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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.)

Objective: Standard treatment for adults with acute myeloid leukemia (AML) involves anthracycline and cytarabine, while alternative regimens are necessary for elderly and frail patients. This study aims to compare the effectiveness and safety of various induction regimens in AML patients., Patients and Methods: The retrospective study included 130 adult AML patients treated at a tertiary care center from January 2014 to December 2022. Patients received one of the following induction regimens: anthracycline and cytarabine (n = 82), azacitidine and venetoclax (n = 11), etoposide and cytarabine (n = 22), or reduced-dose anthracycline and cytarabine (n = 15). Data on demographics, clinical characteristics, treatment-related toxicities, and infectious complications were collected. Outcomes included overall survival and remission rates., Results: The anthracycline and cytarabine regimen demonstrated the highest overall survival rate, although remission rates did not significantly differ among the treatment groups. Patients receiving azacitidine and venetoclax experienced a significantly longer duration of neutropenia. The use of antiviral prophylaxis increased over the study period, reflecting improved management strategies. Infection remained the leading cause of mortality., Conclusions: Effective management of prolonged neutropenia and infections is crucial for improving patient outcomes. Future research should focus on optimizing prophylactic and infection treatment strategies to further enhance survival in AML.

Most patients with Primary Mediastinal B-Cell Lymphoma (PMBCL) are cured by rituximab and doxorubicin-based immunochemotherapy, with or without radiotherapy. In cases with relapsed and refractory (RR) disease the prognosis was historically poor. Recently, immune checkpoint-based strategies have been shown to be highly effective in patients with RR-PMBCL. We report the case of a 23-year-old woman who, due to recurring episodes of symptomatic chemotherapy-induced sinus bradycardia, was unable to receive the planned six courses of immunochemotherapy, mediastinal radiotherapy, and autologous transplantation, leading to the early initiation of a chemo-free strategy. The patient maintains a continuous complete remission at a four-year follow-up after only two cycles of immunochemotherapy followed by nivolumab plus brentuximab vedotin (BV) and pembrolizumab consolidation. Beyond describing an underreported complication of anticancer treatments, the favorable clinical outcome suggests that in PMBCL, a minimal load of chemotherapy, integrated by early PD-1 blockade, with or without BV, may be sufficient to achieve long-term disease control and cure at least in some patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Study Question: What is the impact of the EuroNet-PHL-C2 treatment for boys with classical Hodgkin lymphoma (cHL) on semen parameters?, Summary Answer: More than half of the patients (52%, n = 16/31) had oligozoospermia or azoospermia at 2 years from cHL diagnosis; particularly boys treated for advanced-stage cHL had low sperm counts and motility., What Is Known Already: Chemotherapy and radiotherapy to the inguinal region or testes can impair spermatogenesis and result in reduced fertility. The EuroNet-PHL-C2 trial aims to minimize radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. The present study aims to assess the (gonadotoxic) impact of this treatment protocol on semen parameters and reproductive hormones in boys aged ≤18 years., Study Design, Size, Duration: This international, prospective, multi-centre cohort study was an add-on study to the randomized phase-3 EuroNet-PHL-C2 trial, where the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) was compared to intensified OEPA-DECOPDAC-21 chemotherapy (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide). Patients were recruited between January 2017 and September 2021., Participants/materials, Setting, Methods: Eligibility criteria included male patients, diagnosed with classical HL before or at the age of 18 years, and treated according to the EuroNet-PHL-C2 protocol in any of the 18 participating sites in the Netherlands, Germany, Belgium, Czech Republic, and Austria. Sperm parameters (sperm concentration, progressive motility, sperm volume, and calculated total motile sperm count) were assessed at diagnosis and 2 years after diagnosis in (post)pubertal boys. Laboratory measurements (serum follicle-stimulating hormone (FSH) and inhibin B) were performed in samples drawn at diagnosis, during treatment (2-3 times), and at 2 years post-diagnosis, and (age-adjusted) analyses were conducted separately for pre-pubertal and (post)pubertal boys. Outcomes were compared between the treatment levels (TL1, TL2, and TL3) and consolidation treatment schemes (COPDAC-28 and DECOPDAC-21)., Main Results and the Role of Chance: In total, 101 boys were included in the present analysis: 73 were (post)pubertal (median age 15.4 years, (IQR 14.4; 16.6), 10 TL1, 29 TL2, 34 TL3, 62% of TL2/3 patients received COPDAC-28) and 28 boys were pre-pubertal (median age 9.6 years (IQR 6.6; 11.4), 4 TL1, 7 TL2, 17 TL3, 38% of TL2/3 patients received COPDAC-28). The study included six boys who had received pelvic radiotherapy; none were irradiated in the inguinal or testicular area. At diagnosis, 48 (post)pubertal boys delivered semen for cryopreservation; 19 (40%) semen samples were oligospermic and 4 (8%) were azoospermic. Low sperm concentration (<15 mil/ml) appeared to be related to the HL disease itself, with a higher prevalence in boys who presented with B symptoms (76% vs 26%, aOR 2.3 (95% CI 1.0; 3.8), P = 0.001) compared to those without such symptoms. At 2 -years post-diagnosis, 31 boys provided semen samples for analysis, of whom 12 (39%) boys had oligozoospermia and 4 (13%) had azoospermia, while 22 boys (71%) had low total motile sperm counts (TMSC) (<20 mil). Specifically, the eight boys in the TL3 group treated with DECOPDAC-21 consolidation had low sperm counts and low progressive motility after 2 years (i.e. median sperm count 1.4 mil/ml (IQR <0.1; 5.3), n = 7 (88%), low sperm concentration, low median progressive motility 16.5% (IQR 0.0; 51.2), respectively). Age-adjusted serum FSH levels were significantly raised and inhibin B levels (and inhibin B:FSH ratios) were decreased during chemotherapy in (post)pubertal boys, with subsequent normalization in 80% (for FSH) and 60% (for inhibin B) of boys after 2 years. Only 4 out of the 14 (post)pubertal boys (29%) with low sperm concentrations after 2 years had elevated FSH (>7.6 IU/l), while 7 (50%) had low inhibin B levels (<100 ng/l). In pre-pubertal boys, reproductive hormones were low overall and remained relatively stable during chemotherapy., Limitations, Reasons for Caution: The present analyses included sperm and laboratory measurements up to 2 years post-diagnosis. Long-term reproductive outcomes and potential recovery of spermatogenesis remain unknown, while recovery was reported up to 5- or even 10-year post-chemotherapy in previous studies.Boys who were pre-pubertal at diagnosis were still too young and/or physically not able to deliver semen after 2 years and we could not assess a potential difference in gonadotoxicity according to pubertal state at the time of treatment. Overall, the statistical power of the analyses on sperm concentration and quality after 2 years was limited., Wider Implications of the Findings: Results of the semen analyses conducted among the 31 boys who had provided a semen sample at 2 years post-treatment were generally poor. However, additional long-term and adequately powered data are crucial to assess the potential recovery and clinical impact on fertility. The participating boys will be invited to deliver a semen sample after 5 years. Until these data become available, benefits of intensified chemotherapy in cHL treatment to reduce radiotherapy and lower risk for development of secondary tumours should be carefully weighed against potentially increased risk of other late effects, such as diminished fertility due to the increased chemotherapy burden. Boys with newly diagnosed cHL should be encouraged to deliver sperm for cryopreservation whenever possible. However, patients and clinicians should also realize that the overall state of disease and inflammatory milieu of cHL can negatively affect sperm quality and thereby reduce chance of successful fertility preservation. Furthermore, the measurement of FSH and inhibin B appears to be of low value in predicting low sperm quality at two years from cHL treatment., Study Funding/competing Interest(s): This study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M.-K., D.K., W.H.W., D.H., MC, A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors declare no potential conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin's lymphoma (NHL), is substantially heterogeneous. Approximately 5-10% of DLBCLs express CD5, which makes CD5 + DLBCL a rare subgroup. Different studies have shown that CD5 + DLBCL patients are often older and female and have higher lactate dehydrogenase levels, an Eastern Cooperative Oncology Group (ECOG) performance status > 1, and higher International Prognostic Index (IPI) scores. Moreover, patients often have advanced stage disease with a high incidence of central nervous system (CNS) relapse and bone marrow involvement. CD5 + DLBCL cells are more likely to express MYC, BCL-2, and MUM-1, less likely to express CD10, and most belong to the activated B-cell-like (ABC) subtype. The potential mechanisms underlying the poor prognosis of CD5 + DLBCL patients may be related to CD5-mediated B-cell receptor (BCR)-dependent and -independent pathways. The efficacy of the traditional rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen is unsatisfactory in CD5 + DLBCL patients. Despite supporting evidence from retrospective studies, it is currently unclear whether dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) can improve outcomes in this population. Several new drugs, such as Bruton tyrosine kinase inhibitors (BTKi), BCL-2 inhibitors, and CXCR4 antagonists, as well as immunotherapy, may help to improve the prognosis of CD5 + DLBCL patients, but additional clinical explorations are needed to determine the optimal therapeutic strategy for this disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neuroendocrine neoplasms (NENs) of the liver represent a rare entity. Amongst this group of uncommon diseases primary hepatic neuroendocrine neoplasm (PH-NEN) represent only 0.3% of all NENs. Moreover, PH-NEN has very rarely been reported in pregnancy. We report a 28-year-old young patient with metastatic small cell neuroendocrine carcinoma of the liver complicated with pregnancy. She was evaluated and managed through a multidisciplinary team approach and received two cycles of chemotherapy with a cisplatin/etoposide regimen during the antenatal period and delivered at 37 weeks period of gestation (POG). This case highlights the importance of major challenges faced during the diagnosis and management of this very rare disease in pregnancy and the successful fetomaternal outcome., (© 2024 International Federation of Gynecology and Obstetrics.)

Purpose: Etoposide to standard R-CHOP is used for high-risk diffuse large B-cell lymphoma (DLBCL) in some countries. Due to the lack of randomized trials, a real-world data study using matching methods was used to test the potential effectiveness of R-CHOEP over R-CHOP., Patients and Methods: This study included patients from the Danish Lymphoma Register diagnosed between 2006 and 2020 at the age of 18-60 years with de novo DLBCL and age-adjusted IPI ≥2. R-CHOEP treated patients were matched 1:1 without replacement to R-CHOP treated patients using a hybrid exact and genetic matching technique. Primary endpoints were progression-free survival (PFS) and overall survival (OS)., Results: In total, 396 patients were included; 213 received R-CHOEP and 183 received R-CHOP. Unadjusted 5-year PFS and OS for R-CHOEP were 69% (95% Confidence intervals [CI]; 63%-76%) and 79% (CI;73%-85%) versus 62% (CI;55%-70%) and 76% (CI;69%-82%) for R-CHOP (log-rank test, PFS p = .25 and OS p = .31). A total of 127 patients treated with R-CHOEP were matched to 127 patients treated with R-CHOP. Matching-adjusted 5-year PFS and OS were 65% (CI; 57%-74%) and 79% (CI; 72%-84%) for R-CHOEP versus 63% (CI; 55%-73%) and 79% (CI;72%-87%) for R-CHOP (log-rank test, PFS p = .90 and OS p = .63)., Conclusion: The present study did not confirm superiority of R-CHOEP over R-CHOP for young patients with high-risk DLBCL., (© 2024 The Author(s). European Journal of Haematology 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.)

Treatment of relapsed or refractory diffuse large B-cell lymphoma is difficult. The de novo diffuse large B-cell lymphoma has better prognosis than the transformed diffuse large B-cell lymphoma. The response of CHOP or a similar regimen has an important role in determining response to salvage therapy, in relapse or refractory diffuse large B-cell lymphoma patients. Patients who are non-responder to initial treatment have a very poor chance of responding to therapy for relapse. This was a small scale observational study and was conducted from January 2017 to December 2020 in National Institute of Cancer Research and Hospital, Bangladesh. A total of 34 patients with relapsed or refractory diffuse large B-cell lymphoma were identified at hematology department in National Institute of Cancer Research and Hospital, 28 of them were treated with ICE chemotherapy and 6 with R-ICE chemotherapy as second line regimen. Overall response rate to 2nd line chemotherapy was 64.8%, with 32.4% (11 patients) complete remission and 32.4% (11 patients) partial remission. Median overall survival to second line regimen was 10 months, corresponding to a 4 year overall survival of 32.4% and a 4 year progression free survival was 17.6%. Patient with stable disease/progressive disease median overall survival was 7 months compared with 15 months for complete remission and 9 months for partial remission (p<0.001). Median overall survival was significantly better in patients with international prognostic index 0-2 compared in those with international prognostic index >2 (p=0.010). However improvement of salvage efficacy is an urgent need with new drugs. Further studies are necessary to determine whether this regimen will improve outcomes of relapsed or refractory diffuse large B-cell lymphoma patients.

Objectives: Certain guidelines recommend caution when administering immunotherapy in patients with pre-existing interstitial lung disease (ILD) owing to the high incidence of pneumonitis induced by anti-cancer therapy. A prospective clinical trial assessing the safety of chemoimmunotherapy in patients with small-cell lung cancer (SCLC) and pre-existing ILD is warranted. Therefore, this study evaluated the safety and efficacy of chemoimmunotherapy in patients with extensive-stage (ES)-SCLC and mild idiopathic interstitial pneumonia (IIP)., Methods: In this multicenter prospective trial, patients with ES-SCLC and pre-existing mild chronic fibrosing IIP were recruited. Mild IIP was defined as the exclusion of poor pulmonary function, a definite usual interstitial pneumonia (UIP) pattern, and positivity for autoantibodies in blood tests. The patients received durvalumab, etoposide, and carboplatin every three weeks (induction phase), followed by 1,500 mg durvalumab every four weeks (maintenance phase). The primary endpoint was severe pneumonitis-free rate., Results: Twenty-one patients were included in the analysis. Among them, 13 patients displayed a probable UIP pattern, whereas eight patients exhibited an indeterminate for UIP pattern. Two patients (9.5 %) had pneumonitis of any grade during the induction phase; one had Grade 1 and the other had Grade 5 pneumonitis. No other patient developed pneumonitis during the maintenance phase. The severe pneumonitis-free rate was 95.2 % (95 % confidence interval (CI): 77.3-99.2 %). The median progression-free survival was 5.5 months (95 % CI: 3.6-6.4 months). Median overall survival was 10.7 months (95 % CI: 6.0 months to not reached)., Conclusions: Chemoimmunotherapy is a feasible treatment approach for patients with ES-SCLC and mild IIP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Daichi Fujimoto reports financial support provided by AstraZeneca K.K. Ryota Shibaki received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and MSD KK outside the submitted work. Daichi Fujimoto received grants from AstraZeneca K.K. during the study and personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Janssen Pharmaceutical KK, Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Novartis Pharma KK outside of the submitted work. Eisaku Miyauchi received personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., Pfizer Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Amgen Inc., Thermo Fisher Scientific KK, Nippon Kayaku Co. Ltd., Sysmex Co. Ltd., KYORIN Pharmaceutical Co. Ltd., and Novartis Pharma KK outside the submitted work. Yoko Tsukita received personal fees from AstraZeneca KK, Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., and Boehringer Ingelheim Japan Inc. outside the submitted work. Daisuke Arai has received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck, and Nippon Kayaku Co. outside the submitted work. Yoshihiko Sakata received personal fees from AstraZeneca KK, Amgen, Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Takeda Pharmaceutical Co., Ltd., and Novartis Pharma KK outside the submitted work. Naoki Shingu received personal fees from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Takeda Pharmaceutical Co. Ltd., and MSD KK outside the submitted work. Takashi Kijima received personal fees from Chugai Pharmaceutical Co. Ltd. outside the submitted work. Go Saito received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Pfizer, Daiichi Sankyo Company, and Novartis Pharma KK outside the submitted work. Yuki Sato received personal fees from AstraZeneca KK, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Daiichi Sankyo Co. Ltd., and Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Nippon Kayaku Co., Ltd., and Novartis Pharma KK outside the submitted work. Shinya Sakata received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. outside the submitted work. Yoshihiko Taniguchi received personal fees from AstraZeneca KK, Bristol-Myers Squibb Co. Ltd., and Chugai Pharmaceutical Co. Ltd. outside the submitted work. Akito Hata has received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan KK, Pfizer Inc., and Boehringer Ingelheim outside the submitted work. Hirotaka Matsumoto received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Ono Pharmaceutical Co. Ltd., and Boehringer Ingelheim outside the submitted work. Nobuyuki Yamamoto has received personal fees from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan Inc., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical KK, Terumo, Eli Lilly Japan KK, Novartis Pharma KK, Merck Biopharma, Guardant Health Japan, Accuray Inc., AbbVie, Kyorin Pharmaceutical Co. Ltd., Tsumura & Co., and Miyarisan Pharmaceutical outside the submitted work. Other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this study.]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: IMbrella A is a Phase III extension study that allowed rollover from Roche/Genentech-sponsored atezolizumab trials, including IMpower133, a Phase I/III trial of first-line atezolizumab or placebo plus carboplatin/etoposide in extensive-stage small cell lung cancer. We report outcomes from an exploratory analysis of IMpower133 with extended time-to-event data for patients who rolled over to IMbrella A., Materials and Methods: IMpower133 patients could roll over to IMbrella A to receive atezolizumab 1200 mg intravenously every three weeks if they continued to receive atezolizumab at IMpower133 closure or were in survival follow-up after atezolizumab discontinuation. Overall survival and safety were assessed; only serious adverse events and AEs of special interest were collected in IMbrella A., Results: Eighteen of 26 eligible patients rolled over to IMbrella A. At clinical cutoff (March 16, 2023), median follow-up in the atezolizumab plus carboplatin/etoposide arm (IMpower133 and IMbrella A) was 59.4 months. The three-, four-, and five-year overall survival (95 % CI) estimates were 16 % (11 %-21 %), 13 % (8 %-18 %), and 12 % (7 %-17 %), respectively. In IMbrella A, serious adverse events occurred in three patients (16.7 %), and one adverse event of special interest was reported (grade two hypothyroidism)., Conclusion: This long-term analysis of patients from IMbrella A previously enrolled in IMpower133 provides the first report of five-year overall survival outcomes in patients with extensive-stage small cell lung cancer treated with first-line cancer immunotherapy and chemotherapy. While limited by small patient numbers and lack of long-term data for the IMpower133 control arm, exploratory overall survival analyses in patients treated with atezolizumab plus carboplatin/etoposide compared favorably with historical data with chemotherapy alone. NCT03148418., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report editorial support funded by the Sponsor. Martin Reck reports receiving consulting fees, honoraria and travel support from Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Lily, Novartis, Pfizer, Sanofi, Roche, and Regeneron; and participation on a data safety monitoring or advisory board for Sanofi and Daiichi Sankyo. Rafal Dziadziuszko reports receiving honoraria from Roche, AstraZeneca, Amgen, Novartis, MSD, Bristol Myers Squibb, Takeda, and Pfizer; and materials from Novartis. Shunichi Sugawara reports receiving grants (to institution) from AstraZeneca, Chugai Pharma, MSD, Bristol Myers Squibb, and Ono Pharmaceutical; and honoraria from AstraZeneca, Chugai Pharma, MSD, Bristol Myers Squibb, and Ono Pharmaceutical. Steven Kao reports receiving grants (to institution) from AstraZeneca; honoraria from AstaZeneca, Pfizer, MSD, Bristol Myers Squibb, Roche, Amgen, Beigene, and Boehringer Ingelheim; and travel support from MSD. Maximilian Hochmair reports receiving honoraria from MSD, Roche, Lilly, AstraZeneca, Takeda, Bristol Myers Squibb, and Amgen. Florian Huemer declares no conflict of interest. Gilberto de Castro, Jr reports receiving consulting fees from Daiichi-Sankyo; honoraria from AstraZeneca, Bristol Myers Squibb, Jannsen, Lilly, MSD, Novartis, Roche, Amgen, and Daiichi-Sankyo; travel support from Roche, Amgen, Daiichi-Sankyo, MSD, AstraZeneca, and Bristol Myers Squibb; and participation on a data safety monitoring or advisory board for GlaxoSmithKline, AstraZeneca, MSD, and Novartis. Libor Havel declares no conflict of interest. Reyes Bernabé Caro reports receiving an investigational grant from Roche; honoraria from Roche, Bristol Myers Squibb, Pfizer, MSD, Amgen, Takeda, and AstraZeneca; and participation in a data safety monitoring or advisory board for Takeda, Roche, Bristol Myers Squibb, and AstraZeneca. György Losonczy and Jong-Seok Lee declare no conflict of interest. Dariusz M. Kowalski reports participation on an advisory board and consultancy for Roche, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, MSD, Sanofi-Aventis, Takeda, Pfizer, and Johnson & Johnson. Zoran Andric declares no conflict of interest. Raffaele Califano reports receiving grants (to institution) from Roche and MSD; consulting fees from Roche, MSD, Bristol Myers Squibb, and AstraZeneca; and honoraria from Roche, MSD, and AstraZeneca; membership in the EORTC lung cancer group and ESMO educational publication working group; and stock or stock options in The Christie Private Care and Supportive Care UK. Andrea Veatch, Gregory Gerstner, and Marta Batus declare no conflicts of interest. Stefanie Morris reports employment with and stock or stock options in Roche. Monika Kaul, Vaikunth Cuchelkar, Huafei Li, Bradford J. Danner, and Barzin Y. Nabet report employment with Roche. Stephen V. Liu reports receiving grants from AbbVie, Alkermes, Elevation Oncology, Ellipses, Genentech, Gilead, Merck, Merus, Nuvalent, RAPT, and Turning Point Therapeutics; and consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; and participation on a data safety monitoring for Candel Therapeutics., (Copyright © 2024. Published by Elsevier B.V.)

BACKGROUND AND OBJECTIVE: Recent trials have shown that immune checkpoint inhibitors (ICIs), atezolizumab and durvalumab, in combination with chemotherapy, are effective in treating extensive-disease small-cell lung cancer (ED-SCLC). However, owing to the expensiveness of ICIs, monetary issues arise. The cost-effectiveness of ICI combination treatment with carboplatin plus etoposide (CE) as first-line therapy for patients with ED-SCLC was examined to aid public health policy in Japan., Methods: IMpower 133 and CASPIAN data were used to create a partitioned survival model. Medical expenses and quality-adjusted life years (QALYs) were considered. The analysis period, discount rate, and threshold were set at 20 years, 2%, and 15 million Japanese yen (JPY) [114,068 US dollars (USD)] per QALY, respectively. The incremental cost-effectiveness ratio (ICER) was calculated by gathering reasonable parameters from published reports and combining the costs and effects using parametric models. Monte Carlo simulations, scenario analysis, and one-way sensitivity analyses were employed to quantify uncertainty., Results: After comparing atezolizumab plus CE (ACE) and durvalumab plus CE (DCE) with CE, it was found that the ICERs exceeded the threshold at 35,048,299 JPY (266,527 USD) and 36,665,583 JPY (278,826 USD) per QALY, respectively. For one-way sensitivity and scenario assessments, the ICERs exceeded the threshold, even with considerably adjusted parameters. For the probabilistic sensitivity analyses, there was no probability that the ICER of the ICI combination treatment with chemotherapy would fall below the threshold., Conclusion: ACE and DCE were not cost-effective compared with CE as first-line therapy for ED-SCLC in Japan. Both these therapies exhibited high ICERs., (© 2024. The Author(s).)

Objectives: Despite major advances in treatment options for multiple myeloma (MM), patients refractory to the main drug classes and those with aggressive, especially extramedullary disease, still face a dismal outcome. For these patients, effective therapeutic options are urgently warranted., Methods: In this retrospective study, we report on the safety and efficacy of the intensive combination regimen of pomalidomide plus cisplatin, doxorubicin, cyclophosphamide, and etoposide (Pom-PACE) in patients with relapsed refractory MM (RRMM) or plasma cell leukemia (PCL). A study population of 20 consecutive patients treated with Pom-PACE at two academic centers was included for analysis. All patients had to have a confirmed relapse according to International Myeloma Working Group criteria and adequate organ function prior to the start of therapy. Data were collected by reviewing medical charts. Exploratory analyses were performed with regard to efficacy and safety., Results: Patients were heavily pretreated with a median number of four prior therapies (range: 1-10). All patients were exposed to immunomodulators, proteasome inhibitors, and alkylating agents, 80% were double-class refractory, 40% were triple-class refractory. Extramedullary MM or PCL were present in 15 patients (75%). Overall response rate (ORR) was 68%, with 31% achieving at least a very good partial response. Responses were achieved rapidly with an ORR of 64% after one cycle. Median progression-free survival was 8.9 months (0.92-not reached [NR]) and median overall survival was 11.8 months (3-40.6). Pom-PACE was associated with significant toxicity. All evaluable patients experienced Grade 4 hematological toxicity. However, no treatment related mortality was observed., Conclusion: Pomalidomide-PACE was able to induce rapid responses in heavily pretreated, aggressive RRMM with a manageable toxicity profile and therefore offers an effective salvage regimen and a potential bridging strategy to further treatment options such as chimeric antigen receptor T-cell therapy., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

High-dose therapy followed by autologous hematopoietic cell transplant (AHCT) remains a viable consolidation strategy for a subset of patients with relapsed or refractory (R/R) lymphomas. BEAM (carmustine, etoposide, cytarabine, and melphalan) is widely recognized as the predominant conditioning regimen due to its satisfactory efficacy and tolerability. Nevertheless, shortages of carmustine and melphalan have compelled clinicians to explore alternative conditioning regimens. The aim of this study was to compare the toxicity and transplant outcomes following BEAM, CBV (carmustine, etoposide, cyclophosphamide), BuMel (busulfan, melphalan), and BendaEAM (bendamustine, etoposide, cytarabine, melphalan). We retrospectively analyzed data from 213 patients (CBV 65, BuMel 42, BEAM 68, BendaEAM 38) with R/R lymphomas undergoing AHCT between 2014 and 2020. Multivariate models were employed to evaluate toxicity and transplant outcomes based on conditioning type. Among grade III to IV toxicities, oral mucositis was more frequently observed with BuMel (45%) and BendaEAM (24%) compared to BEAM (15%) and CVB (6%, P ≤ .001). Diarrhea was more common with BendaEAM (42%) and less frequent with BuMel (7%, P = .01). Acute kidney injury was only found after BendaEAM (11%). Febrile neutropenia and infectious complications were more frequent following BendaEAM. Frequencies of other treatment-related toxicities did not significantly differ according to conditioning type. BendaEAM (odds ratio [OR] 3.07, P = .014) and BuMel (OR 4.27, P = .002) were independently associated with higher grade III to IV toxicity up to D+100. However, there were no significant differences in relapse/progression, nonrelapse mortality, progression-free survival, or overall survival among the four regimens. BuMel and BendaEAM were associated with a higher rate of grade III to IV toxicity. Carmustine-based regimens appeared to be less toxic and safer; however, there were no significant differences in transplant outcomes. The utilization of alternative preparative regimens due to drug shortages may potentially lead to increased toxicity after AHCT for lymphoma., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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.)

Background: Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University., Methods: The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m 2 carboplatin and 750 mg/m 2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities., Results: The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths., Conclusions: Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

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.

Although immunotherapy is rapidly changing the treatment approach to r/r diffuse large B cell lymphoma, there is still a place for autologous stem cell transplantation in some patients. The report by Stewart et al. focuses on induction therapy and the importance of the pretransplantation phase. Commentary on: Stewart et al. Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-Outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP. Br J Haematol 2024; 205:881-890., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Neuroendocrine Carcinomas (NECs) prognosis is poor.No standard second-line therapy is currently recognized after failure of platinum-based first-line treatment. FOLFIRI and CAPTEM regimens have shown promising activity in preliminary studies. We aimed to evaluate these regimens in metastatic NEC patients., Methods: This is an open-label, multicenter, randomized non-comparative phase II trial to evaluate the activity and safety of FOLFIRI or CAPTEM in metastatic NEC patients. Primary endpoints were the 12 weeks-Disease Control Rate (12w-DCR) by investigator assessment per RECIST v1.1 and safety per CTCAE v5.0. Additional endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients' serum samples were subject to NGS miRNome profiling in comparison with healthy donors to reveal differentially expressed miRNAs as candidate circulating biomarkers., Results: The study was halted for futility at interim analysis, as the minimum 12w-DCR threshold of 10 out of 25 patients required for the first step was not reached. From 06/03/2017 to 18/01/2021, 53 out of 112 patients were enrolled. Median follow-up was 22.6 months (range: 1.4-60.4). The 12w-DCR was 39.1 % in the FOLFIRI arm and 28.0 % in the CAPTEM arm. In the FOLFIRI subgroup the 12-months OS rate was 28.4 % (95 % CI: 12.7-46.5) while in the CAPTEM subgroup it was 32.4 % (95 % CI: 14.9-51.3). The most common G3-G4 side effects were neutropenia (n = 5, 18.5 %) and anemia (n = 2, 7.4 %) for FOLFIRI and G3-G4 thrombocytopenia (n = 2, 8.0 %), G4 nausea/vomiting (n = 1, 4.0 %) for CAPTEM. Three microRNAs emerged as NEC independent predictors. High expression values were found to be significantly associated with decreased PFS and OS., Conclusion: The safety profile of FOLFIRI and CAPTEM was manageable. FOLFIRI and CAPTEM chemotherapy showed comparable activity in the second-line setting after progression on etoposide/platinum., Gov Identifier: NCT03387592., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Small cell lung cancer (SCLC) is a recalcitrant cancer of neuroendocrine (NE) origin. Changes in therapeutic approaches against SCLC have been lacking over the decades. Here, we use preclinical models to identify a new therapeutic vulnerability in SCLC consisting of the targetable Jumonji lysine demethylase (KDM) family. We show that Jumonji demethylase inhibitors block malignant growth and that etoposide-resistant SCLC cell lines are particularly sensitive to Jumonji inhibition. Mechanistically, small molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes, upregulates ER stress signaling, and triggers apoptotic cell death. Furthermore, Jumonji inhibitors decrease protein levels of SCLC NE markers INSM1 and Secretogranin-3 and of driver transcription factors ASCL1 and NEUROD1. Genetic knockdown of KDM4A, a Jumonji demethylase highly expressed in SCLC and a known regulator of ER stress genes, induces ER stress response genes, decreases INSM1, Secretogranin-3, and NEUROD1 and inhibits proliferation of SCLC in vitro and in vivo. Lastly, we demonstrate that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor SD70) block the growth of SCLC tumor xenografts in vivo. Our study highlights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible approach in light of recently opened clinical trials evaluating this drug class, and establishes KDM4A as a relevant target across SCLC subtypes., (© 2024. The Author(s).)

Introduction: Atezolizumab, carboplatin, and etoposide (ACE) therapy is a standard of care for extensive-disease small cell lung cancer (SCLC); however, its safety data are scarce, limiting generalization to the Japanese population., Methods: This study aimed to compare the safety of ACE versus carboplatin and etoposide (CE) therapies in Japanese patients using the Diagnosis Procedure Combination (DPC) database by comparing the incidence of adverse events (AEs). Retrospective data on clinical background and AEs were extracted from the DPC database. Incidence rates and restricted mean survival times (RMSTs) up to 6 months were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method., Results: A total of 330,774 patients were identified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes, of whom 277 were included in the ACE cohort and 478 in the CE cohort. Among the 19 AEs, the incidence of skin disorder and thyroid dysfunction was significantly higher in the ACE cohort compared with the CE cohort. The adjusted incidence rate ratios were 2.38 (95% confidence interval [CI] 1.04-5.43) for skin disorder and 6.92 (95% CI 2.00-23.89) for thyroid dysfunction. The adjusted RMST differences were - 8.2 days (95% CI - 16.0 to - 0.4 days) for skin disorder and - 8.8 days (95% CI - 15.7 to - 1.9 days) for thyroid dysfunction., Conclusions: This study provides evidence regarding the safety of ACE combination therapy in Japanese clinical practice using the DPC database, with results comparable to those reported in pivotal clinical trials., Trial Registration: UMIN Clinical Trials Registry ID UMIN000041508., (© 2024. The Author(s).)

Background: CD30 expression is universal in anaplastic large-cell lymphoma and is expressed in some other peripheral T-cell lymphoma subtypes. Incorporation of brentuximab vedotin into initial therapy for people with CD30-positive peripheral T-cell lymphomas prolonged progression-free survival, but there is room for improvement, especially for people with non-anaplastic large-cell lymphoma subtypes., Methods: We conducted a multicentre, international, single-arm, phase 2 trial to evaluate the safety and activity of CHEP-BV (cyclophosphamide, doxorubicin, prednisone, brentuximab vedotin, and etoposide) followed by brentuximab vedotin consolidation in patients with CD30-expressing peripheral T-cell lymphomas across five academic centres in the USA and Canada. Adults aged 18 years or older with newly diagnosed, untreated CD30-positive peripheral T-cell lymphomas, Eastern Cooperative Oncology Group score of 0-2, and adequate organ function were eligible to receive six planned cycles of CHEP-BV (ie, 1·8 mg/kg brentuximab vedotin intravenously on day 1, cyclophosphamide 750 mg/m 2 intravenously on day 1, doxorubicin 50 mg/m 2 intravenously on day 1, etoposide 100 mg/m 2 daily intravenously on days 1-3, and prednisone 100 mg daily orally on days 1-5) with prophylactic G-CSF. Patients who responded to the treatment could receive brentuximab vedotin consolidation for up to ten additional cycles either after autologous haematopoietic stem-cell transplantation (HSCT) or directly after CHEP-BV. The primary endpoints were unacceptable toxicity during a 3-plus-3 safety lead-in in participants who received study treatment and completed the safety evaluation period (to confirm the recommended phase 2 dose of brentuximab vedotin in CHEP-BV) and the complete response rate after CHEP-BV induction therapy in participants who received study treatment and had response evaluation. The study was registered at ClinicalTrials.gov (NCT03113500), and this cohort completed the trial. The trial is ongoing with the enrolment of a new cohort., Findings: 54 patients were screened for eligibility and 48 were eligible for the study. The participants (18 [38%] women and 30 [63%] men; 34 [71%] White, four [8%] Black, five [10%] Asian, ten [21%] Hispanic, and 37 [77%] non-Hispanic people) were recruited and enrolled between Dec 4, 2017, and June 14, 2021, and followed up until Aug 25, 2023, when the database was locked for analysis. 48 participants were evaluable for toxicity, and 47 were evaluable for response (one participant died from COVID-19 before response assessment). During the safety lead-in, one of six participants had an unacceptable toxicity (ie, platelet count <10 000 per mm 3 in a participant with extensive bone marrow involvement), and the proposed phase 2 dose of 1·8 mg/kg brentuximab vedotin in CHEP-BV was confirmed. At completion of CHEP-BV, 37 of 47 participants had complete response, yielding a complete response rate of 79% (95% CI 64-89). The most common CHEP-BV-related toxicities of grade 3 or higher were neutropenia (14 [29%] of 48), leukopenia (11 [23%]), anaemia (ten [21%]), febrile neutropenia (ten [21%]), lymphopenia (nine [19%]), and thrombocytopenia (nine [19%]). There were no treatment-related deaths., Interpretation: In patients with mostly CD30-expressing peripheral T-cell lymphomas other than non-anaplastic large-cell lymphoma, CHEP-BV (with or without autologous HSCT) followed by brentuximab vedotin consolidation was safe and active., Funding: SeaGen, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and the National Cancer Institute of the National Institutes of Health., Competing Interests: Declaration of interests AFH reports research funding from Bristol Myers Squibb, Merck, Genentech/F Hoffmann-La Roche, Gilead Sciences, Seattle Genetics, AstraZeneca, and ADC Therapeutics and consultancy for Bristol Myers Squibb, Merck, Genentech/F Hoffmann-La Roche, Kite Pharma/Gilead, Seattle Genetics, Karyopharm, Takeda, Tubulis, AstraZeneca, Genmab, Regeneron, Pfizer, AbbVie, Allogene Therapeutics, Adicet Bio, and Caribou Biosciences. MM reports research funding from Bristol Myers Squibb, Incyte, and Morphosys; consultancy for Novartis, Seattle Genetics, CTI Biopharma, Janssen, and EUSA Pharma; and being part of speakers' bureau for Morphosys and Seattle Genetics. CH reports consultancy for BioLineRx. KJS reports honoraria or consulting for Seagen, Bristol Myers Squibb, Janssen, and AbbVie; research funding from Bristol Myers Squibb and Roche (institutional); participation on a data and safety monitoring committee for Regeneron; and participation on a steering committee for Beigene. SP reports research funding from Acrotech, AstraZeneca, CRISPR, Innate, Legend, Merck, Myeloid, Trillium/Pfizer, and Seagen and consultancy for Acrotech, March Bio, Star, Pfizer, Salarius, and Seagen. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Quadruple-hit lymphomas are extremely rare non-Hodgkin lymphomas with a reported dismal prognosis in the few reported cases. A "quadruple hit" has been defined by the presence of concurrent MYC, BCL2, BCL6, and CCND1 chromosomal rearrangements. We report a new case of a quadruple hit lymphoma in a 73-year-old Hispanic man who presented with an enlarging left-sided neck mass. Computed tomography showed a 1.9-cm mass in left the tonsil with bulky cervical lymphadenopathy. The presence of all four chromosomal rearrangements can reportedly occur with disease progression in both diffuse large B-cell lymphomas and mantle cell lymphomas. Further characterization of the tumor by next-generation sequencing may be of benefit to delineate between these two possibilities. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing were used to confirm and classify the diagnosis. Histologic sections of the cervical lymph node demonstrated an atypical lymphoid infiltrate with large and pleomorphic cells, which were positive for CD20, CD10, BCL1 (Cyclin D1), BCL2, BCL6, and cMYC and negative for CD5 and SOX11 on immunohistochemistry with a Ki-67 proliferative index of 70%. FISH demonstrated MYC, BCL2, BCL6, and CCND1 rearrangements and the diagnosis of high-grade B-cell lymphoma with MYC, BCL2, BCL6, and CCND1 was rendered. Our patient was treated with dose adjusted etoposide, doxorubicin, cyclophosphamide, prednisone, and rituximab chemotherapy and has been in remission for 20 months., (© 2024. The Author(s).)

To investigate the efficacy of the doxorubicin-etoposide-methylprednisolone, DEP) regimen as an effective treatment for adult Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease and analyze prognosis in these patients. Fifty-eight adult patients diagnosed with Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease admitted to Beijing Friendship Hospital from 1st Jan. 2018 to 31st Dec. 2022 were retrospectively included in this study. Patients were grouped according to previous treatment. Clinical data and laboratory characteristics of patients were retrospectively analyzed. The efficacy was evaluated every 2 weeks after initiating the first course of the DEP regimen and until the last inpatient or 31st Dec. 2023. 26 patients were included in Group A and 32 patients were included in Group B due to the previous treatment. After the first course of the DEP regimen, the overall response rate of all patients was 82.8%, with 13.8% in complete response and 69% in partial response. There was no significant statistical objective response rate between the two groups after the DEP regimen, except at 2-week. Serum ferritin, sCD25, ALT, AST, and DBIL concentrations were significantly lower at 2, 4 and 6-week than pre-treatment (P < 0.05). The overall mortality rate is 20.7% (12/58). Importantly, advanced age, initial level of HB and PLT, and central nervous system (CNS) involvement were independent poor risk factors affecting OS in bivariate analysis. The DEP regimen is effective for adult HLH secondary rheumatic disease with a high overall rate and accepted side effects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

High-risk gestational trophoblastic neoplasia encompasses patients with high volumes of disease or diffuse metastatic involvement who are unlikely to achieve remission with single-agent chemotherapy. Etoposide-based multi-drug regimens form the core of high-risk therapy. Second-line therapy includes platinum-based regimens. Increasingly, third-line therapy uses immunotherapy. Surgical intervention may be required to resect foci of resistant disease or manage complications. Treatment should continue until the hCG is less that the reference range for normal, followed by at least 3 cycles of consolidation therapy. At least 2 years of hCG surveillance are advisable for most patients requiring multiagent therapy to encompass 95% of relapses., Competing Interests: Disclosure The authors wish to disclose the support of (1) the Donald P. Goldstein, MD Trophoblastic Tumor Registry Endowment, (2) the Dyett Family Trophoblastic Disease Research and Registry Endowment, (3) the Keith Higgins and the Andrea S. Higgins Research Fund, and the (4) Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro – FAPERJ (E−26/201.166/2022)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.)

The frontline immuno-chemotherapy regimen for HIV-associated non-Hodgkin Lymphoma is dose-adjusted EPOCH ± R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab). Chemotherapy-induced peripheral neuropathy (CIPN), caused by vincristine, is a common adverse effect of EPOCH ± R, negatively impacting long-term patient outcomes. The primary objective of this study was to determine the incidence of CIPN, stratified by HIV status, in patients treated with EPOCH ± R. A retrospective cohort study at a tertiary referral comprehensive cancer center evaluated patients treated with EPOCH ± R from 2011 to 2018. The final sample included 27 patients with HIV compared to 279 without HIV (total n  = 306). Overall, the incidence of CIPN was 29.4% ( n  = 90), including 5 with HIV (18.5%) and 85 without HIV (30.5%). Propensity scores were used to match patients by HIV status. Although no relationship was found between HIV status and neuropathy, CIPN affects too many undergoing treatments for lymphoma, supporting future investigations to minimize toxicities.

The addition of rituximab to standard regimens for primary mediastinal large B-cell lymphoma (PMBCL) has significantly improved overall survival. However, the optimal management of isolated central nervous system (CNS) relapse and role of CNS prophylaxis remains undefined. We present cases of two adolescents with PMBCL who developed isolated CNS relapses. While isolated CNS relapse may be managed with high-dose chemotherapy and autologous stem cell transplant with or without CNS radiotherapy, review of these cases and the literature highlight the need for further work to define risk factors for CNS relapse, and identify patients who may benefit from CNS prophylaxis., (© 2024 Wiley Periodicals LLC.)

A 74-year-old man with obstructive jaundice presented with a thickened distal bile duct wall. A transpapillary forceps biopsy revealed an adenocarcinoma; however, because the tumor image was different from that of a typical cholangiocarcinoma, endoscopic ultrasound-guided fine-needle aspiration was performed on the tumor and enlarged lymph nodes. The tumor cells were positive for synaptophysin and CD56 with a Ki67 labeling index of 95%, and he was diagnosed with small cell neuroendocrine carcinoma. We diagnosed a bile duct tumor with neuroendocrine carcinoma component with lymph node metastasis. Preoperative chemotherapy for neuroendocrine carcinoma was administered because R0 resection was difficult and the risk of postoperative recurrence was high. Three courses of chemotherapy with carboplatin and etoposide resulted in marked tumor shrinkage, and radical resection was performed 3 months after diagnosis. Postoperative pathology revealed adenocarcinoma in the mucosal epithelium and small cell neuroendocrine carcinoma in the submucosa, most of which resolved with chemotherapy. Carboplatin and etoposide were resumed as adjuvant chemotherapy, and 67 months of recurrence-free survival were achieved after surgery., (© 2024. The Author(s).)

The prognosis of patients diagnosed with relapsed or refractory (R/R) T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has consistently been unsatisfactory, with limited treatment options. As reports, the CAG regimen can serve as a salvage treatment for R/R T-ALL/LBL, but there remains a subset of patients who do not benefit from it. Recent studies have indicated that daratumumab (Dara) and venetoclax (Ven) may offer promising therapeutic benefits for T-ALL/LBL. In light of these findings, we conducted a safety and efficacy evaluation of the enhanced treatment regimen, combining Dara and Ven with aclarubicin, cytarabine, granulocyte colony-stimulating factor, and etoposide (CAGE), in patients suffering from R/R T-ALL/LBL. The participants in this phase I trial were patients with R/R T-ALL/LBL who fail to standard treatment regimens. During each 28-day cycle, the patients were treated by Dara, Ven, cytarabine, aclarubicin, granulocyte colony-stimulating factor, etoposide. The primary endpoint of this study was the rate of remission. This report presents the prospective outcomes of 21 patients who received the salvage therapy of Dara and Ven combined with the CAGE regimen (Dara + Ven + CAGE). The objective remission rate (ORR) was determined to be 57.1%, while the complete remission (CR) rate was 47.6%. Notably, patients with the early T-cell precursor (ETP) subtype exhibited a significantly higher remission rate in the bone marrow compared to non-ETP patients (100% vs. 44.4%, p = 0.044). The Dara + Ven + CAGE regimen demonstrated a favorable remission rate in patients with R/R T-ALL/LBL. Moreover, the treatment was well-tolerated., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We aimed to evaluate the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) prophylaxis during chemoimmunotherapy with carboplatin plus etoposide and atezolizumab in extensive-stage small cell lung cancer (ES-SCLC)., Methods: This retrospective, multicenter study enrolled ES-SCLC patients receiving carboplatin plus etoposide and atezolizumab, categorized into G-CSF and non-G-CSF groups. Demographic and disease-related data were collected. Response rates, progression-free survival (PFS), overall survival (OS), and toxicity were analyzed., Results: Of 119 patients (median age: 63 years), the overall response rate (ORR) and disease control rate (DCR) were 72.3% and 81.5%, respectively. In the G-CSF group, the ORR was 76.4% compared to 60.0% in the non-G-CSF group ( p  = 0.33), and the DCR was 85.4% versus 70.0%, respectively ( p  = 0.46). Median PFS was 8.3 months (95% CI, 6.8-9.8) in the G-CSF group and 6.8 months (95% CI, 6.2-7.5) in the non-G-CSF group ( p  = 0.24). Median OS was 13.8 months (95% CI, 9.6-18.1) for the G-CSF group and 10.6 months (95% CI, 7.9-13.3) for the non-G-CSF group ( p  = 0.47). Grade 3 ≥ adverse events were similar between groups (49.4% vs. 33.3%, respectively, p  = 0.12)., Conclusion: G-CSF prophylaxis can be safely used in ES-SCLC patients undergoing carboplatin plus etoposide and atezolizumab regimen without significantly altering efficacy or increasing toxicity.

There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Multidrug chemotherapy for Ewing sarcoma can lead to severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, "Does primary prophylaxis with G-CSF benefit chemotherapy for Ewing sarcoma?" and CQ #2, "Does G-CSF-based intensified chemotherapy improve Ewing sarcoma treatment outcomes?"., Methods: A comprehensive literature search was conducted in PubMed, Cochrane Library, and Ichushi web databases, including English and Japanese articles published from 1990 to 2019. Two reviewers assessed the extracted papers and analyzed overall survival (OS), febrile neutropenia (FN) incidence, infection-related mortality, quality of life (QOL), and pain., Results: Twenty-five English and five Japanese articles were identified for CQ #1. After screening, a cohort study of vincristine, ifosfamide, doxorubicin, and etoposide chemotherapy with 851 patients was selected. Incidence of FN was 60.8% with G-CSF and 65.8% without; statistical tests were not conducted. Data on OS, infection-related mortality, QOL, or pain was unavailable. Consequently, CQ #1 was redefined as a future research question. As for CQ #2, we found two English and five Japanese papers, of which one high-quality randomized controlled trial on G-CSF use in intensified chemotherapy was included. This trial showed trends toward lower mortality and a significant increase in event-free survival for 2-week interval regimen with the G-CSF primary prophylactic use compared with 3-week interval., Conclusion: This review indicated that G-CSF's efficacy as primary prophylaxis in Ewing sarcoma, except in children, is uncertain despite its common use. This review tentatively endorses intensified chemotherapy with G-CSF primary prophylaxis for Ewing sarcoma., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

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.