, the elevation of β-human chorionic gonadotropin (HCG) levels (> 1,000,000) along with the identification of clinical (vaginal lesions) and radiological evidence of distant metastases (bilateral pulmonary nodes) directed us toward pulmonary metastatic choriocarcinoma diagnosis. After the oncology consult, the etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy regimen was started for the patient. She responded well to the treatment and is currently continuing her chemotherapy process., Conclusion: The prognosis of choriocarcinoma is very good if the treatment is started on time. We suggest that clinicians should consider gestational trophoblastic neoplasia in their differential diagnosis of the post-natal period complications, especially after a term and nonmolar pregnancy., (© 2024. The Author(s).)

Small-cell lung cancer (SCLC) remains a disease with poor prognosis, particularly in extensive-stage SCLC (ES-SCLC). Current standard-of-care treatment includes chemotherapy with platinum agents and etoposide plus immunotherapy with atezolizumab or durvalumab, which has achieved a mean overall survival of 12-13 months in clinical trials. However, long-term survival in ES-SCLC, even with the addition of immunotherapy, continues to be rare. We present the case of a middle-aged male patient diagnosed with ES-SCLC who was treated with four cycles of induction chemotherapy (carboplatin and etoposide) and atezolizumab, starting maintenance atezolizumab every 21 days thereafter, and thoracic radiotherapy. After 9 months, he experienced mild disease progression and was rechallenged with six cycles of carboplatin and etoposide with continued atezolizumab. Subsequent imaging showed near-complete disease resolution which has been sustained since. He has continued on maintenance atezolizumab since diagnosis and has achieved 60 months overall survival and 44 months progression-free survival. Throughout treatment, he has maintained a high functional capacity and only experienced one immune-related adverse event. Our patient is representative of a small subset who are capable of achieving durable responses to immunotherapy and his case highlights the need for further research to elucidate the clinical and biological factors driving this response.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome for which early recognition and treatment are essential for improving outcomes. HLH is characterized by uncontrolled immune activation leading to fever, cytopenias, hepatosplenomegaly, coagulation abnormalities, and elevated typical markers. This condition can be genetic or secondary, with the latter often triggered by infections. Here, we present a unique case of HLH secondary to acute otitis media (AOM), a common ear infection., Patient Concerns: We describe a 4-year-old boy who initially presented with a high fever and otalgia, later diagnosed with bilateral AOM. Despite antibiotic treatment, his condition deteriorated., Diagnosis: The patient fulfilled diagnostic criteria for HLH., Interventions: Aggressive treatment by using combination therapy with immunoglobulins, intravenous steroids (dexamethasone), cyclosporine, and etoposide was performed., Outcomes: After 1 month of treatment, improvement in the otologic symptoms was observed, and hematological findings gradually improved and normalized., Lessions: The link between AOM and HLH may be associated with inflammatory responses and immunological mechanisms, highlighting the importance of considering HLH in severe infection cases. This case emphasizes the need for prompt diagnosis and management, especially in secondary HLH scenarios, to improve patient outcomes. It is imperative to be aware of the potential correlation between these 2 conditions, and healthcare professionals should consider the likelihood of HLH., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Chemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy resistance in SCLC patients is generally classified as primary or acquired resistance, each governedby distinct mechanisms that remain inadequately researched., Methods: In this study, we performed transcriptome screening of peripheral blood plasma obtainedfrom 17 patients before and after receiving combined etoposide and platinum treatment. We firs testimated pseudo-single-cell analysis using xCell and ESTIMATE and identified differentially expressed genes (DEGs), then performed network analysis to discover key hub genes involved in chemotherapy resistance., Results: Our analysis showed a significant increase in class-switched memory B cell scores acrossboth chemotherapy resistance patterns, indicating their potential crucial role in mediatingresistance. Moreover, network analysis identifed PRICKLE3 , TNFSFI0 , ACSLl and EP300 as potential contributors to primary resistance, with SNWl , SENP2 and SMNDCl emerging assignificant factors in acquired resistance, providing valuable insights into chemotherapy resistancein SCLC., Discussion: These findings offer valuable insights for understanding chemotherapy resistance and related gene signatures in SCLC, which could help further biological validation studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Fan, Yang and Cun.)

Lung cancer is one of the most malignant tumors with fastest morbidity and mortality. Small cell lung cancer (SCLC) is the most malignant pathological type of lung cancer with early metastasis and poor prognosis. At present, there is a lack of effective indicators to predict prognosis of SCLC patients. Delta-like 3 protein (DLL3) is selectively expressed on the surface of SCLC and is involved in proliferation and invasion. Neuron-specific enolase (NSE) is an enolase isoenzyme that is generally regarded as a biomarker for SCLC and may correlate with stage of SCLC, prognosis and chemotherapy response. NSE can be influenced by different types of factors. To explore the associations between expression levels of DLL3 in tumor tissues with platinum/etoposide chemotherapy response, and assess the prognostic values of DLL3, NSE and other potential prognostic factors in advanced SCLC patients were herein studied. Ninety-seven patients diagnosed with SCLC in Zhongda Hospital from 2014 to 2020 were enrolled in the study. Serum NSE levels were tested using ELISA methods before any treatment. The expression of DLL3 in tumor tissue was detected by Immunohistochemistry (IHC). We investigated the relationship of DLL3 expression with chemotherapy and survival. Progression free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Multivariate Cox-proportional hazard regression was used to identify predictors of PFS and OS. DLL3 was detected in 84.5% (82/97) of all patients' tumor samples by IHC, mainly located on the surface of SCLC cells. Lower DLL3 expression was associated with longer PFS and better chemotherapy response. OS had no significant differences. Multivariate analysis by Cox Hazard model showed that, high DLL3 expression and maximum tumor size >5 cm were independent risk factors for PFS, where NSE < 35 ng/mL and age < 70 were independent prognostic factors for OS. Early stage was independent prognostic factors for PFS and OS (P < .05 log-rank). DLL3 was expressed in the most of SCLCs. DLL3 expression level in the tumor and NSE level in the serum may be useful biomarkers to predict the prognosis of SCLC. DLL3 may be a potential therapeutic target for SCLC in the future., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy., Materials and Methods: Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy., Results: Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications., Conclusion: EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Intensive treatment approaches are required for adult patients with Burkitt lymphoma (BL), although an univocal standard of care still does not exist. The use of frontline autologous stem cells transplantation (ASCT) is debated., Patients and Methods: Between 2004 and 2020, 50 patients with BL were treated with the Berlin-Frankfurt-Münster (BFM). Treatment plan consisted of 3 blocks, A (ifosfamide, vincristine, methotrexate, etoposide, and cytarabine), B (vincristine, cyclophosphamide, methotrexate, and doxorubicin), and C (vindesine, methotrexate, etoposide, and cytarabine), each repeated twice, every 28 days. Rituximab was given at day 1 each block. Intrathecal prophylaxis was given once per each block. ASCT was scheduled at the end of the 6 blocks after conditioning., Results: Median age at onset was 38 years (range 16-72); stages III-IV disease was observed in 82% of cases; bulky disease occurred in 44% of the patients, with B-symptoms in 38%. Stem cell harvest was performed in 72% of patients, who all received a subsequent ASCT. The full 6 blocks treatment was completed in 70% of the patients. The overall response rate was 74%, with a complete response rate of 60%. Ten-year overall survival and progression-free survival were 83.7% and 76.0%, respectively, without reaching the median. Ten-year disease-free survival was 80.3%. Grades 3-4 neutropenia, thrombocytopenia, anemia, and mucositis were seen in 96%, 60%, 32%, and 24% of patients. Infections occurred in 60% of patients., Conclusion: Intensive treatment according to BFM protocol, with rituximab and ASCT, appears feasible, safe, and highly effective in adult patients with BL, as confirmed by long-term survival rates reflecting response maintenance., (© The Author(s) 2024. Published by Oxford University Press.)

SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a devastating subtype of thoracic tumor with SMARCA4 inactivation and is characterized by rapid progression, poor prognosis, and high risk of postoperative recurrence. However, effective treatments for SMARCA4-dUT are lacking. Herein, we describe a patient with SMARCA4-dUT who exhibited an impressive response to the anti-programmed cell death protein-1 (PD-1) antibody (tislelizumab) in combination with conventional chemotherapy (etoposide and cisplatin). To the best of our knowledge, this is the first case of SMARCA4-dUT treated with chemotherapy, comprising etoposide and cisplatin, combined with anti-PD-1 inhibitors. Immunotherapy combined with etoposide and cisplatin may be a promising strategy to treat SMARCA4-dUT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dong, Dai, Wu, Wang, Wu, Du, Tian, Zheng, Zhang, Wang, Cai, Dong, Zhou, Li and Xiao.)

Rationale: Synergic reprogramming of metabolic dominates neuroblastoma (NB) progression. It is of great clinical implications to develop an individualized risk prognostication approach with stratification-guided therapeutic options for NB based on elucidating molecular mechanisms of metabolic reprogramming. Methods: With a machine learning-based multi-step program, the synergic mechanisms of metabolic reprogramming-driven malignant progression of NB were elucidated at single-cell and metabolite flux dimensions. Subsequently, a promising metabolic reprogramming-associated prognostic signature (MPS) and individualized therapeutic approaches based on MPS-stratification were developed and further validated independently using pre-clinical models. Results: MPS-identified MPS-I NB showed significantly higher activity of metabolic reprogramming than MPS-II counterparts. MPS demonstrated improved accuracy compared to current clinical characteristics [AUC: 0.915 vs. 0.657 ( MYCN ), 0.713 (INSS-stage), and 0.808 (INRG-stratification)] in predicting prognosis. AZD7762 and etoposide were identified as potent therapeutics against MPS-I and II NB, respectively. Subsequent biological tests revealed AZD7762 substantially inhibited growth, migration, and invasion of MPS-I NB cells, more effectively than that of MPS-II cells. Conversely, etoposide had better therapeutic effects on MPS-II NB cells. More encouragingly, AZD7762 and etoposide significantly inhibited in-vivo subcutaneous tumorigenesis, proliferation, and pulmonary metastasis in MPS-I and MPS-II samples, respectively; thereby prolonging survival of tumor-bearing mice. Mechanistically, AZD7762 and etoposide-induced apoptosis of the MPS-I and MPS-II cells, respectively, through mitochondria-dependent pathways; and MPS-I NB resisted etoposide-induced apoptosis by addiction of glutamate metabolism and acetyl coenzyme A. MPS-I NB progression was fueled by multiple metabolic reprogramming-driven factors including multidrug resistance, immunosuppressive and tumor-promoting inflammatory microenvironments. Immunologically, MPS-I NB suppressed immune cells via MIF and THBS signaling pathways. Metabolically, the malignant proliferation of MPS-I NB cells was remarkably supported by reprogrammed glutamate metabolism, tricarboxylic acid cycle, urea cycle, etc. Furthermore, MPS-I NB cells manifested a distinct tumor-promoting developmental lineage and self-communication patterns, as evidenced by enhanced oncogenic signaling pathways activated with development and self-communications. Conclusions: This study provides deep insights into the molecular mechanisms underlying metabolic reprogramming-mediated malignant progression of NB. It also sheds light on developing targeted medications guided by the novel precise risk prognostication approaches, which could contribute to a significantly improved therapeutic strategy for NB., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Abstract: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score-matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score-matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.

The aim of the study was to investigate the prognostic significance of the advanced lung cancer inflammation index (ALI) in patients with limited-stage small-cell lung cancer (LS-SCLC) undergoing definite chemo-radiotherapy (CRT). We included 87 patients with LS-SCLC from South Korea, treated between 2005 and 2019 with definite CRT. ALI was calculated using body mass index, serum albumin, and neutrophil-lymphocyte ratio. We categorized 38 patients into the high ALI group (ALI ≥ 44.3) and 48 into the low ALI group (ALI < 44.3). Patients in the high ALI group exhibited longer overall survival (OS) than patients in the low ALI group. In multivariate analysis, prophylactic cranial irradiation (hazard ratio [HR] = 0.366, 95% confidence interval [CI] 0.20-0.66, P = 0.0008), and high ALI (HR = 0.475, 95% CI 0.27-0.84, P = 0.0103) were identified as independent prognostic factors for predicting better OS. Notably, a high ALI score was particularly indicative of longer survival in patients treated with the combination of etoposide and cisplatin. In conclusion, this study demonstrated that a high pretreatment ALI was significantly associated with better OS in patients with LS-SCLC undergoing definite CRT. This suggests that ALI could be a useful tool for predicting prognosis and guiding chemotherapy regimen selections in clinical practice for LS-SCLC., (© 2024. The Author(s).)

Introduction: Trophoblastic neoplasms are often associated with pregnancy, and nongestational trophoblastic neoplasms are extremely rare. Nongestational ovarian choriocarcinoma (NGCO) is a highly aggressive germ cell-derived tumor frequently presenting with early hematogenous metastasis., Patient Concerns: Herein, we report a case of a 28-year-old unmarried woman with regular menstruation who experienced vaginal bleeding 1 week after her last menstrual cycle. Doppler ultrasound revealed bilateral adnexal masses and elevated serum human chorionic gonadotropin (hCG) levels. The patient was initially misdiagnosed as presenting an ectopic pregnancy., Diagnosis: The final pathology confirmed an International Federation of Gynecology and Obstetrics stage IA NGCO with bilateral mature teratoma of the ovary. This is an extraordinary instance of ovarian choriocarcinoma which emerged without any prior gestation, and the patient's lack of a history of pregnancy made the diagnosis ignored., Interventions: After initial surgery and 1 cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy, a laparoscopic fertility-preserving comprehensive staging surgery was performed. Two cycles of chemotherapy with BEP were administered as supplemental therapy postsurgery, and leuprorelin was administered to protect ovarian function., Outcomes: Menstruation resumed 4 months after chemotherapy completion, and tumor indicators were within the normal range. No signs of recurrence were observed at the 36-month follow-up., Conclusion: NGCO should be considered if a female patient exhibits irregular vaginal bleeding and masses in the adnexal area. The present case and our literature review also highlighted that fertility-sparing surgery and multidrug chemotherapy are effective methods for treating NGCO., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation., Materials and Methods: Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction., Results: At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response., Conclusions: Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice., Clinical Trial Registration: Eudract No. 2019-001146-17, NCT04028050., (© The Author(s) 2024. Published by Oxford University Press.)

Background Aims: The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown., Methods: In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively., Results: The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93-51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders)., Conclusions: For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy., Competing Interests: Declaration of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the "classical" protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide-resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage-independent growth of etoposide-resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide-resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide-resistant RB cells. These impacts mirror PTPRE KD effects, indicating a regulation of PTPRE via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and-dependent on the cell line-AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma., Competing Interests: The authors declare no conflicts of interest.

Background: Durvalumab plus etoposide-platinum (DEP) showed sustained overall survival improvements in patients with extensive-stage small-cell lung cancer (ES-SCLC) compared to etoposide-platinum (EP), but adding tremelimumab to DEP (DTEP) did not significantly improve outcomes. A third-party payer perspective is taken here to evaluate the cost-effectiveness of DTEP, DEP, and EP for ES-SCLC., Methods: The cost-effectiveness was evaluated by partitioning survival models into 3 mutually exclusive health states. In this model, clinical characteristics and outcomes were obtained from the CASPIAN. Model robustness was evaluated through 1-way deterministic and probabilistic sensitivity analyses. Outcome measurements included costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio, life-years, incremental net health benefit, and incremental net monetary benefit. The analysis was conducted with a 10-year lifetime horizon in a United States setting., Results: Compared with EP, DEP, and DTEP were associated with an increment of 0.480 and 0.313 life-years, and an increment of 0.247 and 0.165 QALYs, as well as a $139,788 and $170,331 increase in cost per patient. The corresponding ICERs were $565,807/QALY and $1033,456/QALY, respectively. The incremental net health benefit and incremental net monetary benefit of DEP or DTEP were -0.685 QALYs and -$102,729, or -0.971 QALYs and -$145,608 at a willingness to pay threshold of $150,000/QALY, respectively. Compared with DTEP, DEP was dominated. DTEP and DEP were 100% unlikely to be cost-effective if the willingness to pay threshold was $150,000/QALY. DEP was cost-effective compared to EP when durvalumab was priced below $0.994/mg. Compared with EP, DEP, and DTEP were unlikely to be considered cost-effective across all subgroups., Conclusion: DEP and DTEP were not cost-effective options in the first-line treatment for ES-SCLC compared with EP, from the third-party payer perspective in the United States. Compared with DTEP, DEP was dominated., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The recommended treatment for limited-stage small-cell lung cancer (LS-SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4-6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS-SCLC who received either 6 cycles or 4-5 cycles of EP chemotherapy combined with TRT., Materials and Methods: In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS-SCLC patients who received 4-6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4-5 cycles. To assess overall survival (OS) and progression-free survival (PFS), we employed the Kaplan-Meier method after conducting propensity score matching (PSM)., Results: Among the 265 LS-SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4-5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4-5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6-53.1 months) vs. 22.7 months (95% CI, 20.8-29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7-30.5 months) vs. 12.0 months (95% CI, 9.8-14.2 months), respectively, p = 0.006]. The two-year and five-year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4-5 cycles group, respectively., Conclusion: Patients diagnosed with LS-SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4-5 cycles., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Peritoneal lymphomatosis (PL) is a rare lymphoma-associated condition defined as the dissemination of lymphoma cells in the peritoneum. An 82-year-old man presented with abdominal pain, heartburn, and high fever. Radiological findings, including positron emission tomography-computed tomography (PET-CT), and gastrointestinal fiberscopy, showed diffuse thickening of the peritoneum, omentum, and mesentery; however, no lymphadenopathy, hepatosplenomegaly, or gastrointestinal lesions were observed. Under suspicion of peritonitis carcinomatosa of unknown origin, exploratory laparoscopy was performed that revealed multiple white nodules and masses on the surfaces of the peritoneum, mesentery, and intestinal serosa. The histopathological and cytogenetic findings of the peritoneum revealed high-grade B-cell lymphoma, not otherwise specified, and a gain of MYC by fluorescence in-situ hybridization. The patient was treated with two cycles of R-CHOP therapy, followed by six cycles of dose-adjusted EPOCH-R therapy, and a complete metabolic response was confirmed by PET-CT. Since there are no specific radiological findings to confirm the diagnosis of PL, a histopathological diagnosis is usually required. Most PL exhibit an aggressive lymphoma phenotype and can be cured by appropriate chemotherapy. Therefore, early diagnosis and treatment are desirable.

Introduction and Objective: Including additional compounds that disturb the energy metabolism of cancer cells in advanced cancer therapy regimens may be an approach to overcome the problem of drug resistance and the therapeutic effectiveness of classic chemotherapeutics. One of the compounds that decouple oxidative phosphorylation, and thus alter the activity of energy-producing pathways, is 2,4-DNP (2,4- dinitrophenol)., Objective: The aim of the study was to assess the ability of the 2,4-DNP to sensitize prostate cancer cells to the action of cisplatin and etoposide, or to intensify their action., Material and Methods: The research was carried out on three prostate cancer cell lines (LNCaP, PC-3, DU-145. To assess the effect of cisplatin or etoposide with 2,4-DNP on prostate cancer cells, MTT assay, analysis of the cell cycle and apoptosis detection was performed. Oxidative stress was investigated by CellRox fluorescence staining and expression of genes related to antioxidant defence. In addition, analysis was conducted of the expression of genes related to cell cycle inhibition, transporters associated with multi-drug resistance and DNA repair., Results: The study showed that the simultaneous incubation of 2,4-DNP with cisplatin or etoposide enhances the cytotoxic effect of the chemotherapeutic agent only in LNCaP cells (oxidative phenotype)., Conclusions: The enhanced cytotoxic effect of chemotherapeutics by 2,4-DNP may be the result of disturbed redox balance, reduced ability of cells to repair DNA, and the oxidative metabolic phenotype of prostate cancer cells.

Introduction: Immune checkpoint blockade (ICB) with or without chemotherapy has a very modest benefit in patients with small cell lung cancer (SCLC). SCLC tumors are characterized by high tumor mutation burden (TMB) and low PD-L1 expression. Therefore, TMB and PD-L1 do not serve as biomarkers of ICB response in SCLC. CD38, a transmembrane glycoprotein, mediates immunosuppression in non-small cell lung cancer (NSCLC). In this brief report, we highlight the potential role of CD38 as a probable biomarker of immunotherapy response in SCLC., Methods: We evaluated the role of CD38 as a determinant of tumor immune microenvironment in SCLC with bulk and single-cell transcriptomic analyses and protein assessments of clinical samples and preclinical models, including CD38 in vivo blockade., Results: In SCLC clinical samples, CD38 levels were significantly correlated with the gene expression of the immunosuppressive markers FOXP3 , PD-1 and CTLA-4 . CD38 expression was significantly enhanced after chemotherapy and ICB treatment in SCLC preclinical models and clinical samples. A combination of cisplatin/etoposide, ICB, and CD38 blockade delayed tumor growth compared to cisplatin/etoposide., Conclusion: Our study provides a preliminary but important direction toward exploring CD38 as a potential biomarker of ICB response and CD38 blockade as a combination strategy for chemo-immunotherapy in SCLC., Competing Interests: TS has grant funding from Jazz Pharmaceuticals. CR has consulted regarding oncology drug development with AbbVie, Amgen, Astra Zeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros. He serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. JC has equity in Mirati Therapeutics and the provision of services from Sonata Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Taniguchi, Chavan, Chow, Chan, Mukae, Rudin and Sen.)

Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses., Competing Interests: Declaration of interests B.Y.N., H.H., and D.S.S. are co-inventors on a provisional patent application filed by Genentech/Roche related to this manuscript. B.Y.N. is an employee and stockholder of Roche/Genentech. H.H. is an employee and stockholder of Roche/Genentech. R.B. is an employee and shareholder of Roche/Genentech. S.M. is an employee and shareholder of Roche. L.A. is an employee and shareholder of Roche. V.G. is an employee of Rancho Biosciences and a consultant to Roche/Genentech. M.C.L. is an employee of Roche/Genentech. A.M.E. is an employee of Roche/Genentech. M.K.S. is an employee and shareholder of Roche/Genentech. N.S.P. is an employee and shareholder of Roche/Genentech. K.A.S. is an employee of Roche/Genentech. R.J. is an employee and shareholder of Roche/Genentech. C.C. is an employee and shareholder of Roche/Genentech. P.S.C. is an employee and shareholder of Roche/Genentech. M.F. is an employee of Roche/Genentech. S.R. is an employee and shareholder of Roche/Genentech. L.M.M. is an employee and shareholder of Roche/Genentech. H.K. is an employee and shareholder of Roche/Genentech. J.D.M. receives royalties from the NIH and UTSW for distribution of human tumor cell lines and has the following grants: CA070907, CA213274, and CA213338. C.M.G. reports consulting/advisory fees from AstraZeneca, Bristol Myers Squibb, Catalyst Pharmaceuticals, Daiichi Sankyo, G1 Therapeutics, Insights Driven Research, Jazz Pharmaceuticals, and Monte Rosa Therapeutics, as well as speaking/travel fees from Aptitude Health, BeiGene, DAVA Oncology, MJH, and OncLive, and royalties from UpToDate, Inc. J.M.C. has been paid as a consultant for Sonata Therapeutics and also owns stock in Mirati Therapeutics. J.V.H. has advisory or consulting relationships with Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAtla, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, Blueprint Medicine, and Chugai Pharmaceuticals. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros. He serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. L.A.B. has consulted regarding oncology drug development Merck Sharp & Dohme Corp., Arrowhead Pharmaceuticals, Chugai Pharmaceutical Co., AstraZeneca Pharmaceuticals, Genetech Inc., BeiGene, AbbVie, Jazz Pharmaceuticals, Puma Biotechnology, Amgen, and Daiichi Sankyo. S.V.L. served as a paid consultant/advisor for oncology drug development with AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Boehringer-Ingelheim, Bristol-Myers Squibb, Catalyst, AstraZeneca, D2G, Daiichi Sankyo, Eisai, Elevation Oncology Epizyme, Genentech/Roche, Gilead, Guardant Health, Janssen, Ipsen, Jazz Pharmaceuticals, Kowa, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, Turning Point, and Syros. He serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics and has received research funding (to institution). M.R. has received honoraria for lectures and consultancy from Amgen, AstraZeneca, BMS, BeiGene, Boehringer-Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Lilly, Novartis, Pfizer, Regeneron, and Sanofi. He has received compensation for membership of DMSB by Daiichi Sankyo and Sanofi. D.S.S. is an employee and stockholder of Roche/Genentech., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Platinum-etoposide chemotherapy combined with immune checkpoint inhibitors (ICIs) has been recommended as the first-line standard treatment for extensive-stage small-cell lung cancer (ES-SCLC). However, the effect of thoracic radiotherapy (TRT) on these patients is still unknown. This study aimed to evaluate the efficacy and safety of TRT for ES-SCLC patients who responded to first-line ICIs and chemotherapy (CHT)., Methods: Patients who received 4 to 6 cycles of ICIs and CHT as first-line therapy at three hospitals between 2018 and 2022 were included in the analysis. All patients were divided into two groups based on whether they received TRT as first-line treatment, and propensity score matching (PSM) was performed to ensure that the characteristics of two groups were well-balanced. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was toxic effects., Results: A total of 276 patients were included, and the median follow-up time was 22.3 (range, 4.0-53.73) months. After PSM, 197 patients were further analysed, and 99 of whom received TRT. The baseline characteristics were well-balanced between patients in the TRT and non-TRT groups. There were significant differences in PFS between the TRT and non-TRT groups, with the median PFS of 10.76 and 7.63 months, respectively (P = 0.014). Significantly improved OS was observed in the TRT group (21.67 vs. 16.6 months, P = 0.009). In addition, the use of TRT was an independent prognostic factor for PFS and OS of ES-SCLC patients receiving ICIs plus CHT. In terms of safety, no significant increase of any grades adverse event (AE) (P = 0.874) and G3-4 AE (P = 0.909) was observed for patients receiving TRT. Radiation esophagitis, gastrointestinal and hematologic toxicities were the most common AEs in TRT group, which were tolerable. And high-dose radiotherapy was associated with higher incidence of pneumonitis., Conclusion: Addition of TRT showed significant survival benefits and well tolerability in ES-SCLC patients receiving platinum-etoposide CHT and ICIs, which could be a feasible first-line treatment strategy for ES-SCLC patients., (© 2024. The Author(s).)