Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial.

BACKGROUND: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. METHODS: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. INTERPRETATION: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. FUNDING: Takeda Oncology.

Proposal for a multifactorial prognostic score that accurately classifies 3 groups of gastric carcinoma patients with different outcomes after neoadjuvant chemotherapy and surgery.

OBJECTIVE: We have developed a multifactorial histopathological prognostic score (PRSC) for patients with gastric cancer treated with neoadjuvant chemotherapy before surgery for the accurate discrimination of patient subgroups with differing outcomes. BACKGROUND: For patients with gastric cancer who undergo multimodal treatment, the postoperative staging classifications used for nontreated tumors may not accurately predict patient prognosis. METHODS: We evaluated 428 gastric carcinoma specimens after a cisplatin-based chemotherapy. The factors for the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) ypT-category, ypN-category, and histopathological tumor regression were assigned a value from 1 to 3 as follows: ypT0 to 2 = 1 point; ypT3 = 2 points; ypT4 = 3 points; ypN0 = 1 point; ypN1 to 2 = 2 points; ypN3a to 3b = 3 points; less than 10% residual tumor per tumor bed = 1 point; 10% to 50% residual tumor per tumor bed = 2 points; and greater than 50% residual tumor per tumor bed = 3 points. A 3-tiered PRSC based on the sum value was established (group A: 3-4 points; group B: 5-7 points; group C: 8-9 points) and was found to correlate with patient prognosis. RESULTS: The PRSC showed a clear discrimination of 3 significantly different prognostic groups (group A: 76 patients; group B: 210 patients; group C: 142 patients; P < 0.001). In multivariate analyses, including the completeness of resection, tumor diameter, lymphatic vessel invasion, tumor grading, and Lauren classification, the PRSC was the only independent prognostic factor for overall survival (hazard ratio [HR] = 2.03; 95% confidence intervals [CI], 1.49-2.78; P < 0.001). It was slightly superior to the UICC/AJCC staging system (HR = 1.66; 95% CI, 1.20-2.27; P = 0.002) when analyzed with tumor regression as an additional independent factor (HR = 1.27; 95% CI, 1.01-1.62; P = 0.044) included in the analysis. CONCLUSIONS: The proposed PRSC reveals the most accurate prediction of survival for patients with gastric carcinoma after neoadjuvant chemotherapy followed by surgery. The PRSC clearly identifies 3 subgroups with different prognoses and may be helpful for therapeutic decisions.

Adenocarcinomas of the esophagogastric junction are more likely to respond to preoperative chemotherapy than distal gastric cancer.

BACKGROUND: Preoperative chemotherapy has been shown to improve outcome of patients with adenocarcinoma of the esophagogastric junction (AEG) and gastric cancer (GC), and histopathologic response has been identified as an independent prognostic parameter in these patients. A recent meta-analysis has identified patients with AEG as benefiting more from preoperative chemotherapy than patients with GC. The aim of this retrospective analysis was to prove these findings in an experienced single-center large patient cohort because there are currently no recruiting prospective clinical trials. METHODS: In a single center, 551 patients underwent preoperative platin-based chemotherapy followed by oncologic surgery for locally advanced AEG and GC. Pretherapeutic clinical parameters were correlated with histopathologic response to preoperative chemotherapy. RESULTS: Histopathologic response (<10% of residual tumor) was found in 130 patients (24%) and was significantly correlated with overall survival (P<0.0001). Tumor localization at the esophagogastric junction (GE junction), lower baseline cT stage, and baseline cN0 stage were significantly associated with histopathologic response (P=0.034, P=0.015, and P=0.002, respectively). In subgroup analyses, the latter two predictive parameters were confirmed only for AEG (n=378) but not for other GC (n=173). AEG patients who were pretherapeutically staged as having cT3/4, cN0 disease (n=73) were identified as the subgroup with the highest rate of histopathologic response (48%). CONCLUSIONS: AEG is more likely to respond to preoperative chemotherapy than GC, a finding that might help identify patients who would benefit from preoperative chemotherapy.

Oncogenic JAK2V617F requires an intact SH2-like domain for constitutive activation and induction of a myeloproliferative disease in mice.

The oncogenic JAK2V617F mutation is found in myeloproliferative neoplasms (MPNs) and is believed to be critical for leukemogenesis. Here we show that JAK2V617F requires an intact SH2 domain for constitutive activation of downstream signaling pathways. In addition, there is a strict requirement of cytokine receptor expression for the activation of this oncogene. Further analysis showed that the SH2 domain mutation did not interfere with JAK2 membrane distribution. However, coimmunoprecipitated experiments revealed a role for the SH2 domain in the aggregation and cross-phosphorylation of JAK2V617F at the cell membrane. Forced overexpression of cytokine receptors could rescue the JAK2V617F SH2 mutant supporting a critical role of JAK2V617F abundance for constitutive activation. However, under physiologic cytokine receptor expression the SH2 domain is absolutely necessary for oncogenic JAK2V617F activation. This is demonstrated in a bone marrow transplantation model, in which an intact SH2 domain in JAK2V617F is required for the induction of an MPN-like disease. Thus, our results points to an indispensable role of the SH2 domain in JAK2V617F-induced MPNs.

Molecular imaging of proliferation and glucose utilization: utility for monitoring response and prognosis after neoadjuvant therapy in locally advanced gastric cancer.

BACKGROUND: Metabolic imaging of gastric cancer is limited due to the 30% of primary tumors that are not (18)F-fluorodeoxyglucose (FDG) avid. In contrast, the proliferation marker (18)F-fluorothymidine (FLT) has been shown to visualize also non-FDG-avid gastric tumors. In this study we tested whether FLT-positron emission tomography (PET) can improve the predictive potential of molecular imaging for assessing response to neoadjuvant therapy in gastric cancer compared with FDG-PET. METHODS: 45 patients with gastric cancer underwent FDG- and FLT-PET before and 2 weeks after initiation of chemotherapy. FDG/FLT-PET findings and Ki67 immunohistochemistry were correlated with clinical and histopathological response and survival. RESULTS: 14 patients had non-FDG-avid tumors, whereas all tumors could be visualized by FLT-PET. No significant association of clinical or histopathological response with any of the analyzed metabolic parameters [initial standardized uptake value (SUV), SUV after 2 weeks, change of SUV for FDG/FLT] was found. Univariate Cox regression analysis for Ki67 and metabolic parameters revealed significant prognostic impact for survival only for FLT SUV(mean) day 14 (p=0.048) and Ki67 (p=0.006). Multivariate Cox regression analysis (including clinical response, Lauren type, ypN category, and FLT SUV(mean) day 14) revealed Lauren type and FLT SUV(mean) day 14 as the only significant prognostic factors (p=0.006, p=0.002). CONCLUSIONS: FLT uptake 2 weeks after initiation of therapy was shown to be the only imaging parameter with significant prognostic impact. Neither FLT-PET nor FDG-PET were correlated with histopathological or clinical response. However, these data must be interpreted with caution due to the single-center trial study design, relatively short follow-up, poor response rates, and unfavorable prognosis.

18F-FDG PET and 18F-FDG PET/CT for assessing response to therapy in esophageal cancer.

In patients with locally advanced esophageal cancer, preoperative chemotherapy or chemoradiotherapy has been shown to improve outcome with respect to survival. Patients who respond to induction therapy have a significantly improved survival, compared with patients who do not respond to the therapy. However, surrogate markers that predict response or prognosis-especially early in the course of therapy-are not available in clinical routine. In patients with esophageal cancer, PET with the glucose analog (18)F-FDG can be used for assessing response to therapy. Therapy response can be assessed with (18)F-FDG PET and (18)F-FDG PET/CT late, that is, after completion of therapy, and early in the course of therapy. In adenocarcinomas of the esophagogastric junction, (18)F-FDG has been established and validated in several studies as a surrogate marker that allows prediction of response and prognosis, whereas in other studies (18)F-FDG PET was not predictive of response and prognosis. The MUNICON study was an initial unicenter trial showing that a PET-guided treatment algorithm was feasible in patients with adenocarcinomas of the esophagogastric junction. The results of this study are important toward individualization of multimodal treatment. The use of (18)F-FDG PET and PET/CT for therapy monitoring in esophageal cancer is the subject of intense discussion, underlining the need for randomized multicenter studies. From a methodologic point of view, the most important issue in therapy monitoring using (18)F-FDG PET and PET/CT is the standardization of patient preparation, data acquisition and processing, and data interpretation, especially for prospective randomized multicenter studies. In conclusion, single-center studies investigating response assessment in patients with esophageal cancer have provided promising results. In the future, prospective randomized multicenter trials will have to be performed and research will address new imaging probes and innovative therapy regimens.

Imaging proliferation to monitor early response of lymphoma to cytotoxic treatment.

PURPOSE: Positron emission tomography with the thymidine analogue 3'-deoxy-3'-[18F]fluorothymidine (FLT) has been reported to closely reflect lymphoma proliferation in vivo. In this preclinical study, we have investigated if FLT can also be utilized for imaging therapy-induced alterations of the nucleoside metabolism and if FLT is a surrogate marker for early response to cytotoxic treatment. MATERIALS AND METHODS: Immunodeficient mice bearing high-grade lymphoma xenotransplants were treated with the cytotoxic agent doxorubicin (day 0). In the time course of day +1 to +9, antiproliferative effects were assessed non-invasively with FLT-PET and correlated to changes of the proliferation fraction and induction of apoptosis, as assessed by immunohistochemistry. RESULTS: Tumor growth in untreated animals was significantly higher than in treated animals. In FLT-PET scans, these observations correlated with a significant decrease of tumor-to-background ratio in the therapy group already at day 1. Likewise, median tumor-to-muscle ratio of FLT uptake already declined at day 1. The proliferation fraction assessed by Ki-67 immunohistochemistry decreased after chemotherapy, while activated caspase 3 increased, suggesting both cell cycle arrest and induction of apoptosis as underlying mechanisms of the observed PET-signal alterations. CONCLUSION: In a lymphoma xenotransplant model, we show that positron emission tomography using the proliferation marker FLT is suitable to detect early response to cytotoxic treatment. A significant decrease of FLT uptake but not tumor growth was detectable already 24 h after therapy and correlated with reduced proliferation and induction of apoptosis. Thus, FLT-PET has a potential for imaging early response to treatment in malignant lymphoma.

Antihuman epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab enhances cytolytic activity of class I-restricted HER2-specific T lymphocytes against HER2-overexpressing tumor cells.

The monoclonal antibody trastuzumab (Herceptin) directed against the human epidermal growth factor receptor 2 (HER2) results in tumor regressions when administered to patients with HER2-overexpressing breast cancer. One of the underlying mechanisms of this antibody-induced tumor regression is based on the internalization and degradation of HER2 by tumor cells on interaction with trastuzumab, subsequently inhibiting signal transduction pathways. As antibody-induced degradation of HER2 is likely to be accompanied with increased numbers of HER2 peptides presented with MHC, we asked whether trastuzumab-treated tumor cells were more susceptible to CTL-mediated lysis. Here we show that the cytolytic activity of human, HER2-specific CD8(+) CTLs is augmented by anti-HER2 antibody trastuzumab. HER2-reactive CTL clones lyse class I-matched, HER2-overexpressing tumor cells more efficiently after treatment with trastuzumab. The potentially synergistic activity of HER2-specific antibody and CTL encourages the development of an HER2-targeted immunotherapy using a combination of inhibitory antibodies and CTLs for patients with HER2-overexpressing tumors.

(18)F-FDG PET-guided salvage neoadjuvant radiochemotherapy of adenocarcinoma of the esophagogastric junction: the MUNICON II trial.

UNLABELLED: Previous studies demonstrated that chemotherapy-induced changes in tumor glucose metabolism measured with (18)F-FDG PET identify patients who benefit from preoperative chemotherapy and those who do not. The prognosis for chemotherapy metabolic nonresponders is poorer than for metabolic responders. Therefore, we initiated this prospective trial to improve the clinical outcome of metabolic nonresponders using a salvage neoadjuvant radiochemotherapy. METHODS: Fifty-six patients with locally advanced adenocarcinomas of the esophagogastric junction were included. Tumor glucose uptake was assessed by (18)F-FDG PET before chemotherapy and 14 d after initiation of chemotherapy. PET nonresponders received salvage neoadjuvant radiochemotherapy, whereas metabolic responders received neoadjuvant chemotherapy for 3 mo before surgery. RESULTS: Thirty-three patients were metabolic responders, and 23 were nonresponders. Resection was performed on 54 patients. R0 resection rate was 82% (95% confidence interval [CI], 66%-91%) in metabolic responders and 70% (95% CI, 49%-84%) in metabolic nonresponders (P = 0.51). Major histologic remissions were observed in 12 metabolic responders (36%; 95% CI, 22%-53%) and 6 nonresponders (26%; 95% CI, 13%-46%). One-year progression-free rate was 74% ± 8% in PET responders and 57% ± 10% in metabolic nonresponders (log rank test, P = 0.035). One-year overall survival was comparable between the groups (∼80%), and 2-y overall survival was estimated to be 71% ± 8% in metabolic responders and 42% ± 11% in PET nonresponders (hazard ratio, 1.9; 95% CI, 0.87-4.24; P = 0.10). CONCLUSION: This prospective study showed the feasibility of a PET-guided treatment algorithm. However, by comparing the groups of nonresponding patients in the current trial and the previous published MUNICON (Metabolic response evalUatioN for Individualisation of neoadjuvant Chemotherapy in Esophageal and esophagogastric adeNocarcinoma) I trial, increased histopathologic response was observed after salvage radiochemotherapy, but the primary endpoint of the study to increase the R0 resection rate was not met. The prognosis of the subgroup of PET nonresponders remains poor, indicating their different tumor biology.

MALT1 directs B cell receptor-induced canonical nuclear factor-kappaB signaling selectively to the c-Rel subunit.

NF-kappaB (Rel) transcription factors control physiological and pathological immune cell function. The scaffold proteins Bcl-10 and MALT1 couple antigen-receptor signals to the canonical NF-kappaB pathway and are pivotal in lymphomagenesis. Here we found that Bcl-10 and MALT1 differentially regulated B cell receptor-induced activation of RelA and c-Rel. Bcl-10 was essential for recruitment of the kinase IKK into lipid rafts for the activation of RelA and c-Rel, for blocking apoptosis and for inducing division after B cell receptor ligation. In contrast, MALT1 participated in survival signaling but was not involved in IKK recruitment or activation and was dispensable for RelA induction and proliferation. MALT1 selectively activated c-Rel to control a distinct subprogram. Our results provide mechanistic insights into B cell receptor-induced survival and proliferation signals and demonstrate the selective control of c-Rel in the canonical NF-kappaB pathway.