Publications by authors named "Jaffer A Ajani"

503 Publications

Narrative review of pembrolizumab for the treatment of esophageal cancer: evidence and outlook.

Ann Transl Med 2021 Jul;9(14):1189

Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China.

Objective: Based on the current evidence, review the efficacy and safety profile of pembrolizumab, along with its shortcomings, in an effort to define future research directions.

Background: The survival outcome of esophageal cancer (EC) is poor, especially in patients with advanced stage. Palliative surgery, chemotherapy, radiotherapy and chemoradiotherapy have limited efficacy in prolonging the survival time. Currently, immunotherapies, including adoptive cell therapy-based, antibody-based, and vaccine-based therapies, are attracting considerable attention. The mechanism of immunotherapy lies in the modification of immune response and prevention of immune escape. Immunomodulatory agents can block the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway, thereby allowing lymphocytes to attack tumor cells. This class of drugs has the potential to treat a variety of tumors and may substantially improve overall survival (OS) in some patients. Multiple clinical trials have shown that pembrolizumab has good efficacy and safety, enhances the EC treatment paradigm, and has even become the first-line treatment of choice for patients with PD-L1-positive recurrent or metastatic EC.

Methods: We reviewed the results of clinical trials of pembrolizumab for EC and gastroesophageal cancer presented at Embase, PubMed, the American Society of Clinical Oncology (ASCO) annual meetings, and the Cochrane Central Register of Controlled Trials.

Conclusions: Pembrolizumab has good efficacy and tolerability profiles, and has emerged as a second-line option for the treatment of PD-L1-positive locally advanced or metastatic ESCC. Pembrolizumab has many promising applications, and further investigations into its mechanisms should be conducted.
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http://dx.doi.org/10.21037/atm-21-2804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350624PMC
July 2021

Impediments to therapeutic advances for patients with gastroesophageal adenocarcinoma.

Authors:
Jaffer A Ajani

Transl Gastroenterol Hepatol 2021 25;6:49. Epub 2021 Jul 25.

Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (Email:

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http://dx.doi.org/10.21037/tgh.2020.03.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343420PMC
July 2021

Influence of Baseline Positron Emission Tomography in Metastatic Gastroesophageal Cancer on Survival and Response to Therapy.

Oncology 2021 5;99(10):659-664. Epub 2021 Aug 5.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: The value of baseline fluorodeoxyglucose-positron emission tomography-computed tomography (PET-CT) remains uncertain once gastroesophageal cancer is metastatic. We hypothesized that assessment of detailed PET-CT parameters (maximum standardized uptake value [SUVmax] and/or total lesion glycolysis [TLG]), and the extent of metastatic burden could aid prediction of probability of response or prognosticate.

Methods: We retrospectively analyzed treatment-naive patients with stage 4 gastroesophageal cancer (December 2002-August 2017) who had initial PET-CT for cancer staging at MD Anderson Cancer Center. SUVmax and TLG were compared with treatment outcomes for the full cohort and subgroups based on metastatic burden (≤2 or >2 metastatic sites).

Results: We identified 129 patients with metastatic gastroesophageal cancer who underwent PET-CT before first-line therapy. The median follow-up time was 61 months. The median overall survival (OS) was 18.5 months; the first progression-free survival (PFS) was 5.5 months. SUVmax or TLG of the primary tumor or of all metastases combined had no influence on OS or PFS, whether the number of metastases was ≤2 or >2. Overall response rates (ORRs) to first-line therapy were 48% and 45% for patients with ≤2 and >2 metastases, respectively (nonsignificant). ORR did not differ based on low or high values of SUVmax or TLG.

Conclusions: This is the first assessment of a unique set of PET-CT data and its association with outcomes in metastatic gastroesophageal cancer. In our large cohort of patients, detailed analyses of PET-CT (by SUVmax and/or TLG) did not discriminate any parameters examined. Thus, baseline PET-CT in untreated metastatic gastroesophageal cancer patients has limited or no utility.
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http://dx.doi.org/10.1159/000517842DOI Listing
September 2021

Chemoradiotherapy followed by Active Surveillance Versus Standard Esophagectomy for Esophageal Cancer: A Systematic Review and Individual Patient Data Meta-Analysis.

Ann Surg 2021 May 11. Epub 2021 May 11.

*Department of Surgery, Erasmus MC - University Medical Center, Rotterdam, the Netherlands †Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ‡Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America §University of Lille, Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, F-59000 Lille, France ¶Division of Upper Gastro-Intestinal Surgery, Department of Surgery, Humanitas University, Humanitas Clinical and Research Center-IRCCS, Milan, Italy ||Department of Oncological Surgery, Veneto Institute of Oncology (IOV-IRCCS), Padua, Italy **Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ††Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ‡‡Department of Surgery, Connolly Hospital, Dublin, Ireland §§Department of Public Health, Erasmus MC - University Medical Center, Rotterdam, the Netherlands.

Objective: To compare overall survival of patients with a clinically complete response (cCR) undergoing active surveillance versus standard esophagectomy.

Summary Background Data: One-third of patients with esophageal cancer have a pathologically complete response in the resection specimen after neoadjuvant chemoradiotherapy. Active surveillance may be of benefit in patients with cCR, determined with diagnostics during response evaluations after chemoradiotherapy.

Methods: A systematic review and meta-analysis was performed comparing overall survival between patients with cCR after chemoradiotherapy undergoing active surveillance versus standard esophagectomy. Authors were contacted to supply individual patient data. Overall and progression free survival were compared using random effects meta-analysis of randomized or propensity score matched data. Locoregional recurrence rate was assessed. The study-protocol was registered (PROSPERO:CRD42020167070).

Results: Seven studies were identified comprising 788 patients, of which after randomization or propensity score matching yielded 196 active surveillance and 257 standard esophagectomy patients. All authors provided individual patient data. The risk of all-cause mortality for active surveillance was 1.08 (95%Confidence Interval (CI):0.62-1.87,p = 0.75) after intention-to-treat analysis and 0.93 (95%CI:0.56-1.54,p = 0.75) after per-protocol analysis. The risk of progression or all-cause mortality for active surveillance was 1.14 (95%CI:0.83-1.58,p = 0.36). Five-year locoregional recurrence rate during active surveillance was 40% (95%CI:26%-59%). 95% of active surveillance patients undergoing postponed esophagectomy for locoregional recurrence had radical resection.

Conclusions: Overall survival was comparable in patients with cCR after chemoradiotherapy undergoing active surveillance or standard esophagectomy. Diagnostic followup is mandatory in active surveillance and postponed esophagectomy should be offered to operable patients in case of locoregional recurrence.
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http://dx.doi.org/10.1097/SLA.0000000000004930DOI Listing
May 2021

Patient-derived cell lines and orthotopic mouse model of peritoneal carcinomatosis recapitulate molecular and phenotypic features of human gastric adenocarcinoma.

J Exp Clin Cancer Res 2021 Jun 23;40(1):207. Epub 2021 Jun 23.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Background: Gastric adenocarcinoma with peritoneal carcinomatosis (PC) is therapy resistant and leads to poor survival. To study PC in depth, there is an urgent need to develop representative PC-derived cell lines and metastatic models to study molecular mechanisms of PC and for preclinical screening of new therapies.

Methods: PC cell lines were developed from patient-derived PC cells. The tumorigenicity and metastatic potential were investigated by subcutaneously (PDXs) and orthotopically. Karyotyping, whole-exome sequencing, RNA-sequencing, and functional studies were performed to molecularly define the cell lines and compare genomic and phenotypic features of PDX and donor PC cells.

Results: We established three PC cell lines (GA0518, GA0804, and GA0825) and characterized them in vitro. The doubling times were 22, 39, and 37 h for GA0518, GA0804, and GA0825, respectively. Expression of cancer stem cell markers (CD44, ALDH1, CD133 and YAP1) and activation of oncogenes varied among the cell lines. All three PC cell lines formed PDXs. Interestingly, all three PC cell lines formed tumors in the patient derived orthotopic (PDO) model and GA0518 cell line consistently produced PC in mice. Moreover, PDXs recapitulated transcriptomic and phenotypic features of the donor PC cells. Finally, these cell lines were suitable for preclinical testing of chemotherapy and target agents in vitro and in vivo.

Conclusion: We successfully established three patient-derived PC cell lines and an improved PDO model with high incidence of PC associated with malignant ascites. Thus, these cell lines and metastatic PDO model represent excellent resources for exploring metastatic mechanisms of PC in depth and for target drug screening and validation by interrogating GAC for translational studies.
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http://dx.doi.org/10.1186/s13046-021-02003-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223395PMC
June 2021

First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.

Lancet 2021 07 5;398(10294):27-40. Epub 2021 Jun 5.

Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.

Methods: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.

Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.

Interpretation: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.

Funding: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.
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http://dx.doi.org/10.1016/S0140-6736(21)00797-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436782PMC
July 2021

Benchmarks for nodal yield and ratio for node-positive gastric cancer.

Surgery 2021 Oct 28;170(4):1231-1239. Epub 2021 May 28.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: We aimed to elucidate prognostic markers of node-positive gastric cancers with a focus on examined lymph nodes and lymph node ratio.

Methods: Patients treated with curative-intent gastrectomy at The University of Texas MD Anderson Cancer Center from 1995-2019 were evaluated. Patients with non-metastatic, node-positive gastric cancers were considered for analysis.

Results: Of 775 patients, 281 met the inclusion criteria. The mean age was 58 years, 61% were male, 51% were White, 65% received preoperative therapy, and 71% of tumors were located in the gastric body. The median overall survival was 3.6 years, and 1-, 5-, and 10-year overall survival rates were 91%, 41%, and 29%, respectively. pN3 category was associated with worse overall survival (hazard ratio 1.79, P = .001) and recurrence-free survival (hazard ratio 1.92, P = .004). Nodal burden was associated with aggressive biologic traits in primary tumors, including higher rates of lymphovascular and perineural invasion and lower preoperative therapy response rates. By receiver-operative characteristic analysis, threshold values of ≥30 examined lymph nodes and <30% lymph node ratio were most discriminant for overall survival. On adjusted analysis, positive margins, additional organ resection, <30 examined lymph nodes, and ≥30% lymph node ratio were associated with worse recurrence-free survival and overall survival. Among patients with high node burden (pN3), <30 examined lymph nodes remained significant on adjusted survival analysis.

Conclusion: Greater than or equal to 30 examined lymph nodes and <30% lymph node ratio were significantly associated with longer recurrence-free survival and overall survival, independent of lymphadenectomy type. These prognostic benchmarks should be considered in the surgical management of gastric cancer in the United States.
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http://dx.doi.org/10.1016/j.surg.2021.04.026DOI Listing
October 2021

Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.

N Engl J Med 2021 04;384(13):1191-1203

From the Charles A. Sammons Cancer Center at Baylor University Medical Center, Dallas (R.J.K.), and the University of Texas M.D. Anderson Cancer Center, Houston (J.A.A.); Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland (J.K., P.K.); the University Hospital Cologne, Department of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, Gastrointestinal Cancer Group Cologne, Cologne (T.Z.), and University Medical Center of Johannes Gutenberg-University Mainz (M.M.) - both in Germany; University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven (E.V.C.), and Ghent University Hospital, Ghent (K.G.) - both in Belgium; University Lille, Claude Huriez University Hospital, Lille (G.P.), and Pontchaillou University Hospital, Department of Gastroenterology, University of Rennes 1, INSERM Unité 1242, Rennes (A.L.) - both in France; Fundación Favaloro, Buenos Aires (G.M.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore (J.F.); Akita University Hospital, Akita, Japan (S.M.); Duke Cancer Institute, Durham, NC (H.U.); Princess Margaret Cancer Centre, Toronto (E.E.), and Queen Elizabeth II Health Sciences Centre, Halifax, NS (S.S.) - both in Canada; the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (C.G.); Florida Cancer Specialists and Research Institute, Fort Myers (S.Z.); University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (A.H.K.); St. John of God Murdoch Hospital, Murdoch, WA, Australia (K.F.); Sfantul Nectarie Oncology Center, Craiova, Romania (M.S.); Bristol Myers Squibb, Princeton, NJ (J.Z., L.Z., M.L., P.S., K.K.); and Dana-Farber Cancer Institute, Boston (J.M.C.).

Background: No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer.

Methods: We conducted CheckMate 577, a global, randomized, double-blind, placebo-controlled phase 3 trial to evaluate a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer. Adults with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease were randomly assigned in a 2:1 ratio to receive nivolumab (at a dose of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks) or matching placebo. The maximum duration of the trial intervention period was 1 year. The primary end point was disease-free survival.

Results: The median follow-up was 24.4 months. Among the 532 patients who received nivolumab, the median disease-free survival was 22.4 months (95% confidence interval [CI], 16.6 to 34.0), as compared with 11.0 months (95% CI, 8.3 to 14.3) among the 262 patients who received placebo (hazard ratio for disease recurrence or death, 0.69; 96.4% CI, 0.56 to 0.86; P<0.001). Disease-free survival favored nivolumab across multiple prespecified subgroups. Grade 3 or 4 adverse events that were considered by the investigators to be related to the active drug or placebo occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. The trial regimen was discontinued because of adverse events related to the active drug or placebo in 9% of the patients in the nivolumab group and 3% of those in the placebo group.

Conclusions: Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 577 ClinicalTrials.gov number, NCT02743494.).
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http://dx.doi.org/10.1056/NEJMoa2032125DOI Listing
April 2021

Loss of ARID1A activates mTOR signaling and SOX9 in gastric adenocarcinoma-rationale for targeting deficiency.

Gut 2021 Mar 30. Epub 2021 Mar 30.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: Gastric adenocarcinoma (GAC) is a lethal disease with limited therapeutic options. Genetic alterations in chromatin remodelling gene AT-rich interactive domain 1A () and mTOR pathway activation occur frequently in GAC. Targeting the mechanistic target of rapamycin (mTOR) pathway in unselected patients has failed to show survival benefit. A deeper understanding of GAC might identify a subset that can benefit from mTOR inhibition.

Methods: Genomic alterations in were analysed in GAC. Mouse gastric epithelial cells from and wild-type mice were used to determine the activation of oncogenic genes due to loss of Arid1A. Functional studies were performed to determine the significance of loss of ARID1A and the sensitivity of ARID1A-deficient cancer cells to mTOR inhibition in GAC.

Results: More than 30% of GAC cases had alterations (mutations or deletions) of ARID1A and ARID1A expression was negatively associated with phosphorylation of S6 and SOX9 in GAC tissues and patient-derived xenografts (PDXs). Activation of mTOR signalling (increased pS6) and SOX9 nuclear expression were strongly increased in Arid1A mouse gastric tissues which could be curtailed by RAD001, an mTOR inhibitor. Knockdown of ARID1A in GAC cell lines increased pS6 and nuclear SOX9 and increased sensitivity to an mTOR inhibitor which was further amplified by its combination with fluorouracil both in vitro and in vivo in PDXs.

Conclusions: The loss of ARID1A activates pS6 and SOX9 in GAC, which can be effectively targeted by an mTOR inhibitor. Therefore, our studies suggest a new therapeutic strategy of clinically targeting the mTOR pathway in patients with GAC with ARID1A deficiency.
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http://dx.doi.org/10.1136/gutjnl-2020-322660DOI Listing
March 2021

Determinants of Survival for Patients with Neoadjuvant-Treated Node-Negative Gastric Cancer.

Ann Surg Oncol 2021 Oct 22;28(11):6638-6648. Epub 2021 Mar 22.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: This study sought to determine prognostic markers for disease recurrence and survival in a cohort of neoadjuvant-treated, node-negative gastric cancer patients (ypT0-4N0M0).

Methods: Clinicopathologic data from patients treated with neoadjuvant therapy followed by curative-intent gastrectomy at the University of Texas MD Anderson Cancer Center from 1995 to 2017 were evaluated. Patients with AJCC TNM stage ypT0-4N0M0 were considered for analysis.

Results: The inclusion criteria were met by 212 patients with a mean age of 58.3 years. Of these patients, 60 % were male, 53 % were Caucasian, 87 % received chemoradiation, and 13 % received chemotherapy. The findings showed a median overall survival (OS) rate of 11.3 years, a 5-year survival rate of 72 %, and a 10-year survival rate of 57 %. During a median follow-up period of 5.5 years, 38.2 % of the patients died. In the multivariable analysis, ypT4-stage and nodal yield fewer than 16 were significantly associated with reduced OS. Cancer classified as ypT4 had more aggressive biologic traits, including lymphovascular and perineural invasion, and was treated more aggressively with total gastrectomy and additional organ resection despite frequent positive margins. Depth of invasion remained significantly associated with worse outcome after the analysis controlled for nodal yield and possible stage migration. Compared with ypT0-3 tumors, ypT4 cancers were associated with significantly more recurrences (13 % vs. 45 %; p < 0.05), and the primary modes of failure for ypT4 lesions were local recurrence and peritoneal metastases (88 % of recurrences).

Conclusions: Depth of primary tumor invasion and nodal yield were significantly associated with OS among the patients with ypT0-4N0M0 gastric cancer. Serosal invasion (ypT4) was associated with a high rate of peritoneal recurrence, and trials of intraperitoneal therapy targeting these patients should be considered.
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http://dx.doi.org/10.1245/s10434-021-09625-4DOI Listing
October 2021

Drug resistance and Cancer stem cells.

Cell Commun Signal 2021 02 15;19(1):19. Epub 2021 Feb 15.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.

Therapy resistance is a major problem when treating cancer patients as cancer cells develop mechanisms that counteract the effect of therapeutic compounds, leading to fit and more aggressive clones that contribute to poor prognosis. Therapy resistance can be both intrinsic and/or acquired. These are multifactorial events, and some are related to factors including adaptations in cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), deregulation of key signaling pathways, drug efflux through ABC transporters, acquired mutations, evading apoptosis, and activation of DNA damage response among others. Among these factors, CSCs represent the major source of therapy resistance. CSCs are a subset of tumor cells that are capable of self-renewal and multilineage progenitor expansion that are known to be intrinsically resistant to anticancer treatments. Multiple clones of CSCs pre-exist, and some can adopt and expand easily to changes in the tumor microenvironment (TME) and/or in response to radio- and chemotherapy. A combination of both intrinsic and extrinsic factors contributes to CSC-mediated therapy resistance. In this review, we will focus on CSCs and therapy resistance as well as suggest strategies to eliminate CSCs and, therefore, overcome resistance. Video abstract.
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http://dx.doi.org/10.1186/s12964-020-00627-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885480PMC
February 2021

Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1).

J Clin Oncol 2021 03 12;39(9):990-1000. Epub 2021 Feb 12.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastases. A phase I and Ib study of modified oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) with ADX revealed encouraging antitumor activity in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Materials And Methods: This phase III, randomized, double-blinded, placebo (PBO)-controlled multicenter study investigated the efficacy and safety of mFOLFOX6 with and without ADX in patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma. Random assignment was 1:1 to mFOLFOX6 + ADX or mFOLFOX6 + PBO. ADX/PBO 800 mg was infused on days 1 and 15 of each 28-day cycle. Protocol therapy was given until disease progression or intolerance. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), objective response rate (RECIST 1.1), and safety.

Results: Between September 2015 and May 2017, 432 patients were randomly assigned, 218 to ADX and 214 to PBO. The median OS was 12.5 versus 11.8 months in the ADX and PBO groups, respectively. The median PFS was 7.5 versus 7.1 months in the ADX and PBO groups, respectively. The objective response rate was 51% in the ADX group and 41% in the PBO group. Among the subgroup analyses, patients of age ≥ 65 years had an improved OS and PFS with ADX versus PBO; the values and CIs were not adjusted for multiplicity. There were no meaningful differences in the safety profile of the ADX versus PBO groups.

Conclusion: The addition of ADX to mFOLFOX6 did not improve OS in unselected patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma.
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http://dx.doi.org/10.1200/JCO.20.02755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078292PMC
March 2021

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

Oncologist 2021 05 22;26(5):e780-e793. Epub 2021 Feb 22.

Department of Radiation Oncology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.

Background: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined.

Materials And Methods: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model.

Results: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate.

Conclusion: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC.

Implications For Practice: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.
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http://dx.doi.org/10.1002/onco.13707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100558PMC
May 2021

Preoperatively Treated Diffuse-Type Gastric Adenocarcinoma: Glucose vs. Other Energy Sources Substantially Influence Prognosis and Therapy Response.

Cancers (Basel) 2021 Jan 23;13(3). Epub 2021 Jan 23.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Diffuse type of gastric adenocarcinoma (dGAC) generally confers a poor prognosis compared to intestinal type. Some dGACs are not avid on fluorine-18 fluoro-2-deoxy-D-glucose PET (FDG-PET) while others seem to consume glucose avidly. We analyzed the outcomes based on the avidity (high with standardized uptake value (SUV) > 3.5 or low with SUV ≤ 3.5) of the primary on baseline FDG-PET. We retrospectively selected 111 localized dGAC patients who had baseline FDG-PET (all were treated with preoperative chemotherapy and chemoradiation). FDG-PET avidity was compared with overall survival (OS) and response to therapy. The mean age was 59.4 years and with many females (47.7%). The high-SUV group (58 (52.3%) patients) and the low-SUV group (53 (47.7%) patients) were equally divided. While the median OS for all patients was 49.5 months (95% CI: 38.5-98.8 months), it was 98.0 months (95% CI: 49.5-NE months) for the low-SUV group and 36.0 months for the high-SUV ( = 0.003). While the median DFS for all patients was 38.2 months (95%CI: 27.7-97.6 months), it was 98.0 (95% CI: 36.9-NE months) months for the low-SUV group was and only 27.0 months (95% CI: 15.2-63.2 months) for the high-SUV group ( = 0.005). Clinical responses before surgery were more common in the low-SUV group but overall we observed only 4 pathologic complete responses in 111 patients. Our unique data suggest that if dGACs used glucose as an energy source then the prognosis was very poor while non-glucose sources improved prognosis. Multi-platform (including metabolomics) profiling of dGACs would yield useful biologic understanding.
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http://dx.doi.org/10.3390/cancers13030420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866002PMC
January 2021

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma.

Gut 2021 Jan 24. Epub 2021 Jan 24.

Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objective: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.

Methods: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.

Results: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes () that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.

Conclusions: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.
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http://dx.doi.org/10.1136/gutjnl-2020-321175DOI Listing
January 2021

ARID1A Mutation May Define an Immunologically Active Subgroup in Patients with Microsatellite Stable Colorectal Cancer.

Clin Cancer Res 2021 03 7;27(6):1663-1670. Epub 2021 Jan 7.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: AT-rich interactive domain 1A () is commonly mutated in colorectal cancer, frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch repair during DNA replication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models, but its role in patients with colorectal cancer is being explored.

Experimental Design: The DNA sequencing and gene expression profiling of patients with colorectal cancer were extracted from The Cancer Genome Atlas and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. IHC for T-cell markers was performed on a separate cohort of patients.

Results: Twenty-eight of 417 patients with microsatellite stable (MSS) colorectal cancer (6.7%) had mutation. Among 58 genes most commonly mutated in colorectal cancer, mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold, < 0.001). In MSS, mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFNγ expression (Δ score +1.91, < 0.001). Compared with wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and gene sets (e.g., antigen presentation, cytotoxic T-cell function, and immune checkpoints) was observed in mutant cases. This was validated by unsupervised differential expression of genes related to immune response and further confirmed by higher infiltration of T cells in IHC of tumors with mutation ( = 0.01).

Conclusions: The immunogenicity of -mutant cases is likely due to an increased level of neoantigens resulting from increased tumor mutational burden and frameshift mutations. Tumors with mutation may be more susceptible to immune therapy-based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956157PMC
March 2021

Concurrent lymphovascular and perineural invasion after preoperative therapy for gastric adenocarcinoma is associated with decreased survival.

J Surg Oncol 2021 Mar 5;123(4):911-922. Epub 2021 Jan 5.

Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background And Objectives: We sought to evaluate the impact of lymphovascular invasion (LVI) and perineural invasion (PNI) on survival outcomes in gastric cancer patients treated with preoperative therapy.

Methods: Patients with gastric cancer treated with preoperative therapy and potentially curative resection were stratified according to the presence of LVI, PNI, or both. Kaplan-Meier and Cox regression analyses were used to evaluate the impact on overall survival (OS) and disease-free survival (DFS).

Results: The study included 281 patients, of whom 93 (33%) had LVI, 69 (25%) had PNI, 51 (18%) had both LVI and PNI, and 170 (61%) had neither. LVI and PNI were each associated with higher ypT and ypN categories and more positive lymph nodes (all p < .001), associations that were emphasized with both factors present. On multivariable analyses, ypN (p < .001) and concurrent LVI/PNI (hazard ratio [HR]: 2.62; 95% confidence interval [CI]: 1.55-4.45; p = .001) were predictive of OS and DFS (ypN: p < .001; both LVI/PNI: HR: 2.27; 95% CI: 1.34-3.82; p = .002).

Conclusions: Gastric cancer patients with concurrent LVI and PNI after preoperative therapy have more advanced disease and worse survival outcomes than patients with neither or only one of these factors.
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http://dx.doi.org/10.1002/jso.26367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906958PMC
March 2021

Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma.

Nat Med 2021 01 4;27(1):141-151. Epub 2021 Jan 4.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.
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http://dx.doi.org/10.1038/s41591-020-1125-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074162PMC
January 2021

Potential Molecular Targets in the Setting of Chemoradiation for Esophageal Malignancies.

J Natl Cancer Inst 2021 Jun;113(6):665-679

Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Although the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.
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http://dx.doi.org/10.1093/jnci/djaa195DOI Listing
June 2021

Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma.

Gut 2021 Nov 17;70(11):2055-2065. Epub 2020 Dec 17.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objective: Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes.

Design: We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts.

Results: alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets and ). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts.

Conclusion: This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.
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http://dx.doi.org/10.1136/gutjnl-2020-322707DOI Listing
November 2021

Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma.

Br J Cancer 2021 03 10;124(5):963-974. Epub 2020 Dec 10.

Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Background: Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC).

Methods: We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance.

Results: ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens.

Conclusions: F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.
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http://dx.doi.org/10.1038/s41416-020-01198-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921654PMC
March 2021

Genetic alterations and expression characteristics of ARID1A impact tumor immune contexture and survival in early-onset gastric cancer.

Am J Cancer Res 2020 1;10(11):3947-3972. Epub 2020 Nov 1.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center Houston, TX 77030, USA.

The AT-rich Interactive Domain 1A (ARID1A) is one of the most frequently mutated genes in gastric cancer. Here, we found that genetic variants in noncoding regions of ARID1A associated with altered protein levels by target sequencing. Notably, tumors with ARID1A variants in the 3'untranslated region (3'UTR) exhibited remarkably increased heterogeneity of ARID1A protein. In general, genetic variants and protein deficiency of ARID1A in tumors were associated with a better survival. Strikingly, altered patterns and heterogeneity of ARID1A protein expression were observed in peritumor tissues and carried significant implications in defining tumor immune contexture by multiplex immunohistochemistry. By analyzing the spatial distribution of TILs, we showed that reduced ARID1A protein levels in both tumor and peritumor tissues were significantly correlated with increased density and proximity of TILs to tumor cells. In contrast, high heterogeneity of ARID1A expression was associated with increased TIL density, but reduced proximity of TILs to tumor cells. Collectively, our study characterized ARID1A genetic alterations and its protein expression patterns in EOGC, demonstrating new strategies for clinically assessing its molecular impact on tumor onset and progression, tumor immune response, and patient survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716160PMC
November 2020

Why should localized gastric adenocarcinoma patients fare poorly after adjunctive therapy compared to surgery alone?

Chin Clin Oncol 2021 Jun 18;10(3):32. Epub 2020 Nov 18.

Department of Gastrointestinal Medical Oncology, U.T. U.T. M.D. Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.21037/cco-20-199DOI Listing
June 2021

Comparison of laparoscopy versus mini-laparotomy for jejunostomy placement in patients with gastric adenocarcinoma.

Surg Endosc 2020 Nov 10. Epub 2020 Nov 10.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Herman Pressler, Unit 1484, Houston, TX, 77030, USA.

Background: Optimal nutrition is challenging for patients with gastric and gastroesophageal adenocarcinoma and often requires feeding tube placement prior to preoperative therapy. Feeding jejunostomy (FJ) placement via mini-laparotomy is technically easier to perform than laparoscopic FJ. The purpose of this study was to compare outcomes in patients with gastric adenocarcinoma undergoing laparoscopic versus mini-laparotomy FJ placement.

Methods: A retrospective cohort study was performed of patients with gastric adenocarcinoma receiving laparoscopic versus mini-laparotomy FJ at a single tertiary referral center from 2000 to 2018. 30-day outcomes included complications, conversion to laparotomy, reoperation, length of stay, and readmission.

Results: A total of 656 patients met the inclusion criteria and were studied. The majority of patients were male (68.1%) with a mean age of 60.6 years. The difference in surgical approach remained relatively stable over time. Overall, 82 (12.5%) patients experienced complications, and three (0.5%) patients died postoperatively. While readmission and conversion to open laparotomy did not differ between groups, overall complications (10.5% vs. 20.8%, p = 0.002), Clavien-Dindo ≥ 3 complications (4.0% vs. 8.9%, p = 0.021), length of stay (4.1 vs. 5.6 days, p < 0.001), and reoperation (0.9% vs. 4.0%, p = 0.002) favored the laparoscopic over mini-laparotomy group.

Conclusion: The current study helps clarify the risk of FJ placement in patients with gastric adenocarcinoma requiring nutritional support. Laparoscopic FJ placement has lower overall morbidity and length of stay compared to mini-laparotomy. However, caution is needed in preventing and identifying the rare causes of postoperative mortality that may be associated with laparoscopic FJ placement.
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http://dx.doi.org/10.1007/s00464-020-08155-6DOI Listing
November 2020

Treatment Patterns for Gastroesophageal Junction Adenocarcinoma in the United States.

J Clin Med 2020 Oct 29;9(11). Epub 2020 Oct 29.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Drive, Unit 1484, Houston, TX 77030, USA.

Despite the increasing incidence of gastroesophageal junction adenocarcinoma (GEJA), the optimal treatment strategy for the disease remains unknown. The objective of this study was to describe treatment patterns for GEJA in the United States. The National Cancer Database was searched to identify all patients who underwent resection of the lower esophagus, abdominal esophagus, and/or gastric cardia for GEJA between 2006 and 2016. Patients were grouped by clinical disease stage: early localized (L; T1-2N0), locally advanced (LA; T3-4N0), regional (R; T1-2N+), or regionally advanced (RA; T3-4N+). The search identified 28,852 GEJA patients. The dominant age range was 60-69 years (39%). Most patients were men (85%), and most were white (92%). Most L patients (69%) underwent upfront surgery, whereas most LA, R, and RA patients received neoadjuvant therapy (NAT; 86%, 80%, and 90%, respectively). Among patients who received NAT, 85% received chemoradiotherapy. Adjuvant therapy was relatively uncommon across all groups (15-20%). In the LA, R, and RA groups, overall survival was greater in patients who received NAT compared to upfront surgery ( < 0.001). With the exception of patients with early localized node-negative disease, most GEJA patients receive neoadjuvant chemoradiotherapy despite the lack of prospective trials reporting survival benefit over chemotherapy alone.
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http://dx.doi.org/10.3390/jcm9113495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692279PMC
October 2020

Trastuzumab upregulates programmed death ligand-1 expression through interaction with NK cells in gastric cancer.

Br J Cancer 2021 02 26;124(3):595-603. Epub 2020 Oct 26.

Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Background: The predictive significance of programmed death ligand 1 (PD-L1) for programmed death 1 (PD-1) inhibitors remains unclear in gastric cancer (GC) due to the dynamic alteration by treatments. We aimed to elucidate the effects of trastuzumab (Tmab) on PD-L1 expression in GC.

Methods: PD-L1 expression was evaluated by multicolour flow cytometry analysis after co-culturing GG cell lines and immune cells with Tmab. IFN-γ in the co-culture experiments was quantified. Immunohistochemistry (IHC) for PD-L1 expression using clinical samples was also performed to confirm PD-L1 alteration by Tmab.

Results: PD-L1 expression was significantly upregulated by Tmab in HER2-amplified GC cell lines co-cultured with peripheral blood mononuclear cells (PBMCs). PD-L1 upregulation by Tmab was also observed in the GC cells co-cultured with NK cells in time-dependent manner, but not with monocytes. IFN-γ concentration in conditioned media from co-cultured PBMCs and NK cells with Tmab was significantly higher and anti-IFN-γ significantly suppress the Tmab-induced PD-L1 upregulation. IHC also suggested PD-L1 upregulation after Tmab treatment.

Conclusions: Tmab can upregulate PD-L1 expression on GC cells through interaction with NK cells. These results suggest clinical implications in the assessment of the predictive significance of PD-L1 expression for PD-1 inhibitors.
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http://dx.doi.org/10.1038/s41416-020-01138-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851117PMC
February 2021

LncRNA PVT1 Is a Poor Prognosticator and Can Be Targeted by PVT1 Antisense Oligos in Gastric Adenocarcinoma.

Cancers (Basel) 2020 Oct 15;12(10). Epub 2020 Oct 15.

Department of Gastrointestinal Medical Oncology, Unit 0426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

Gastric adenocarcinoma (GAC) is inherently resistant or becomes resistant to therapy, leading to a poor prognosis. Mounting evidence suggests that lncRNAs can be used as predictive markers and therapeutic targets in the right context. In this study, we determined the role of lncRNA-PVT1 in GAC along with the value of inhibition of PVT1 using antisense oligos (ASOs). RNA scope in situ hybridization was used to analyze PVT1 expression in tumor tissue microarrays (TMAs) of GAC and paired normal tissues from 792 patients. Functional experiments, including colony formation and invasion assays, were performed to evaluate the effects of PVT1 ASO inhibition of PVT1 in vitro; patient-derived xenograft models were used to evaluate the anti-tumor effects of PVT1 ASOs in vivo. LncRNA-PVT1 was upregulated in GACs compared to the matched adjacent normal tissues in the TMA. LncRNA PVT1 expression was positively correlated with larger tumor size, deeper wall invasion, lymph node metastases, and short survival duration. Inhibition of PVT1 using PVT1 ASOs significantly suppressed tumor cell growth and invasion in vitro and in vivo. PVT1 expression was highly associated with poor prognosis in GAC patients and targeting PVT1 using PVT1 ASOs was effective at curtailing tumor cell growth in vitro and in vivo. Thus, PVT1 is a poor prognosticator as well as therapeutic target. Targeting PVT1 using PVT1 ASOs provides a novel therapeutic strategy for GAC.
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http://dx.doi.org/10.3390/cancers12102995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602573PMC
October 2020

Molecular biology and immunology of gastric cancer peritoneal metastasis.

Transl Gastroenterol Hepatol 2020 5;5:57. Epub 2020 Oct 5.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Peritoneal metastases occur in 55-60% of patients with gastric cancer (GC) and are associated with a 2% 5-year overall survival rate. There are limited treatment options for these patients, and no targeted therapy or immunotherapy is available. Rational therapeutic targets remain to be found. In this review, we present the published literature and our own recent experience in molecular biology to identify important molecules and signaling pathways as well as cellular immunity involved in the peritoneal metastasis of GC. We also suggest potential novel strategies for improving the outcomes of GC patients with peritoneal metastasis.
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http://dx.doi.org/10.21037/tgh.2020.02.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530317PMC
October 2020
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