Early failure is still a poor prognostic factor in patients with relapsed or refractory large B-cell lymphoma in the era of CAR T-cell therapy.

Patients with refractory or relapsed (R/R) large B-cell lymphoma (LBCL) refractory to first-line chemotherapy or with early relapse have poor outcomes. While chimeric antigen receptor (CAR) T-cell therapy has impressive efficacy after two or more lines of chemotherapy, it's still uncertain if these outcomes remain consistent in the context of third-line CAR T-cell therapy. We conducted a retrospective study of 107 R/R LBCL patients. Patients with relapse 12 months or more after their first-line chemoimmunotherapy (late failure: n = 25) had significantly longer overall survival (OS) than patients with refractory disease or relapse within 12 months (early failure: n = 82) (median OS: not achieved vs. 18.4 months; P < 0.001). Among patients who proceeded to autologous hematopoietic stem-cell transplantation (auto-HSCT), those with late failure had significantly longer event-free survival (EFS) than those with early failure (median EFS: 26.9 vs. 3.1 months; P = 0.012). However, no significant difference in EFS was detected among patients who underwent CAR T-cell therapy (median EFS: not reached vs. 11.8; P = 0.091). Cox regression with restricted cubic spline demonstrated that timing of relapse had significant impact on EFS in patients with auto-HSCT but not in patients with CAR T-cell therapy. Of patients who were scheduled for CAR T-cell therapy, those with late failure were significantly more likely to receive CAR T-cell therapy than those with early failure (90% vs. 57%; P = 0.008). In conclusion, patients with early failure still experienced poor outcomes after the approval of third-line CAR T-cell therapy.

Therapeutic target biomarkers of patient-derived xenograft models of gastric-type cervical adenocarcinoma.

Background: Most cervical adenocarcinomas are associated with human papillomavirus (HPV). Gastric-type cervical adenocarcinoma (GAS), an HPV-independent adenocarcinoma, shows an aggressive clinical feature, resulting in a poor prognosis. Resistance to chemotherapy poses a difficulty in managing patients with metastatic GAS. We aimed to establish patient-derived xenografts (PDXs) of tumors from two patients with GAS and evaluated protein biomarkers for drug development using immunohistochemistry. Methods: Two PDXs were established 78 and 48 days after transplanting the patient's tumor tissues into immunodeficient mice, respectively. PDX and patient's tumor samples were stained for HER2, HER3, PMS2, MSH6, PanTrk, and ARID1A to evaluate biomarkers for therapeutic targets. In addition, whole exome sequencing and RNA sequencing were performed on available samples. Results: The pathological findings in morphological features and immunohistochemical profiles from the established PDXs were similar to those from the patients' surgical tumor specimens. HER3 was overexpressed in the patient's tumors, and the corresponding PDX tumors and HER2 was weakly stained in both types of tumor samples. In all PDX and patient tumor samples, PMS2, MSH6, and ARID1A were retained, and PanTrk was not expressed. In addition, a total of 10 samples, including tumor tissue samples from 8 other GAS patients, were evaluated for HER3 expression scores, all of which were 2 + or higher. Conclusions: In summary, we evaluated biomarkers for therapeutic targets using newly established PDX models of GAS. Frequent HER3 overexpression and HER2 expression in GAS tumors suggest the possibility of new treatments for patients with GAS by targeting HER3 and HER2.

Clinical outcomes in transplant-eligible patients with relapsed or refractory diffuse large B-cell lymphoma after second-line salvage chemotherapy: A retrospective study.

OBJECTIVE: The prognosis of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Although patients who fail first-line salvage chemotherapy are candidates for second-line salvage chemotherapy, the optimal treatment strategy for these patients has not yet been established. METHODS: The present, single-center, retrospective study included transplant-eligible patients with R/R DLBCL who received second-line salvage chemotherapy with curative intent. RESULTS: Seventy-six patients with R/R DLBCL received second-line salvage chemotherapy. Eighteen (23.7%) patients were responders to the first-line salvage chemotherapy. The overall response rate was 39.5%, and overall survival (OS) was significantly longer in patients who responded to second-line salvage chemotherapy than those who did not. Forty-one patients who proceeded to potentially curative treatment (autologous hematopoietic stem cell transplantation [ASCT], chimeric antigen receptor [CAR] T-cell therapy, or allogeneic hematopoietic stem cell transplantation) had a better prognosis than those who did not. Among the 46 patients who failed to respond to the second-line salvage regimen, only 18 (39.1%) could proceed to the curative treatments. However, among the 30 patients who responded to the second-line salvage regimen, 23 (76.7%) received one of the potentially curative treatments. Among 34 patients who received CAR T-cell therapy, OS was significantly longer in those who responded to salvage chemotherapy immediately prior to CAR T-cell therapy than in those who did not respond. In contrast, the number of prior lines of chemotherapy was not identified as a statistically significant prognostic factor of survival. No significant difference was detected in OS between patients receiving ASCT and those receiving CAR T-cell therapy after the response to second-line salvage chemotherapy. DISCUSSION: In this study, we demonstrated that chemosensitivity remained a crucial factor in predicting survival outcomes following CAR T-cell therapy irrespective of the administration timing, and that both ASCT and CAR T-cell therapy were acceptable after the response to second-line salvage chemotherapy.

[Polatuzumab vedotin, bendamustine, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma, including the outcome as a bridging treatment to CAR-T cell therapy or allogeneic hematopoietic stem cell transplant].

Pola-BR (polatuzumab vedotin, bendamustine, and rituximab) therapy received approval for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in Japan in March 2021. There have been few reports on the efficacy and safety of Pola-BR therapy in Japanese clinical practice. A retrospective analysis was performed on twenty-nine patients with R/R DLBCL who received Pola-BR therapy at our institution (intent to cellular immunotherapy cohort: 20 patients, stand-alone treatment cohort: nine patients). The overall response rate was 69.0% (complete response 27.6%). The median progression-free survival was 5.1 months, with a 9.5-month median overall survival. In the intent to cellular immunotherapy cohort, 11 of 19 patients received chimeric antigen receptor T-cell (CAR-T) infusions, and one patient received allogeneic stem cell transplantation. Four patients received Pola-BR therapy, including bendamustine before leukapheresis, and all produced CAR-T products successfully. 3 of the 28 patients experienced grade3 or higher adverse events, and two required treatment discontinuation. Our single institution, a real-world cohort of R/R DLBCL patients showed high efficacy outcomes and a tolerable toxicity profile for Pola-BR therapy, which is comparable to previous studies. More cases are needed to determine its impact on CAR-T therapy and stem cell transplantation.

Hemoglobin-platelet index as a prognostic factor in patients with peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with a poor prognosis. The International Prognostic Index (IPI) and the Prognostic Index for PTCL-unspecified (PIT) is used to predict the prognosis of PTCL. The hemoglobin-platelet index (HPI), based on anemia and thrombocytopenia status, is associated with the prognosis of diffuse large B-cell lymphoma. However, its significance in terms of predicting the prognosis of PTCL has not been fully investigated. We herein retrospectively analyzed 100 patients with newly diagnosed PTCL in our department. At a median follow-up of 3.2 years, the median progression-free survival (PFS) and overall survival (OS) was 0.72 (95% confidence interval [CI]: 0.56-1.2) years and 2.0 (95% CI: 1.5-4.7) years, respectively. Multivariate analysis revealed that elevated lactic dehydrogenase (LDH) and hypoalbuminemia were independent adverse variables for PFS. The HPI showed significant predictive value for both PFS and OS. As a new prognostic model comprising the HPI, LDH, and albumin, the LA-HPI allowed the stratification of patients into four distinct risk subgroups: low risk (zero risk factors), low-intermediate risk (one risk factors), high-intermediate risk (two or three risk factors), or high risk (four risk factors). The PFS and OS differed significantly among the patients by the LA-HPI score. The LA-HPI demonstrated better predictive performance compared to the IPI, PIT, and HPI. Our data demonstrated the prognostic utility of the HPI in patients with PTCL. The LA-HPI, incorporating four readily obtainable parameters, exhibited superior performance compared to traditional indices.

Utility of the frailty score for predicting prognosis and individualizing treatment intensity in elderly patients with diffuse large B cell lymphoma.

The optimal dose intensity of chemotherapy for elderly patients with diffuse large B cell lymphoma (DLBCL) remains controversial because of concerns about adverse events and comorbidities related to the patients' frailty. This single-center study retrospectively analyzed patients aged ≥ 70 years who were newly diagnosed with DLBCL and received chemotherapy between 2004 and 2022. Survival outcomes and treatment-related mortality (TRM) were stratified according to geriatric assessment variables, and the influence of chemotherapy dose intensity on outcomes was assessed using the frailty score with a Cox hazards model with restricted cubic spline (RCS) in patients aged 70-79 years. In total, 337 patients were included. The frailty score accurately predicted prognosis (5-year overall survival [OS]: 73.1%, 60.2%, and 29.7% in fit, unfit, and frail patients, respectively; P < 0.001) and TRM (5-year TRM: 0%, 5.4%, and 16.8 in fit, unfit, and frail patients, respectively; P < 0.001). Cox regression with RCS demonstrated a linear association between dose intensity and survival outcomes. Initial dose intensity (IDI) and relative dose intensity (RDI) had a significant impact on OS in fit patients. However, IDI and RDI had no significant effect on survival in non-fit (unfit and frail) patients. The frailty score identified non-fit patients with poorer survival and a higher risk of TRM. While fit patients were likely to benefit from full-dose R-CHOP, unfit and frail patients would likely benefit more from attenuated R-CHOP. This study suggested a potential role for the frailty score in individualizing treatment intensity in elderly patients with DLBCL.

[Curative Resection after Chemotherapy for Advanced Extensive Cholangiocarcinoma-A Case Report].

A 73-year-old, male patient presented with the chief complaint of epigastric pain and received the diagnosis of extensive cholangiocarcinoma after a close examination. Extensive extension of the malignancy into the right and left hepatic ducts precluded a curative resection, and the patient received GC therapy. After 11 courses of GC over about 1 year, no new lesions or tumor progression was observed, and a bile duct mapping biopsy was performed to investigate the possibility of resection conversion. The results showed a marked decrease in atypia, and reactive atypia was diagnosed. A pancreaticoduodenectomy was performed, and histopathologically negative margins were obtained. The response to treatment was Grade Ⅱa according to the Evans classification. At 23 months after the start of treatment and 12 months after surgery, the patient is recurrence-free without adjuvant chemotherapy. Although the evidence for conversion surgery for biliary tract cancer has not been established, the long-term outcomes may be favorable.

[A Case of a Two-Stage Robotic-Assisted Surgery for a Neuroendocrine Tumor of the Pancreatic Tail with Simultaneous Single Liver Metastasis].

As medical insurance coverage for robotic surgery has been expanded in the field of gastrointestinal surgery in Japan, the number of cases undergoing robotic surgery for hepato-biliary-pancreatic disease has been increasing. Therefore, cases with malignant tumors and metastatic lesions tend to undergo robotic operation for both primary tumors and metastases. Herein, we report a case of neuroendocrine tumor(NET)in the pancreatic tail with simultaneous single liver metastasis, which was treated with two-stage robotic-assisted surgery. A 67-year-old female underwent a computed tomography scan and a hypovascularized tumor in the pancreatic tail region and liver was found. A biopsy of the pancreatic tumor by endoscopic ultrasound-guided fine needle aspiration demonstrated a NET G1-2. The liver lesion was diagnosed as a metastatic tumor, considering the other examinations. The patient underwent a robotic distal pancreatectomy(RDP)and was histopathologically diagnosed as NET G2. Sixty-three days after the RDP, a two-stage partial liver resection for the metastatic tumor was performed under robotic assistance. Curative resection was achieved through two-stage robot-assisted surgery, there were no postoperative complications.

[Tisagenlecleucel for relapsed/refractory diffuse large B-cell lymphoma: real-world data from single institute experience].

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the approach to patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study retrospectively analyzed patients treated with commercially available tisagenlecleucel at our hospital and evaluated its safety and effectiveness. Of the 21 patients evaluated, any grade and grade ≥3 cytokine release syndrome (CRS) occurred in 85.7% and 9.5% of the patients, respectively. A total of 66.7% received tocilizumab and 28.6% received glucocorticoids for the treatment of CRS. The complete response (CR) rate at 3 months was 61.9% (95% confidence interval [CI] 38.4-81.9). After a median follow-up of 6.3 months following CAR-T infusion, the progression-free survival (PFS) and overall survival rates at 6 months were 53.1% (95%CI 28.3-72.7) and 69.2% (95%CI 43.7-84.9), respectively. Severe cytopenia and hypogammaglobulinemia occurred frequently following CAR-T infusion. Eight patients (38.1%) had comorbidities that would have made them ineligible for leukapheresis in the JULIET trial. However, the presence of comorbidities at the time of leukapheresis had no significant effect on the rates of CR, PFS, and adverse events. Tisagenlecleucel for r/r DLBCL in the real-world setting showed high efficacy and manageable safety profile comparable with the pivotal trial.

Poor Treatment Outcomes with Second-Line Chemotherapy in Advanced Synovial Sarcoma.

INTRODUCTION: Synovial sarcoma (SS) predominantly affects adolescents and young adults. Doxorubicin with or without ifosfamide therapy is the standard first-line treatment for unresectable or metastatic SS. However, there is no standard second-line chemotherapy regimen. The purpose of the current study was to evaluate the outcomes of second-line chemotherapy for patients with SS. METHODS: We retrospectively evaluated the outcomes of 61 patients with unresectable or metastatic SS who had received first-line chemotherapy at our institution between 1997 and 2017. Patients who received second-line chemotherapy were included in the analysis. Outcomes of the chemotherapy were evaluated. RESULTS: Among the 61 patients treated with first-line chemotherapy, we identified 32 patients who received second-line chemotherapy. Most patients (62.5%) were under 40 years of age. Regarding second-line chemotherapy regimens, 6 (18.8%) patients were treated with doxorubicin with/without ifosfamide, 6 (18.8%) with ifosfamide and etoposide, 4 (12.5%) with docetaxel and gemcitabine, 5 (15.6%) with pazopanib, 2 (6.2%) with trabectedin, and 1 (3.1%) with eribulin. The overall response rate according to the Response Evaluation Criteria in Solid Tumors for all patients was 9.4%. Eleven patients (34.3%) achieved disease-control for >6 months. The median follow-up duration was 15.2 months. The 1-year progression-free and overall survival rates were 33.1% and 67.1%, respectively. CONCLUSION: Our exploratory study revealed that the response rate of second-line chemotherapy regimens for patients with SS was 9.4%. Therefore, there is an urgent need to develop more active therapeutic regimens for SSs.

Neutrophil-to-lymphocyte ratio as a prognostic factor for patients with metastatic or recurrent breast cancer treated using capecitabine: a retrospective study.

BACKGROUND: Eribulin or capecitabine monotherapy is the next cytotoxic chemotherapy option for patients with metastatic or recurrent breast cancer who have previously received an anthracycline or a taxane. However, it is unclear what factors can guide the selection of eribulin or capecitabine in this setting, and prognostic factors are needed to guide appropriate treatment selection. The neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor for eribulin-treated patients, although it is unclear whether it is a prognostic factor for capecitabine-treated patients. Therefore, we analysed the ability of the NLR to predict oncological outcomes among patients who received capecitabine after previous anthracycline or taxane treatment for breast cancer. METHODS: We retrospectively reviewed the medical records of patients with metastatic or recurrent breast cancer who had previously received anthracycline or taxane treatment at the National Cancer Center Hospital between 2007 and 2015. Patients were included if they received eribulin or capecitabine monotherapy as first-line, second-line, or third-line chemotherapy. Analyses of overall survival (OS) and progression-free survival (PFS) were performed according to various factors. RESULTS: Between 2007 and 2015, we identified 125 eligible patients, including 46 patients who received only eribulin, 34 patients who received only capecitabine, and 45 patients who received eribulin and capecitabine. The median follow-up period was 19.1 months. Among eribulin-treated patients, an NLR of <3 independently predicted better OS. Among capecitabine-treated patients, an NLR of <3 independently predicted better PFS but not better OS. In addition, a lymphocyte-to-monocyte ratio of ≥5 was associated with better PFS and OS. CONCLUSIONS: To the best of our knowledge, this is the first study to evaluate whether the NLR is a prognostic factor for capecitabine-treated patients with metastatic or recurrent breast cancer. However, the NLR only independently predicted PFS in this setting, despite it being a useful prognostic factor for other chemotherapies.

Clinical impact of controlling nutritional status score on the prognosis of patients with diffuse large B-cell lymphoma.

The controlling nutritional status (CONUT) score is a nutritional index calculated from serum albumin and total cholesterol levels and lymphocyte counts. Its role in predicting clinical outcomes of diffuse large B-cell lymphoma (DLBCL) has not been evaluated. In this retrospective study, data from 476 patients with DLBCL were analyzed. The cutoff value of the CONUT score was set as 4. CONUT score significantly stratified the overall survival (OS) and the progression-free-survival (PFS) (5-year OS, 49.0% vs 83.2%, P < .001; 5-year PFS, 46.1% vs 73.1%, P < .001) of the patients. Among patients at high-intermediate or high risk, as per the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), 5-year OS was lower in patients with high CONUT scores than in those with low CONUT scores (high-intermediate risk, 51.2% vs 75.5%, P < .001; high risk, 29.9% vs 63.3%, P = .007). Additionally, in patients with high CONUT scores, maintenance of relative dose intensity (RDI) of chemotherapy did not affect the 5-year OS (RDI > 80% vs RDI ≤ 80%: 59.8% vs 50.9%, P = .73). In the present study, we have demonstrated that the CONUT score is an independent prognostic factor in patients with DLBCL.

A new prognostic score comprising lactate dehydrogenase, albumin and neutrophil to lymphocyte ratio to predict sensitivity to first-line chemotherapy in patients with peripheral T-cell lymphomas.

No standard therapy for peripheral T-cell lymphomas (PTCLs) has been established, and treatment outcomes are poor. Upfront stem cell transplantation has been investigated in several studies, some of which have reported promising outcomes. However, some patients maintain long-term remission after chemotherapy alone. It is thus important to predict sensitivity to first-line chemotherapy to optimize treatment strategies. In the present study, we retrospectively analyzed time to treatment failure (TTF) of first-line chemotherapy in 59 patients with PTCLs. On multivariate analysis for TTF, elevated lactate dehydrogenase level, hypoalbuminemia, and high neutrophil-to-lymphocyte ratio were significant prognostic factors. Using these three factors, we also developed a new model that effectively distinguished patient outcomes. The TTF rate at 1 year from diagnosis was 71.4% in patients with score 0 (0 factor), 31.8% with score 1 (1 factor) and 4.5% with score 2 (2-3 factors) (P < 0.001). The prognostic power was superior to that of the Prognostic Index for PTCL-unspecified score. Patients with scores of 1 and 2 had poor TTF, and may be candidates for upfront stem cell transplantation if they respond to first-line chemotherapy. Further investigation in a larger cohort is warranted to determine the general applicability of this score.