Metastatic Adenocarcinoma of Intestinal Origin in Reconstructed Ureters.

In patients with long ureteral defects, the use of bowel segments for reconstruction is an effective but suboptimal alternative because the bowel is not resistant to the potential carcinogenic effects of urine. Primary malignancies in reconstructed conduits have been scarcely described in the literature. This case report elaborates on a case of metastatic adenocarcinoma arising in ureters reconstructed using small intestinal segments. A 49-year-old with Eagle-Barrett syndrome presented with abdominal pain and was found to have irregular enhancement of the right ureteropelvic junction and small, non-specific liver lesions. Biopsy of the liver lesions showed poorly differentiated adenocarcinoma with immunohistochemistry staining consistent with small intestinal origin. The patient was treated as a tumor of GI origin with chemotherapy and subsequently underwent microwave ablation of his liver metastases. He also received concurrent chemoradiation for residual disease at the ureteral conduit. PET scan images done after completion of treatment showed resolution of all lesions. Further research into alternative structures that could be used to create conduits and screening methods for these patients is imperative to reduce the incidence of such malignancies.

Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort.

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

Administration of corticosteroid therapy for HELLP syndrome in pregnant women: evidences from seven randomized controlled trials.

BACKGROUND: HELLP syndrome, featuring hemolysis, elevated liver enzymes, and thrombocytopenia, is life-threatening disease of pregnancy that triggers comorbidities in both pregnant women and the fetus/newborn. This study provides an updated systematic review and meta-analysis of relevant studies to assess the therapeutic efficacy of corticosteroids in maternal and neonatal outcomes. METHODS: Randomized control trials (RCTs) regarding the use of corticosteroids in the HELLP population from three electronic databases, including Ovid MEDLINE, Ovid EMBASE, andCochrane Central Register of Controlled Trials, were searched from database inception to 23 March 202323 March 2023. RESULTS: A total of 485 patients treated with corticosteroids from 7 RCTs were included. Compared to placebo, corticosteroids therapy failed to significantly improve the maternal outcomes regard to maternal morbidity (RR = 1.36, 95%CI [0.45, 4.10]), eclampsia (RR = 1.16, 95%CI [0.76, 1.77]), acute renal failure (RR = 0.71, 95%CI [0.41, 1.22]), pulmonary edema (RR = 0.34, 95%CI [0.10, 1.15]) and oliguria (RR = 1.08, 95%CI [0.75, 1.54]). In addition, pooled data showed that it wasn't significant differences between corticosteroids therapy and placebo regarding neonatal outcomes. CONCLUSIONS: This study compared the efficacy of corticosteroids in patients with HELLP syndrome, revealing that corticosteroids did not provide any significant benefit in clinical outcomes for pregnant women and newborns with HELLP. The conclusions of this study must be verified by a larger sample of high-quality RCTs.

Circulating Tumor Cell Subpopulations Predict Treatment Outcome in Pancreatic Ductal Adenocarcinoma (PDAC) Patients.

There is a high clinical unmet need to improve outcomes for pancreatic ductal adenocarcinoma (PDAC) patients, either with the discovery of new therapies or biomarkers that can track response to treatment more efficiently than imaging. We report an innovative approach that will generate renewed interest in using circulating tumor cells (CTCs) to monitor treatment efficacy, which, in this case, used PDAC patients receiving an exploratory new therapy, poly ADP-ribose polymerase inhibitor (PARPi)-niraparib-as a case study. CTCs were enumerated from whole blood using a microfluidic approach that affinity captures epithelial and mesenchymal CTCs using anti-EpCAM and anti-FAPα monoclonal antibodies, respectively. These antibodies were poised on the surface of two separate microfluidic devices to discretely capture each subpopulation for interrogation. The isolated CTCs were enumerated using immunophenotyping to produce a numerical ratio consisting of the number of mesenchymal to epithelial CTCs (denoted "Φ"), which was used as an indicator of response to therapy, as determined using computed tomography (CT). A decreasing value of Φ during treatment was indicative of tumor response to the PARPi and was observed in 88% of the enrolled patients (n = 31). Changes in Φ during longitudinal testing were a better predictor of treatment response than the current standard CA19-9. We were able to differentiate between responders and non-responders using ΔΦ (p = 0.0093) with higher confidence than CA19-9 (p = 0.033). For CA19-9 non-producers, ΔΦ correctly predicted the outcome in 72% of the PDAC patients. Sequencing of the gDNA extracted from affinity-selected CTC subpopulations provided information that could be used for patient enrollment into the clinical trial based on their tumor mutational status in DNA repair genes.

Microsatellite Instability with BRAF V600E Associated with Delayed Presentation but Poor Survival in Stage III Colorectal Cancer.

Colorectal cancer (CRC) has tremendous molecular and genetic heterogeneity, making it a difficult cancer to treat. Two of the key prognostic indicators of CRC include microsatellite instability (MSI) and BRAF V600E mutation. Here, we performed a retrospective survival analysis on 145 stage II and III CRC patients treated at the University of Kansas Cancer Center between 2009 and 2020. Of the 145 patients, BRAF V600E was observed in 15% patients and MSI in 28% patients. Median survival was not reached for stage II. For stage III, patients with BRAF V600E showed poor overall survival, which worsened with concurrent presence of MSI [χ2=6.4, p=0.01]. Eighty-five percent of this group was found to have right-sided CRC. For stage III, overall survival (OS) was 27 months, 37 months, 87 months and not reached for MSI-H/BRAF V600E, MSS/BRAF V600E, MSS/BRAF WT and MSI-H/BRAF WT, respectively. Although associated with poor prognosis, presence of MSI in BRAF V600E patients was associated with delayed disease presentation (mean age 77) compared to those with stable microsatellite (mean age 63) [p=0.01]. Although median survival between the groups could not be assessed for stage II due to very few deaths and/or inadequate length of study, comparison of survival trend suggests that BRAF V600E, rather than MSI, is what drives prognosis in stage II CRC. Our findings suggest that prognostic value of MSI is more relevant for stage III than stage II CRC. Patients with MSI-H and BRAF V600E have advantage of late presentation, although at the cost of poor overall prognosis.

Real world outcomes in patients with neuroendocrine tumor receiving peptide receptor radionucleotide therapy.

Aim: 177Lu-Dotatate (Lu-177), a form of peptide receptor radionuclide therapy (PRRT), was approved by Food and Drug Administration (FDA) for the treatment of somatostatin-receptor-positive neuroendocrine tumors (NETs) in 2018. Clinical trials prior to the FDA approval of Lu-177 showed favorable outcomes but there is limited published real world outcomes data. This study aims to describe and analyze real world outcomes of patients with NET who received Lu-177. Methods: After obtaining institutional review board approval, retrospective evaluation was performed to analyze the efficacy of Lu-177 for somatostatin receptor-positive gastro-entero-pancreatic NETs (GEP-NETs) patients at the University of Kansas Cancer Center between June 2018 and September 2021. This study aims to determine the response rate to the treatment of the entire cohort and subgroups. Results: A total of 65 patients received Lu-177 of which 58 completed treatment. The 58 patients had a median age of 61.5 years, 24 females and 34 males, 86% Caucasian and 12% black. The origins of NETs were primarily small bowel (n = 24) and pancreatic (n = 14). Pathology showed grades 1 (n = 21), 2 (n = 25), and 3 (n = 4) and were primarily well-differentiated tumors (n = 4). Among the cohort, 52 patients had imaging to assess response with 14 (26.9%) patients with partial response (PR), 31 (59.6%) with stable disease (SD), and 7 (13.5%) with progressive disease (PD). In a subset analysis, patients with non-functional disease (n = 29) had higher rates of PR 42.3% (compared to 11.5%, P = 0.0147) and higher disease control rate of 96% (compared to 78%, P = 0.042) than patients with functional disease (n = 29). Patients with non-functional disease had a lower PD of 3.85% (compared to 23%, P = 0.0147) than those with functional disease. Conclusions: This real world outcomes analysis of NETs treated with Lu-177 shows improved PR when compared to the initial clinical trials and is promising for patients. In addition, patients with non-functional tumors were found to have a statistically significant improved response rate which has not been described in the literature before. If these study findings are validated in a larger cohort they may guide patient selection for Lu-177 therapy in the future.

A phase II study of perioperative pembrolizumab plus mFOLFOX in patients with potentially resectable esophagus, gastroesophageal junction (GEJ), and stomach adenocarcinoma.

BACKGROUND: Perioperative chemotherapy/chemoradiation is standard in esophageal/gastric/gastroesophageal junction (GEJ) adenocarcinoma, immune checkpoint inhibitors (ICI) effect in setting of metastatic and postoperatively. This study is to assess ICI + chemotherapy perioperatively. METHODS: Patients with locally advanced (T1N1-3M0 or T2-3NanyM0) potentially resectable esophageal/gastric/GEJ adenocarcinoma by PET/EUS/CT and staging-laparoscopy, were treated preoperative 4 cycles mFOLFOX6 (Oxaliplatin 85 mg/m2 /Leucovorin 400 mg/m2 /5-FU bolus 400 mg/m2 then infusion 2400 mg/m2 for 46 h q2weeks) and 3 cycles pembrolizumab (200 mg q3week). Those without distal disease post-neoadjuvant and eligible for resection underwent surgery. Postoperative treatment was initiated at 4-8 weeks with 4 cycles mFOLFOX and 12 cycles pembrolizumab. The primary objective is pathological response (ypRR with tumor regression score, TRS ≤2). The expression of ICI-related markers PD-L1 (CPS), CD8, and CD20 were analyzed before and after preoperative therapy. RESULTS: Thirty-seven patients completed the preoperative treatment. Twenty-nine patients had curative R0 resection. 6/29 (21%; 95% CI: 0.08-0.40) achieved ypCR with TRS 0 in resected patients. 26/29 (90%; 95% CI: 0.73-0.98) had ypRR with TRS ≤2. Twenty-six patients finished adjuvant therapy with a median 36.3-month follow-up. Three patients had recurrence/metastatic disease (at 9-, 10-, 22 months enrollment) with one dead at 23 months, and two are still alive at 28 and 36.5 months. The remaining (23/26) are free of disease with 3 years DFS of 88.5% and 3 years OS of 92.3%. There were no unexpected toxicities. Preoperative ICI + chemotherapy enhanced immune responses significantly with increasing expression of PD-L1 (CPS ≥10, p = 0.0078) and CD8 (>5%, p = 0.0059). CONCLUSIONS: The perioperative pembrolizumab and mFOLFOX combination in resectable esophageal/gastric/GEJ adenocarcinoma is very effective with 90% ypRR, 21% ypCR, and impressive long-time survival benefits.

Circulating Tumor DNA as a Minimal Residual Disease Assessment and Recurrence Risk in Patients Undergoing Curative-Intent Resection with or without Adjuvant Chemotherapy in Colorectal Cancer: A Systematic Review and Meta-Analysis.

Emerging data have suggested that circulating tumor DNA (ctDNA) can be a reliable biomarker for minimal residual disease (MRD) in CRC patients. Recent studies have shown that the ability to detect MRD using ctDNA assay after curative-intent surgery will change how to assess the recurrence risk and patient selection for adjuvant chemotherapy. We performed a meta-analysis of post-operative ctDNA in stage I-IV (oligometastatic) CRC patients after curative-intent resection. We included 23 studies representing 3568 patients with evaluable ctDNA in CRC patient post-curative-intent surgery. Data were extracted from each study to perform a meta-analysis using RevMan 5.4. software. Subsequent subgroup analysis was performed for stages I-III and oligometastatic stage IV CRC patients. Results showed that the pooled hazard ratio (HR) for recurrence-free survival (RFS) in post-surgical ctDNA-positive versus -negative patients in all stages was 7.27 (95% CI 5.49-9.62), p < 0.00001. Subgroup analysis revealed pooled HRs of 8.14 (95% CI 5.60-11.82) and 4.83 (95% CI 3.64-6.39) for stages I-III and IV CRC, respectively. The pooled HR for RFS in post-adjuvant chemotherapy ctDNA-positive versus -negative patients in all stages was 10.59 (95% CI 5.59-20.06), p < 0.00001. Circulating tumor DNA (ctDNA) analysis has revolutionized non-invasive cancer diagnostics and monitoring, with two primary forms of analysis emerging: tumor-informed techniques and tumor-agnostic or tumor-naive techniques. Tumor-informed methods involve the initial identification of somatic mutations in tumor tissue, followed by the targeted sequencing of plasma DNA using a personalized assay. In contrast, the tumor-agnostic approach performs ctDNA analysis without prior knowledge of the patient's tumor tissue molecular profile. This review highlights the distinctive features and implications of each approach. Tumor-informed techniques enable the precise monitoring of known tumor-specific mutations, leveraging the sensitivity and specificity of ctDNA detection. Conversely, the tumor-agnostic approach allows for a broader genetic and epigenetic analysis, potentially revealing novel alterations and enhancing our understanding of tumor heterogeneity. Both approaches have significant implications for personalized medicine and improved patient outcomes in the field of oncology. The subgroup analysis based on the ctDNA method showed pooled HRs of 8.66 (95% CI 6.38-11.75) and 3.76 (95% CI 2.58-5.48) for tumor-informed and tumor-agnostic, respectively. Our analysis emphasizes that post-operative ctDNA is a strong prognostic marker of RFS. Based on our results, ctDNA can be a significant and independent predictor of RFS. This real-time assessment of treatment benefits using ctDNA can be used as a surrogate endpoint for the development of novel drugs in the adjuvant setting.

A novel outpatient regimen in management of fluoropyrimidine-induced cardiotoxicity.

INTRODUCTION: Fluoropyrimidines (FP) are cornerstone drugs in the treatment of gastrointestinal (GI) malignancies. Cardiotoxicity secondary to an FP chemotherapy is a serious complication. There are no standardized guidelines on the treatment of FP induced cardiotoxicity which may result in interruption and even discontinuation of life saving treatment. We present our experience in FP rechallenge using a novel outpatient regimen based on our "up-front" triple agent antianginal protocol. METHODS: We report the retrospective study of the patients with suspected FP induced cardiotoxicity. Patients meeting the criteria were selected by C3OD (curated cancer clinical outcomes database) at Kansas University Medical Center (KUMC). We identified all patients with gastrointestinal malignancies who had suspected FP induced cardiotoxicity from January 2015 to March 2022. We then included the patients who were rechallenged with planned fluoropyrimidine regimen utilizing the three drug KU-protocol. We utilized a novel regimen by repurposing the already FDA-approved anti-anginal drugs in a manner that minimizes the risk of hypotension and bradycardia. RESULTS: In this retrospective study, 10 patients with suspected fluoropyrimidine induced cardiotoxicity were included from January-2015 to March-2022 at KUMC. Out of 10 patients who were rechallenged utilizing KU-protocol, eight patients (80%) were able to complete the previously planned fluoropyrimidine regimen. None of the patients required ER visits or hospital admission due to cardiac symptoms during the rechallenge utilizing the KU-protocol. CONCLUSIONS: Utilizing our novel outpatient regimen, we have successfully and safely allowed re-challenge of FP chemotherapy with good tolerability and completion of the intended course of chemotherapy without recurrent morbidity.

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results.

This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n = 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5 months, and median overall survival (OS) 8.7 months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.

Epidermal Growth Factor Receptor Inhibitor Treatment Timing does not Impact Survival in Stage 4 Colon Cancer Treatment: A Retrospective Study.

Introduction: Colon cancer impacts the lives of Kansans and those across the United States. Epidermal growth factor receptor (EGFR) inhibitors, such as panitumumab and cetuximab, have gained popularity as first-line treatment for stage 4 colon cancer despite their toxicities and have been used by clinicians in later lines of therapy. EGFR inhibitors have been proven to be an efficacious first-line treatment for stage 4 colon cancer, but no study has investigated outcomes comparing EGFR inhibitors as first-line treatment to its use as second- or third-line treatment. This study investigated EGFR inhibitor therapy estimated overall survival when used as first-, second-, and third-line treatment for stage 4 colon cancer. Methods: A retrospective review was done for patients with stage 4 colon cancer who underwent EGFR inhibitor treatment at a large academic center from November 2007 to August 2021. The patients were stratified into five groups by the line in which they received the EGFR inhibitor treatment. A log-rank test was used to analyze the groups, and the median survival for each group was determined. Results: A total of 68 patients were reviewed; 18 received first-line, 23 received second-line, 18 received third-line, 6 received fourth-line, and 3 received sixth-line treatment with an EGFR inhibitor. Fourth- and sixth-line therapies were excluded due to small patient size. There was no significant difference in estimated survival time between any of the lines. Median survival of the therapies was found. Conclusions: There was no statistical difference in survival between the first-, second-, or third-line groups, which may provide justification for its use as a second- or third-line therapy.

Evaluation of the Durability of the Immune Humoral Response to COVID-19 Vaccines in Patients With Cancer Undergoing Treatment or Who Received a Stem Cell Transplant.

Importance: The durability of the antibody response to COVID-19 vaccines in patients with cancer undergoing treatment or who received a stem cell transplant is unknown and may be associated with infection outcomes. Objective: To evaluate anti-SARS-CoV-2 spike protein receptor binding domain (anti-RBD) and neutralizing antibody (nAb) responses to COVID-19 vaccines longitudinally over 6 months in patients with cancer undergoing treatment or who received a stem cell transplant (SCT). Design, Setting, and Participants: In this prospective, observational, longitudinal cross-sectional study of 453 patients with cancer undergoing treatment or who received an SCT at the University of Kansas Cancer Center in Kansas City, blood samples were obtained before 433 patients received a messenger RNA (mRNA) vaccine (BNT162b2 or mRNA-1273), after the first dose of the mRNA vaccine, and 1 month, 3 months, and 6 months after the second dose. Blood samples were also obtained 2, 4, and 7 months after 17 patients received the JNJ-78436735 vaccine. For patients receiving a third dose of an mRNA vaccine, blood samples were obtained 30 days after the third dose. Interventions: Blood samples and BNT162b2, mRNA-1273, or JNJ-78436735 vaccines. Main Outcomes and Measures: Geometric mean titers (GMTs) of the anti-RBD; the ratio of GMTs for analysis of demographic, disease, and treatment variables; the percentage of neutralization of anti-RBD antibodies; and the correlation between anti-RBD and nAb responses to the COVID-19 vaccines. Results: This study enrolled 453 patients (mean [SD] age, 60.4 [13,1] years; 253 [56%] were female). Of 450 patients, 273 (61%) received the BNT162b2 vaccine (Pfizer), 160 (36%) received the mRNA-1273 vaccine (Moderna), and 17 (4%) received the JNJ-7846735 vaccine (Johnson & Johnson). The GMTs of the anti-RBD for all patients were 1.70 (95% CI, 1.04-2.85) before vaccination, 18.65 (95% CI, 10.19-34.11) after the first dose, 470.38 (95% CI, 322.07-686.99) at 1 month after the second dose, 425.80 (95% CI, 322.24-562.64) at 3 months after the second dose, 447.23 (95% CI, 258.53-773.66) at 6 months after the second dose, and 9224.85 (95% CI, 2423.92-35107.55) after the third dose. The rate of threshold neutralization (≥30%) was observed in 203 of 252 patients (80%) 1 month after the second dose and in 135 of 166 patients (81%) 3 months after the second dose. Anti-RBD and nAb were highly correlated (Spearman correlation coefficient, 0.93 [0.92-0.94]; P < .001). Three months after the second dose, anti-RBD titers were lower in male vs female patients (ratio of GMTs, 0.52 [95% CI, 0.34-0.81]), patients older than 65 years vs patients 50 years or younger (ratio of GMTs, 0.38 [95% CI, 0.25-0.57]), and patients with hematologic malignant tumors vs solid tumors (ratio of GMTs, 0.40 [95% CI, 0.20-0.81]). Conclusions and Relevance: In this cross-sectional study, after 2 doses of an mRNA vaccine, anti-RBD titers peaked at 1 month and remained stable over the next 6 months. Patients older than 65 years of age, male patients, and patients with a hematologic malignant tumor had low antibody titers. Compared with the primary vaccine course, a 20-fold increase in titers from a third dose suggests a brisk B-cell anamnestic response in patients with cancer.

Pembrolizumab plus azacitidine in patients with chemotherapy refractory metastatic colorectal cancer: a single-arm phase 2 trial and correlative biomarker analysis.

BACKGROUND: DNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC. METHODS: We conducted a phase 2 single-arm trial evaluating activity and tolerability of pembrolizumab plus azacitidine in patients with chemotherapy-refractory mCRC (NCT02260440). Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg SQ on days 1-5, every 3 weeks. A low fixed dose of azacitidine was chosen in order to reduce the possibility of a direct cytotoxic effect of the drug, since the main focus of this study was to investigate its potential immunomodulatory effect. The primary endpoint of this study was overall response rate (ORR) using RECIST v1.1., and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor tissue was collected pre- and on-treatment for correlative studies. RESULTS: Thirty chemotherapy-refractory patients received a median of three cycles of therapy. One patient achieved partial response (PR), and one patient had stable disease (SD) as best confirmed response. The ORR was 3%, median PFS was 1.9 months, and median OS was 6.3 months. The combination regimen was well-tolerated, and 96% of treatment-related adverse events (TRAEs) were grade 1/2. This trial was terminated prior to the accrual target of 40 patients due to lack of clinical efficacy. DNA methylation on-treatment as compared to pre-treatment decreased genome wide in 10 of 15 patients with paired biopsies and was significantly lower in gene promoter regions after treatment. These promoter demethylated genes represented a higher proportion of upregulated genes, including several immune gene sets, endogenous retroviral elements, and cancer-testis antigens. CD8+ TIL density trended higher on-treatment compared to pre-treatment. Higher CD8+ TIL density at baseline was associated with greater likelihood of benefit from treatment. On-treatment tumor demethylation correlated with the increases in tumor CD8+ TIL density. CONCLUSIONS: The combination of pembrolizumab and azacitidine is safe and tolerable with modest clinical activity in the treatment for chemotherapy-refractory mCRC. Correlative studies suggest that tumor DNA demethylation and immunomodulation occurs. An association between tumor DNA demethylation and tumor-immune modulation suggests immune modulation and may result from treatment with azacitidine. Trial registration ClinicalTrials.gov, NCT02260440. Registered 9 October 2014, https://clinicaltrials.gov/ct2/show/NCT02260440 .

Pre-operative Carboplatin/Paclitaxel Versus 5-Fluorouracil (5-FU)-based Chemoradiotherapy for Older Adults With Esophageal Cancer.

BACKGROUND/AIM: This study aimed to compare the efficacy and tolerability of pre-operative platinum/5-fluorouracil (P5F) and carboplatin/paclitaxel (CP), in combination with radiation therapy in older adults with locally advanced, stage I-III esophageal cancer. PATIENTS AND METHODS: We retrospectively reviewed 51 patients aged ≥70 years who underwent chemoradiotherapy followed by esophagectomy for stage I-III esophageal cancer between 2008 and 2018. Pathological complete response (pCR) and survival rates were compared across the two chemotherapy regimen arms. RESULTS: Treatment completion (p=0.28), pCR (p=0.89), and partial response rates were similar across both chemotherapy groups. Overall survival (OS) and disease-free survival (DFS) were similar across both groups with HR=0.80 (p=0.62) and HR=0.72 (p=0.72) respectively. CONCLUSION: The lesser toxic CP regimen may be used in older patients with locally advanced esophageal cancer, with tumor response and survival rates similar to P5F chemotherapy.

Tumor-initiating stem cell shapes its microenvironment into an immunosuppressive barrier and pro-tumorigenic niche.

Tumor-initiating stem cells (TSCs) are critical for drug resistance and immune escape. However, the mutual regulations between TSC and tumor microenvironment (TME) remain unclear. Using DNA-label retaining, single-cell RNA sequencing (scRNA-seq), and other approaches, we investigated intestinal adenoma in response to chemoradiotherapy (CRT), thus identifying therapy-resistant TSCs (TrTSCs). We find bidirectional crosstalk between TSCs and TME using CellPhoneDB analysis. An intriguing finding is that TSCs shape TME into a landscape that favors TSCs for immunosuppression and propagation. Using adenoma-organoid co-cultures, niche-cell depletion, and lineaging tracing, we characterize a functional role of cyclooxygenase-2 (Cox-2)-dependent signaling, predominantly occurring between tumor-associated monocytes and macrophages (TAMMs) and TrTSCs. We show that TAMMs promote TrTSC proliferation through prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, which enhances ß-catenin activity via AKT phosphorylation. Thus, our study shows that the bidirectional crosstalk between TrTSC and TME results in a pro-tumorigenic and immunosuppressive contexture.