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Simple Summary: The major histocompatibility complex (MHC) class I genes, encompassing the human leukocyte antigen (HLA) class I and the beta-2 microglobulin (B2M) genes, play a key role in neoantigens presentation to the immune system. We analyzed allelic imbalance (AI) of the respective chromosomal regions by multiplex PCRs using microsatellite markers in biopsies of 158 patients with gastric/gastroesophageal adenocarcinoma before neoadjuvant platinum/fluoropyrimidine chemotherapy (CTx) for an association with clinical outcome of the patients. AI with no marker was significantly associated with response or survival. However, subgroup analysis revealed interesting differences. Of note, AI at markers of the HLA region was associated with a decreased survival only in responding but not in non-responding patients. No associations were observed for B2M markers. Our results underline the importance of intact neoantigen presentation specifically for responding patients and may help explain an unexpectedly poor survival of a patient despite significant tumor regression after neoadjuvant CTx. We aimed to determine the clinical and prognostic relevance of allelic imbalance (AI) of the major histocompatibility complex (MHC) class I genes, encompassing the human leukocyte antigen (HLA) class I and beta-2 microglobulin (B2M) genes, in the context of neoadjuvant platinum/fluoropyrimidine chemotherapy (CTx). Biopsies before CTx were studied in 158 patients with adenocarcinoma of the stomach or gastroesophageal junction. The response was histopathologically evaluated. AI was detected by multiplex PCRs analysis of four or five microsatellite markers in HLA and B2M regions, respectively. AI with no marker was significantly associated with response or survival. However, subgroup analysis revealed differences. AI at marker D6S265, close to the HLA-A gene, was associated with an obvious increased risk in responding (HR, 3.62; 95% CI, 0.96–13.68, p = 0.058) but not in non-responding patients (HR, 0.92; 95% CI, 0.51–1.65, p = 0.773). Markers D6S273 and D6S2872 showed similar results. The interaction between AI at D6S265 and response to CTx was significant in a multivariable analysis (p = 0.010). No associations were observed for B2M markers. Our results underline the importance of intact neoantigen presentation specifically for responding patients and may help explain an unexpectedly poor survival of a patient despite significant tumor regression after neoadjuvant platinum/fluoropyrimidine CTx. [ABSTRACT FROM AUTHOR]

Tumour budding (TB) has been associated with adverse clinicopathological factors and poor survival in a plethora of therapy‐naïve carcinoma entities including gastric adenocarcinoma (GC). As conventional histopathological grading is usually omitted in the post‐neoadjuvant setting of GC, our study aimed to investigate the prognostic impact of TB in GCs resected after neoadjuvant therapy. We evaluated TB according to the criteria from the International Tumour Budding Consensus Conference (ITBCC) in 167 post‐neoadjuvant resections of intestinal‐type GC and correlated the results with overall survival (OS) and clinicopathological parameters. GCs were categorised into Bd1 (0–4 buds, low TB), Bd2 (5–9 buds, intermediate TB), and Bd3 (≥10 buds, high TB). Carcinomas with intermediate and high TB were significantly enriched in higher ypTNM stages and strongly associated with reduced 5‐year OS in univariable analyses (p < 0.001). In multivariable analyses including sex, age, resection status, UICC stage, and tumour regression grading, TB remained a stage‐independent predictor of survival (p < 0.001, hazard ratio Bd2: 2.60, Bd3: 4.74). The assessment of TB according to the ITBCC criteria provides valuable prognostic information in the post‐neoadjuvant setting of intestinal‐type GC and may be a considerable substitute for the conventional grading system in GCs after neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

We investigated the clinical impact of elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in the context of neoadjuvant chemotherapy (CTx) in gastric/gastro‐oesophageal adenocarcinomas. We analysed 583 resected tumours (272 without and 311 after CTx) and 142 tumour biopsies before CTx. If at least two or three of the five tetranucleotide repeat markers tested showed instability, the tumours were defined as EMAST (2+) or EMAST (3+), respectively. Expression of mismatch repair proteins including MSH3 was analysed using immunohistochemistry. Microsatellite instability (MSI) and Epstein–Barr virus (EBV) positivity were determined using standard assays. EMAST (2+) and (3+) were detected in 17.8 and 11.5% of the tumours, respectively. The frequency of EMAST (2+) or (3+) in MSI‐high (MSI‐H) tumours was 96.2 or 92.5%, respectively, demonstrating a high overlap with this molecular subtype, and the association of EMAST and MSI status was significant (each overall p < 0.001). EMAST (2+ or 3+) alone in MSI‐H and EBV‐negative tumours demonstrated only a statistically significant association of EMAST (2+) positivity and negative lymph node status (42.3% in EMAST (2+) and 28.8% in EMAST negative, p = 0.045). EMAST alone by neither definition was significantly associated with overall survival (OS) of the patients. The median OS for EMAST (2+) patients was 40.0 months (95% confidence interval [CI] 16.4–63.6) compared with 38.7 months (95% CI 26.3–51.1) for the EMAST‐negative group (p = 0.880). The median OS for EMAST (3+) patients was 46.7 months (95% CI 18.2–75.2) and 38.7 months (95% CI 26.2–51.2) for the negative group (p = 0.879). No statistically significant association with response to neoadjuvant CTx was observed (p = 0.992 and p = 0.433 for EMAST (2+) and (3+), respectively). In conclusion, our results demonstrate a nearly complete intersection between MSI‐H and EMAST and they indicate that EMAST alone is not a distinct instability type associated with noticeable clinico‐pathological characteristics of gastric carcinoma patients. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus positivity (EBV(+)) and high‐microsatellite instability (MSI‐H) have been identified as molecular subgroups in gastric carcinoma. The aim of our study was to determine the prognostic and predictive relevance of these subgroups in the context of platinum/5‐fluorouracil (5‐FU) based preoperative chemotherapy (CTx). Additionally, we investigated the clinical relevance of the low‐MSI (MSI‐L) phenotype. We analysed 760 adenocarcinomas of the stomach or the gastro‐oesophageal junction encompassing 143 biopsies before CTx and 617 resected tumours (291 without and 326 after CTx). EBV was determined by PCR and in situ hybridisation for selected cases. MSI was analysed by PCR using five microsatellite markers and classified as MSI‐H and MSI‐L. Frequencies of EBV(+), MSI‐H and MSI‐L in the biopsies before CTx were 4.2, 10.5 and 4.9% respectively. EBV(+) or MSI‐H did not correlate with response, but MSI‐L was associated with better response (p = 0.011). In the resected tumours, frequencies of EBV(+), MSI‐H and MSI‐L were 3.9, 9.6 and 4.5% respectively. Overall survival (OS) was significantly different in the non‐CTx group (p = 0.014). Patients with EBV(+) tumours showed the best OS, followed by MSI‐H. MSI‐L was significantly associated with worse OS (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.21–4.04, p = 0.01). In the resected tumours after CTx, MSI‐H was also associated with increased OS (HR, 0.54; 95% CI, 0.26–1.09, p = 0.085). In multivariable analysis, molecular classification was an independent prognostic factor in the completely resected (R0) non‐CTx group (p = 0.035). In conclusion, MSI‐H and EBV(+) are not predictive of response to neoadjuvant platinum/5‐FU based CTx, but they are indicative of a good prognosis. In particular, MSI‐H indicates a favourable prognosis irrespective of treatment with CTx. MSI‐L predicts good response to CTx and its negative prognostic effect for patients treated with surgery alone suggests that MSI‐L might help to identify patients with potentially high‐benefit from preoperative CTx. [ABSTRACT FROM AUTHOR]

Background: Standard of care primary treatment of carcinoma of locally advanced squamous cell head and neck cancer (LAHNSCC) consists of platinum-based concomitant chemo-irradiation. Despite progress in the treatment of LAHNSCC using modern radiotherapy techniques the outcome remains still poor. Using IMRT with SIB the escalation of total dose to the GTV is possible with the aim to improve clinical outcome. This study tests the hypothesis if radiation dose escalation to the GTV improves 2-year-LRC and -OS after concomitant chemo-irradiation.Methods: The ESCALOX trial is a prospective randomized phase III study using cisplatin chemo-irradiation and the SIB-IMRT concept in patients with LAHNSCC of the oral cavity, oropharynx or hypopharynx to escalate the total dose to the GTV up to 80.5 Gy. Chemotherapy is planned either in the 1st and 5th week (cisplatin 20 mg/m2/d d 1-5 and d 29-33) or weekly (cisplatin 40 mg/m2/d) during RT. RT is delivered as SIB with total doses of 80.5 Gy/70.0 Gy/56.0 Gy with 2.3 Gy/2.0 Gy and 1.6 Gy in the experimental arm and in the control arm with 70.0 Gy/56.0 Gy with 2.0 Gy and 1.6 Gy. A pre-study with dose escalation up to 77.0 Gy/70.0 Gy/56.0 Gy with 2.2 Gy/2.0 Gy and 1.6 Gy is demanded by the German federal office of radiation protection (BfS). In the translational part of the trial 100 of the randomised patients will be investigated by 18-F-FMiso-PET-CT for the presence and behaviour of tumor hypoxia twice in the week before treatment start.Discussion: The primary endpoint of the pre-study is acute radiation induced toxicity. Primary endpoint of the main trial is 2-year-LRC. By using the dose escalation up to 80.5 Gy to the GTV of the primary tumor and lymph nodes > 2 cm a LRC benefit of 15% at 2 years should be expected. The ESCALOX trial is supported by Deutsche Forschungsgemeinschaft (DFG); Grant No.: MO-363/4-1.Trial Registration: ClinicalTrials.gov Identifier: NCT 01212354 , EudraCT-No.: 2010-021139-15. [ABSTRACT FROM AUTHOR]

Background: NOTCH signaling can exert oncogenic or tumor suppressive functions and can contribute to chemotherapy resistance in cancer. In this study, we aimed to clarify the clinicopathological significance and the prognostic and predictive value of NOTCH1 and NOTCH2 expression in gastric cancer (GC). Methods: NOTCH1 and NOTCH2 expression was determined immunohistochemically in 142 primarily resected GCs using tissue microarrays and in 84 pretherapeutic biopsies from patients treated by neoadjuvant chemotherapy. The results were correlated with survival, response to therapy, and clinico-pathological features. Results: Primarily resected patients with NOTCH1-negative tumors demonstrated worse survival. High NOTCH1 expression was associated with early-stage tumors and with significantly increased survival in this subgroup. Higher NOTCH2 expression was associated with early-stage and intestinal-type tumors and with better survival in the subgroup of intestinal-type tumors. In pretherapeutic biopsies, higher NOTCH1 and NOTCH2 expression was more frequent in non-responding patients, but these differences were statistically not significant. Conclusion: Our findings suggested that, in particular, NOTCH1 expression indicated good prognosis in GC. The close relationship of high NOTCH1 and NOTCH2 expression with early tumor stages may indicate a tumor-suppressive role of NOTCH signaling in GC. The role of NOTCH1 and NOTCH2 in neoadjuvantly treated GC is limited. [ABSTRACT FROM AUTHOR]

Simple Summary: Here we report a sex- and age-specific analysis of 717 patients with gastric/gastro-esophageal adenocarcinomas treated with or without neoadjuvant chemotherapy (CTx) regarding overall survival (OS) and response to CTx. The analysis was also performed in molecular subtypes determined previously. Females demonstrated a significantly increased OS particularly in the group of patients treated with neoadjuvant CTx. Specifically in this patient group and taken into account the molecular subtypes, females with high microsatellite instability (MSI-H) showed the best survival followed by the male MSI-H, the female microsatellite stable (MSS) group and the male MSS group. Thus, we show an effect of sex on OS in gastric/gastro-esophageal cancer in particular for patients treated with neoadjuvant CTx. The superior survival of women with MSI-H tumors among the CTx patients implies that the combined consideration of these factors could contribute to an individualized treatment of the patients. We aimed to investigate patients with gastric/gastro-esophageal adenocarcinomas for sex- and age-specific differences regarding overall survival (OS) and response to neoadjuvant chemotherapy (CTx) under consideration of tumor specific molecular subtypes. Overall, 717 patients were analyzed, including 426 patients treated with and 291 treated without neoadjuvant CTx. Microsatellite instability (MSI) and Epstein-Barr virus positivity (EBV+) were determined previously. Females demonstrated a significantly increased OS (p = 0.035), particularly in the subgroup treated with CTx (p = 0.054). No significant differences regarding age were found. In the molecular subgroups, no sex-related differences were observed in the non-CTx group. However in the CTx group, females with MSI-high (H) tumors showed the best OS (p = 0.043), followed by the male MSI-H (p = 0.198) and female MSS (p = 0.114) compared to the male MSS group as reference. The interaction between sex and MSI in this patient group was noticeable (p = 0.053) and was included as a relevant factor in multivariable analyses. In conclusion, our results show an effect of sex on OS in gastric/gastro-esophageal cancer specifically for patients treated with neoadjuvant CTx. The superior survival of women with MSI-H tumors after neoadjuvant CTx implies that combined consideration of these factors could contribute to an individualized treatment of the patients. [ABSTRACT FROM AUTHOR]

We investigated the prognostic and predictive impact of p53 expression for gastric cancer (GC) patients treated without or with preoperative chemotherapy (CTx) and its relationship with specific molecular GC subtypes. Specimens from 694 GC patients (562 surgical resection specimens without or after CTx, 132 biopsies before CTx) were analyzed by p53 immunohistochemistry. High (H) and low (L) microsatellite instability (MSI) and Epstein–Barr virus positivity were determined previously. Our results show that aberrant p53 expression was a negative prognostic factor in uni- and multivariable analysis in the resection specimens cohort (each p < 0.01). Subgroup analysis showed the strongest prognostic effect for patients with distally located tumors or no CTx treatment. In the biopsy cohort before CTx, p53 did not predict response or survival. p53 expression was significantly different among the molecular subtypes in surgical resection and bioptic specimens with strong association of altered p53 with MSI-L. Patients with MSI-H and aberrant p53 showed the worst survival in the biopsy cohort. In conclusion, the prognostic impact of p53 in GC differs according to tumor localization and CTx. Altered p53 is characteristic for MSI-L, and the p53 status in biopsies before CTx delineates MSI-H subtypes with inverse prognostic impact. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: DNA methylation contributes to carcinogenesis by mediating transcriptional regulation and chromatin remodelling, which may influence the effect of DNA-damaging drugs. We examined the prognostic and predictive impact of DNA methyltransferase (DNMT) 1 and 3b expression in gastric carcinomas (GC) treated by neoadjuvant chemotherapy. In vitro, DNMT1 expression and chemosensitivity were investigated for a functional relationship and the DNMT inhibitor decitabine (DAC) was tested as an alternative treatment option. Patients and methods: DNMT1/3b expression was analysed immunohistochemically in 127 pretherapeutic biopsies of neoadjuvant (platinum/5-fluorouracil)-treated GC patients and correlated with response and overall survival (OS). Short hairpin RNA technology was used to knockdown DNMT1 in the GC cell line, AGS. The chemosensitivity of GC cell lines to DAC alone and to DAC in combination with cisplatin was analysed by XTT or colony formation assays. Results: High DNMT1 and DNMT3b expression was found in 105/127 (83%) and 79/127 (62%) carcinomas, respectively. Patients with low DNMT1 expression demonstrated a significantly better histopathological/clinical response (P =0.03/P =0.008) and OS (P log-rank =0.001). In vitro, knockdown of DNMT1 caused an increased chemosensitivity towards cisplatin. Combined treatment with cisplatin and DAC showed a synergistic effect leading to increased cytotoxicity in the cisplatin-resistant cell line AGS. Conclusion: Low DNMT1 expression defines a subgroup of GC patients with better outcomes following platinum/5FU-based neoadjuvant chemotherapy. In vitro data support a functional relationship between DNMT1 and cisplatin sensitivity. Besides its potential use as a predictive biomarker, DNMT1 may represent a promising target for alternative therapeutic strategies for a subset of GC patients. [Copyright &y& Elsevier]

Abstract: Purpose: We evaluated DNA polymorphisms in genes related to DNA repair, cell-cycle control and tumour microenvironment to determine possible associations with response and survival in neoadjuvant-treated gastric cancer patients. Patients and methods: One hundred and seventy eight patients who received platinum/5FU-based chemotherapy were genotyped for 10 polymorphisms in nine genes (ERCC1: Asn118Asn, C > T; ERCC1: 8092C>A; TP53: Arg72Pro, G A; STK15: Phe31Ile, A > T; VEGF: 936C > T; TNF-α: -308G > A; interleukin-1b (IL-1B): -511C > T; IL-1 receptor antagonist (IL-1RN): variable tandem repeat; IL-8: -251T > A). Genotypes were correlated with histopathological and clinical response and overall (OS) and progression-free survival (PFS). Results: Only the cyclinD1 genotypes were associated with clinical response (). Significantly worse survival rates were noted in patients homozygous for the G-allele as compared to patients with the AG or AA genotypes of the cyclinD1 polymorphism (OS: Plog-rank =0.024; PFS: Plog-rank =0.007) and in patients homozygous for the short allele compared to all other genotypes at the IL-1RN polymorphic locus (OS: Plog-rank =0.026; PFS: Plog-rank =0.013). The combination of both unfavourable genotypes demonstrated strong prognostic relevance (OS: Plog-rank =0.006; PFS: Plog-rank =0.001). Multivariate analysis for OS in the group of completely resected patients (n =139) revealed statistical significance for ypM (P <0.001), histopathological response (P <0.001) and the combined cyclinD1/IL-1RN genotypes (P =0.043). Conclusion: The cyclinD1 and IL-1RN polymorphisms were associated with survival. The combination of specific cyclinD1 and IL-1RN genotypes showed a particular prognostic relevance and should be considered an independent prognostic marker for neoadjuvant-treated gastric cancer patients. [Copyright &y& Elsevier]