Hematologic cancers that recur after allogeneic hematopoietic stem-cell transplantation are often difficult to treat. A small pilot study suggests that ipilimumab may induce durable responses in a ...subgroup of patients with these cancers.
Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only cure for many patients who have advanced hematologic cancers, principally through the induction of a graft-versus-tumor effect.
1
Unfortunately, more than one third of patients who have undergone transplantation have a relapse of disease.
2
The prognosis for these patients is poor; the majority die within 1 year after relapse despite salvage chemotherapy, donor-lymphocyte infusion, or retransplantation.
3
–
5
Immune escape (i.e., tumor evasion of the donor immune system) contributes to relapse after allogeneic HSCT, and immune checkpoint inhibitory pathways probably play an important role.
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The engagement of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed . . .
Background
Conversion therapy is an option for unresectable metastatic gastric cancer when distant metastases are controlled by chemotherapy; however, the feasibility and efficacy remain unclear. ...This study aimed to assess the feasibility and efficacy of conversion therapy in patients with initially unresectable gastric cancer treated with docetaxel, cisplatin, and S-1 (DCS) chemotherapy by evaluating clinical outcomes.
Methods
One hundred unresectable metastatic gastric cancer patients, enrolled in three DCS chemotherapy clinical trials, were retrospectively evaluated. The patients received oral S-1 (40 mg/m
2
b.i.d.) on days 1–14 and intravenous cisplatin (60 mg/m
2
) and docetaxel (50–60 mg/m
2
) on day 8 every 3 weeks. Conversion therapy was defined when the patients could undergo R0 resection post-DCS chemotherapy and were able to tolerate curative surgery.
Results
Conversion therapy was achieved in 33/100 patients, with no perioperative mortality. Twenty-eight of the 33 patients (84.8 %) achieved R0 resection, and 78.8 % were defined as histological chemotherapeutic responders. The median overall survival (OS) of patients who underwent conversion therapy was 47.8 months (95 % CI 28.0–88.5 months). Patients who underwent R0 resection had significantly longer OS than those who underwent R1 and R2 resections (
P
= 0.0002). Of the patients with primarily unresectable metastases, 10 % lived >5 years. Among patients who underwent conversion therapy, multivariate analysis showed that the pathological response was a significant independent predictor for OS.
Conclusions
DCS safely induced a high conversion rate, with very high R0 and pathological response rates, and was associated with a good prognosis; these findings warrant further prospective investigations.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour ...shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC 33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27-0.74; p < 0.001. In patients with left-sided tumours, treatment with chemotherapy plus cetuximab yielded longer OS than chemotherapy plus bevacizumab (50.6 vs 27.8 months, HR 0.55; 95% CI 0.32-0.97; p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32-0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28-0.68, p < 0.001, respectively). Moreover, ETS and/or high DpR achieved in patients with right-sided mCRC receiving chemotherapy plus cetuximab were associated with significantly better OS than in those lacking ETS and with low DpR (34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Immune checkpoint inhibitors (ICIs) are the standard treatment for metastatic colorectal cancer (mCRC) with high microsatellite instability (MSI-H). Among immune-related adverse events (irAEs), ...drug-induced sarcoidosis-like reactions (DISR) are often difficult to differentiate from cancer progression.
This is a case of a woman in her mid-60s, with mCRC (RAS wild/BRAF mutant/MSI-H) and abdominal lymph node metastasis, treated with four courses of ipilimumab + nivolumab every 3 weeks, followed by nivolumab every 2 weeks as third-line treatment. After treatment, the original lymph node metastases shrank, but hilar/mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epithelioid granulomas without necrosis, indicating a sarcoidosis-like reaction. Fluorodeoxyglucose-positron emission tomography scan showed abnormal subcutaneous accumulation in bilateral forearms and bilateral knee joints. Biopsy of the cutaneous lesions was also performed, which revealed epithelioid granulomas. As the patient had no symptoms in other organs, no specific therapeutic intervention was administered. After the discontinuation of immunotherapy, the sarcoidosis-like reaction regressed without cancer relapse.
Clinicians should be aware of the possibility of DISR as an irAE during the ICI treatment of mCRC. In suspected cases of DISR following ICI therapy, it is important to differentiate between cancer progression and DISR through histological diagnosis for the subsequent strategy, as radiological and serological findings are not definitive.
Abstract only
297
Background: An association between improved responses to chemotherapy after exposure to vaccine-based immunotherapy has been previously reported in other cancers. However, it is ...unclear whether the chemotherapy response improves after exposure to immunotherapy, such as immune checkpoint inhibitors (ICIs). The objective of this retrospective study was to evaluate whether chemotherapy (4th-line) would yield improved efficacy when given after exposure to anti-PD-1 antibody in metastatic gastric cancer (mGC). Methods: We investigated retrospectively clinical characteristics at baseline of mGC patients who received chemotherapy after progression of anti-PD-1 antibody (Nivolumab) between February 2018 and July 2019. Anti-PD-1 antibody was adapted as third-line therapy. Inclusion criteria for the analysis reported herein: histologically proven adenocarcinoma; ECOG PS 0-2; adequate organ functions; and received chemotherapy including 5-fluoropyrimidines (5-FU), platinum, and taxane or irinotecan. We evaluated efficacy outcomes, including ORR, DCR by RECIST version 1.1, PFS, and OS. Results: Out of 27 treated with anti-PD-1 antibody, 10 patients were evaluable for responses and eligible to be included in this analysis. Patient characteristics were as follows: median age (range), 72 (50-88) years; male/female, 8/2; ECOG PS (0/1/2), 4/5/1; HER2 (+/-), 5/5; histology (differentiated/undifferentiated), 5/5; metastatic lesions (LN/peritoneum/liver/lung), 5/3/1/3; number of metastatic sites (1/≥2), 5/5; number of prior CTx regimens (3/4/5), 10/0/0; median period (range) from first line CTx, 18.8 (7.9-47.1) months; and CTx regimens (CPT-11/PTX/S-1+Oxaliplatin), 7/2/1; Among the 10 patients, 1 achieved a partial response, giving an ORR of 10.0%. Six patients had stable disease and three had progressive disease. The DCR was 70%. Median PFS and OS were 5.5M and 8.5M, respectively. These were no new irAEs appeared during CTx. Conclusions: In mGC patients, our study demonstrated that increased efficacy to cytotoxic agents chemotherapy given after exposure to ICI was higher as compared to our historical data from the pre-anti-PD1 era. Updated results will be presented.
CD4
Regulatory T cells (Treg) play a critical role in maintaining immune homeostasis. Various Treg subsets have been identified, however the heterogeneity of Treg subpopulations during development ...remains uncharacterized. Using mass cytometry we obtained single cell data on expression of 35 functional markers to examine the heterogeneity of Treg cells at birth and in adults. Unsupervised clustering algorithms FlowSOM and ACCENSE were used to quantify Treg heterogeneity. As expected, Treg in umbilical cord blood were predominately naïve while Treg in adult blood were predominately central memory and effector memory cells. Although umbilical cord blood Treg are mostly naïve cells, we observed multiple phenotypic Treg subsets in cord blood. Nevertheless, peripheral blood in adults contained higher percentages of Treg and the heterogeneity of Treg was significantly increased in adults. We also studied Treg heterogeneity throughout a 2-year period after allogeneic hematopoietic stem cell transplantation (alloHSCT) and in patients with chronic graft-versus-host disease (cGVHD). Treg heterogeneity recovered rapidly after alloHSCT and gradually increased in the first two years post-transplant. However, patients with cGVHD had significantly fewer distinct Treg subpopulations, proposing a correlation between a disrupted Treg heterogeneity and cGVHD. Our study is the first to compare human Treg heterogeneity at birth, in healthy adults and in patients after alloHSCT with and without cGVHD. This approach to characterize Treg heterogeneity based on expression of a large panel of functional markers may enable future studies to identify specific Treg defects that contribute to immune dysfunction.
Pancreatic cancer (PC) is highly aggressive with multiple oncogenic mutations. The efficacy of current chemotherapy is poor, and new therapeutic targets are needed. The forkhead box (FOX) proteins ...are multidirectional transcriptional factors strongly implicated in malignancies. Their expression is consistently suppressed by several oncogenic pathways such as PI3K/AKT signaling activated in PC. A recent study showed that class IIa histone deacetylases (HDAC) can act as a transcriptional suppressor. In this study, we hypothesized that HDAC class IIa inhibition would upregulate FOXO3a expression, thereby inducing its transcription-dependent antitumor effects.
We confirmed the change of FOXO3a expression and the effect of the cell growth inhibition by HDAC class IIa inhibition in AsPC-1 cells. Because FOXO3a is subject to ubiquitylation-mediated proteasome degradation, we examined the synergistic activation of FOXO3a by HDAC class IIa selective inhibitor TMP269 combined with proteasome inhibitor carfilzomib.
We observed that TMP269 induced FOXO3a expression in a dose-dependent manner and inhibited cell growth in AsPC-1 cells. G1/S arrest was observed. FOXO3a expression was further increased and cell growth inhibition was dramatically enhanced by TMP269 combined with carfilzomib.
Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.
We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old woman was transferred to our hospital because ...of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency.
Treatment with anti-EGFR antibody has been shown to prolong survival in patients with RAS wild-type metastatic colorectal cancer (mCRC). However, even patients who initially respond to anti-EGFR ...antibody therapy, almost without exception, develop resistance to the therapy and then fail to respond. Secondary mutations in the mitogen-activated protein (MAPK) signaling pathway (mainly in NRAS and BRAF) have been implicated in anti-EGFR resistance. However, the process by which resistant clones develop during therapy has not been elucidated, and considerable intrapatient and interpatient heterogeneity exists. Circulating tumor DNA (ctDNA) testing has recently allowed the noninvasive detection of heterogeneous molecular alterations that underlie the evolution of resistance to anti-EGFR. In this report, we describe our observation of genomic alterations in
and
in a patient with acquired resistance to anti-EGFR antibody drugs by tracking clonal evolution using serial ctDNA anaylsis.
A 54-year-old woman was initially diagnosed with sigmoid colon cancer with multiple liver metastases. After receiving first-line mFOLFOX + cetuximab, second-line FOLFIRI + ramucirumab, third-line trifluridine/tipiracil + bevacizumab, fourth-line regorafenib, and fifth-line CAPOX + bevacizumab, she was rechallenged with CPT-11 + cetuximab. The best response to anti-EGFR rechallenge therapy was a partial response.
in the ctDNA was assessed during treatment. The
status changed from wild type to mutant type, back to wild type, and again to mutant type (
codon 61) during the course of treatment.
In this report, tracking of ctDNA allowed us to describe clonal evolution in a case in which we observed genomic alterations in
and
in a patient who acquired resistance to anti-EGFR antibody drugs during treatment. It is reasonable to consider repeat molecular interrogation during progression in patients with mCRC by using ctDNA analysis, which could help to identify patients who may benefit from a rechallenge strategy.
Cisplatin plus 5‐fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how ...definitive chemoradiotherapy with docetaxel, nedaplatin, and 5‐fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib‐III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2) and nedaplatin (50 mg/m2) on days 1 and 8, and a continuous infusion of 5‐fluorouracil (400 mg/m2/day) on days 1‐5 and 8‐12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end‐point was the completion rate of the protocol treatment. Twenty‐eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty‐five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment‐related deaths and major surgical complications did not occur. Estimated 2‐year progression‐free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305).
This phase II study investigated a regimen of neoadjuvant chemotherapy for resectable esophageal squamous cell carcinoma using docetaxel, nedaplatin, and 5‐fluorouracil (DNF), which indicated that DNF was well tolerated and effective. A completion rate for protocol treatment was 89.3%, and all patients who underwent surgery achieved an R0 resection. The overall response rate was 87.0%, with a pathological complete response rate of 32.0%. The 2‐year survival rate was 77.2%.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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