Major Histopathological Response Research Articles

Surgical outcomes of patients with resectable non-small-cell lung cancer receiving neoadjuvant immunotherapy with nivolumab plus relatlimab or nivolumab: Findings from the prospective, randomized, multicentric phase II study NEOpredict-Lung.

8500 Background: Feasibility of surgical resection for non-small-cell lung cancer (NSCLC) after preoperative immune checkpoint inhibitor therapy (PICIT) with PD-1/PD-L1 and CTLA-4 inhibitors has been established. This study reports the first data on surgery after preoperative LAG-3 inhibition in NSCLC patients. Methods: Patients with histologically confirmed NSCLC stage IB, II or IIIA (UICC 8th edition) were randomized to receive two preoperative doses (q14d) of nivolumab (240 mg, arm A), or nivolumab (240 mg) plus relatlimab (80 mg, arm B). Primary study endpoint was the number of patients undergoing curatively intended surgery within 43 days of initiation of PICIT. Surgery was performed following the institutional standards. Outcomes and perioperative events were prospectively recorded. Results: 60 patients (29 female) were randomized 1:1 from 4/2020 to 7/2022. All patients were operated within 43 days after initiation of PICIT. Median age in arm A was 65 (43-78) years and 67 (44-81) years in arm B. Clinical UICC stages were similar between both arms. Central tumor location was present in 50% in arm A and 45% in arm B. R0 resection was achieved in 57 patients (95% ITT population, 98,3% curatively resected population). Two patients had pleural carcinosis only detected at surgery, and 1 patient had R1 resection. Resection was performed by lobectomy (n=23 and 24), bilobectomy (2 and 1), sleeve lobectomy (5 and 4) and combined lobectomy+segmentectomy (0 and 1). Surgical approach was either by videothoracoscopy (n=60% and 63,3%) or thoracotomy (n=40% and 36,6%). Conversion was required in 3 vs. 2 patients. Median operation time was 149 (77-234) and 165 (61-205) minutes. Median number of resected lymph nodes was 15 (3-52) and 10 (3-50). Intraoperative bleeding from the pulmonary artery was observed in 1 patient in each arm and was managed without sequelae. Postoperative complications occurred in 33,3% and 26,6%. Median hospital stay was 7 (2-22) and 5,5 (2-24) days. Complete or major histopathological response was observed in 27% and 30%. Overall perioperative 30-day mortality was 0%. No negative impact on adjuvant therapy was observed. The 12 months OS rate across both arms was 96% (95% Cl: 83-99%), the DFS rate was 91 % (78-97%). Conclusions: Curative surgical resection following neoadjuvant combined PD-1/LAG-3 inhibition was equally safe and feasible as after PD-1 inhibition alone. Perioperative course, complications rate and outcome are comparable to other neoadjuvant regimens. Standard adjuvant therapies can be safely administered in this setting. Clinical trial information: NCT04205552 .

Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO)

BackgroundThe IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC).MethodsIn a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable...

LBA37 A randomized, multicentric phase II study of preoperative nivolumab plus relatlimab or nivolumab in patients with resectable non-small cell lung cancer (NEOpredict-Lung)

Preoperative immune checkpoint inhibitor therapy (PICIT) is a promising approach in curative treatment of non-small-cell lung cancer (NSCLC). This study explores the feasibility and efficacy of targeting PD-1 and LAG-3 prior to resection. Patients with histologically confirmed NSCLC stage IB, II or IIIA (UICC 8th edition) were randomized to receive two preoperative doses (q14d) of nivolumab (240 mg, arm A), or nivolumab (240 mg) plus relatlimab (80 mg, arm B). The primary study endpoint was the feasibility of curatively intended surgery within 43 days of start of PICIT. Secondary endpoints include pathological and radiological response rates, disease-free and overall survival rates (DFS, OS) and safety. Exploratory endpoints are addressed by translational research. From March 4, 2020 to July 15, 2022, 60 patients have been randomized. The primary endpoint was met by all patients. R0 resection rate was 98%, excluding 2 patients with pleural carcinosis, which had been undetected by preoperative imaging. PICIT-related adverse events were as expected with grade ≥ 3 events in 4 (arm A) and 2 (arm B) patients. Two patients treated in arm A died within 90 days of surgery. The 12 months OS rate across both arms was 96% (95% CI: 83-99%), the DFS rate was 91% (78-97%). Radiological response rates were 11% (arm A) and 27% (arm B) per RECIST (full population), and 41% (arm A) and 38% (B) per PERCIST (30 patients from one center). Complete or major histopathological response rates were 28% (arm A) and 32% (arm B). In 60% (arm A) and 71% (arm B) of resections after PICIT ≤ 50% vital tumor cells were observed.Table: LBA37Arm A (nivolumab)Arm B (nivolumab/relatlimab)n [female, male]30 (15, 15)30 (13, 17)Age [years] (median, range)64 (43-77)65 (43-81)Histology- adenocarcinoma1315- squamous109- adenosquamous22- other54UICC stage- I B910- II A61- II B1116- III A33- other10PD-L1 [TPS]- 0%89- 1-49%1215- ≥50%106 Open table in a new tab Preoperative immune checkpoint inhibition with nivolumab and relatlimab is safe and feasible in patients with curatively resectable NSCLC. High histopathological response rates indicate clinical efficacy, which merits further study supplementing with biomarker analyses for future patient selection.

Clinical Utility of Circulating Tumor Cells for Predicting Major Histopathological Response after Neoadjuvant Chemoradiotherapy in Patients with Esophageal Cancer.

Background: A “surgery as needed” approach may be offered to patients with esophageal cancer (EC) who achieve major histopathological response (MaHR) after neoadjuvant chemoradiotherapy (nCRT). However, the utility of clinical response assessment (CRE) for predicting histopathological response to nCRT remains limited. Circulating tumor cells (CTCs) hold promise as biomarkers of response to nCRT. Methods: We analyzed the clinical utility of post-nCRT CTCs, alone or in combination with CRE, in the prediction of MaHR. We defined MaHR as either the lack or a limited presence (≤10%) of vital residual tumor cells in the resected esophageal specimen in the absence of nodal involvement. Results: Of the 48 study patients, 27 (56%) achieved MaHR. Patients with MaHR had a significantly lower CTCs count compared with those without (3.61 ± 4.53 versus 6.83 ± 5.22 per mL of blood, respectively; P = 0.027). Using a cutoff for positivity of 5 CTCs per mL of blood, the combination of CTCs and CRE allowed achieving a negative predictive value for MaHR of 93% (95% confidence interval [CI] = 70–99%) along with a false negative rate of 5% (95% CI = 1–33%). Conclusion: CTCs count assessed in combination with CRE can potentially help identify patients with EC who achieved MaHR after nCRT.

Perioperative EOX treatment in operable locally advanced gastroesophageal adenocarcinoma: Prediction of tumor response by FDG –PET and histopathology

PurposeThe aim of this retrospective single-center analysis was to evaluate the feasibility of fluorine-18 fluorodeoxyglucose (FDG)-PET imaging in evaluating metabolic response of preoperative chemotherapy in the treatment of locally advanced operable gastroesophageal adenocarcinoma and to investigate the association between histopathologic and FDG-PET response and overall survival. MethodsPatients with locally advanced adenocarcinoma of distal esophagus, gastroesophageal junction or stomach were assessed for the study during 2008–2012. After evaluation with endoscopy, computed tomography and FDG-PET, patients with clinical stage II or III disease were assigned for perioperative EOX (epirubicin-oxaliplatin-capecitabine) treatment targeted at three cycles both pre- and postoperatively, if possible. Metabolic response was evaluated by repeated FDG-PET during or right after the second chemotherapy cycle. Becker tumor regression grade (TRG) was used to evaluate histopathologic response. For statistical purposes, the clinically significant cut-off for tumor maximum standardized uptake value (SUVmax) change (SUVδ%) was set at −35%. Results54 patients were included in the study. 53 PET images were obtained before chemotherapy, 11 (21%) of those were PET negative. A major metabolic response was detected in 19 patients and major histopathologic response in 14 patients. No statistically significant association was observed between SUVδ% and histopathological responses. Median overall survival (OS) time of the patients was 49.9 months. No association between OS and PET response was found in our study. The administration of all six cycles of perioperative EOX was associated with improved OS. ConclusionsFollow-up PET during or right after second preoperative chemotherapy cycle did not assist in identifying patients with favorable histopathological response or OS.

P2.02-055 Pathologic Mediastinal Nodal and Metabolic Tumor Response to Predict Overall Survival in Stage IIIA-N2 NSCLC after Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy (NCT) is a therapeutic option that is used in patients with resectable stage IIIA-N2 NSCLC. We previously hypothesized that combined major histopathological mediastinal nodal response (≤10% residual tumor cells in nodal tissue) and metabolic FDG-PET response (ΔSUVmax ≥60%) on the primary tumor could be regarded as a powerful surrogate of overall survival (OS) in stage IIIA-N2 NSCLC given NCT and confirmed mediastinal nodal disease at diagnosis. This phase II prospective multicenter study aimed to validate the predictive power for OS of our restaging algorithm. Patients with resectable stage IIIA-N2 NSCLC having mediastinal nodal disease proven by endosonography and primary tumor SUVmax at least 2.5 were eligible. All patients were scheduled for 3 cycles of NCT followed by video-assisted mediastinoscopy (VAM). A standardized PET/CT was performed at baseline, after one and three cycles. The primary endpoint was the predictive power for longer OS of a major histopathological mediastinal nodal response at VAM combined with a pre-defined primary tumor ΔSUVmax ≥60% at PET (good prognosis group) compared to all other situations (poor prognosis group). Under an assumption of a 2-year OS of 80% compared to 30% for the good versus poor prognosis group, respectively, 48 patients were required to have 80% power with 2-sided alpha of 0.05. We enrolled 32 patients between 2009 and 2014. Two patients demonstrated stage IV at PET/CT after cycle one. All 3 cycles were given to 30 patients of whom 29 underwent VAM and 22 underwent surgical resection. Objective response rate (RECIST 1.1) was 44%. Complete pathological response occurred in 2 patients. Median OS was 26 months (all 2-year events occurred). In ITT, combined major histopathologic nodal and metabolic tumor response was associated with a trend towards longer OS (HR 0.29, 95%CI 0.14-1.09, P=0.07). Major histopathologic mediastinal nodal response was significantly associated with longer OS (HR 0.25, 95%CI 0.02-0.51, P=0.006), while metabolic ΔSUVmax ≥60% primary tumor response was only associated with a trend towards better OS (HR 0.41, 95%CI 0.17-1.27, P=0.14). Complete pathological response to NCT in stage IIIA-N2 NSCLC is infrequent and therefore not useful as a surrogate for OS. Combined major pathologic nodal and metabolic tumor response was associated with a trend towards longer OS. By contrast, a major histopathologic mediastinal nodal response with ≤10% residual tumor cells at VAM is well suited to be adopted as a surrogate of OS.

Prognosis of patients with esophageal squamous cell carcinoma who achieve major histopathological response after neoadjuvant chemoradiotherapy

BackgroundThe purpose of this study was to investigate the prognosis and its predictors in patients with esophageal squamous cell carcinoma (ESCC) who achieve major histopathological response (MaHR) after neoadjuvant chemoradiotherapy (nCRT). MethodsWe examined a total of 187 ESCC patients who achieved MaHR following nCRT and survived the perioperative period. MaHR was defined as either absence or <10% vital residual tumor cells (VRTC) in the resected esophagus without nodal involvement. Univariate and multivariate analyses were used to identify factors significantly associated with overall survival (OS). ResultsAt the time of analysis, 113 patients (60.4%) were dead (5-year OS = 48%; median survival time = 54.8 months). The amount of VRTC (1–10% versus 0% VRTC; hazard ratio [HR] = 1.9, P < 0.001) and the thoroughness of histopathological examination (standard [≤ 4 tumor blocks] versus thorough [> 4 tumor blocks], HR = 1.57; P = 0.013) were independent predictors of OS in multivariate analysis. A stepwise increase in OS was observed in the following groups: patients with 1–10% VRTC identified by the standard protocol, patients with 1–10% VRTC identified by the thorough protocol, patients with 0% VRTC identified by the standard protocol, and patients with 0% VRTC identified by the thorough protocol (5-year OS rates = 20%, 40%, 50%, and 62%, respectively, P < 0.001). ConclusionsIn ESCC patients who achieve MaHR after nCRT, the presence of microscopical residual disease and the thoroughness of histopathological examination are associated with survival.

Morphological aspects of the hepatic response to neoadjuvant therapy

IntroductionTherapy of metastatic colorectal carcinoma has greatly evolved in recent years. Surgery is still the best curative option and can improve survival in stage IV disease. Neoadjuvant chemotherapy (NAC) has emerged as a widely used therapeutic option before surgery. Pathologists have developed several systems to grade response, mainly adapting the grading systems used for the response in primary esophageal or rectal tumors. There are many reports confirming the prognostic utility of these grading systems. However, there have been fewer references to the potential significance of the pattern of histological response. The objective of the present study is to describe the histopathological lesions found in the tumor bed after NAC and their potential significance in terms of prognosis. Material and methodsWe reviewed the files of patients with colorectal carcinoma that developed hepatic metastasis during follow-up and received NAC before surgical resection of metastasis. We gathered demographic, analytical and morphological data of the cases, and also reviewed the hepatic resection samples to measure the pathological response to chemotherapy according to Blazer's criteria, and to define the predominant patterns of response (mucin pools, fibrosis or necrosis). We also determined the presence of satellitosis, measured the thickness of the tumor-normal interface (TNI) as proposed by Maru et al., and searched for vascular and bile duct invasion. All these pieces of information were collected in an Excel database and analyzed with SPSS 20.0 for Windows statistical package. The outcome measures were disease-free survival and overall survival in months since the first surgery to resect metastatic disease. ResultsFifty patients fulfilled the inclusion criteria for the present study. All of them had received a chemotherapeutic regimen mainly based on platinum, associated or not with targeted drugs (18% received anti-EGFR drugs and 24% anti-VEGFR drugs). Of the primaries, 66% were of sigmoid-rectal origin, and 32% of the cases showed a major histopathological response to therapy (including 3 cases with a complete response). In 76% of the tumors, the predominant histological pattern was necrosis, followed by fibrosis (57.4%). Mucin pools were the predominant feature in 23.4% of the tumors. We found satellitosis (microscopic tumor nodules separated by more than 1mm from the principal tumor) in 53.2% of the cases. A prominent inflammatory reaction was found in 19% of the cases, and it was mainly composed of lymphocytes and hystiocytes (70% of the cases). Vessel invasion was seen in 30% of the cases, and perineural invasion was only found in 4%. We found no case of bile duct invasion by the tumor. The thickness of the TNI measured less than 2.5mm in 60% of the present series. Statistical analysis of the series revealed that thickness of the tumor-liver interface was significantly associated with recurrence and overall survival. We found a significant association between response and thickness of the tumor-normal liver interface. In our series, the presence of satellitosis tended to predict a shorter DFS. The comparison of Kaplan–Meier curves with the log-rank test showed a significant association between overall survival and the presence of mucin pools and fibrosis in the tumor bed. The other histopathological factors did not predict differences in prognosis. These differences were independent of the use of targeted drugs. DiscussionThe pathological reports of hepatic metastasis from colorectal carcinoma resected after NAC usually indicate only the number, the size and the response of the tumor cells to therapy, apart from the distance to the resection margin of the specimen. Few reports have analyzed the possible prognostic significance of the different kinds of histopathological responses. The results of the present study indicate that those tumors with extensive pools of mucin show a significantly worse prognosis as compared to tumors with less mucin secretion. Fibrosis indicates a better prognosis, except when desmoplasia is present. Our study further supports the prognostic significance of the thickness of the tumor-hepatic interface. We conclude that pathology reports should specify the kind of histopathological response to therapy, besides grading it, because this might add significant prognostic information.

Serum microRNA profiles as prognostic or predictive markers in the multimodality treatment of patients with gastric cancer.

Despite the implementation of multimodality treatment strategies, the persistently poor prognosis of gastric cancer patients is predominantly caused by the lack of predictive markers for response assessment in the neoadjuvant setting, preventing individualized therapy. Therefore, the identification of novel predictive and prognostic markers for application in the multimodality treatment of gastric cancer patients is required. The aim of the present study was to characterize the serum microRNA (miRNA/miR) profile of gastric cancer patients undergoing multimodality therapy to identify possible prognostic and predictive markers. The study consisted of 32 patients with gastric cancer who had undergone either primary surgical resection (n=14) or neoadjuvant therapy followed by surgical resection (n=18). Histopathological regression was defined as a major histopathological response when the resected specimens contained <10% vital residual tumor cells. Intratumoral miRNA was isolated from pre-operative or post-neoadjuvant blood serum samples. Initially, microarray analyses were performed in six of the patients that received neoadjuvant treatment (three responders versus three non-responders), to assess the amplification profile of dysregulated miRNAs. Based on these findings, possible predictive or prognostic markers were validated in all study patients by performing single reverse transcription-polymerase chain reaction (RT-PCR) analysis. Depending on the extent of the histopathological regression, a differential miRNA expression profile was identified in the microarray analyses. Based on the amplification profile, miR-21, miR-29a and miR-221 were selected for additional validation. However, the single RT-PCR measurements of the three selected miRNAs did not exhibit any prognostic or predictive value in the patients treated with primary resection or neoadjuvant therapy and resection. Thus, the current pilot study failed to identify a prognostic or predictive value in selected miRNAs using single RT-PCR measurements, however, the microarray results revealed a differential microRNA expression profile depending on the histopathological regression. The findings of the present study may have been affected by the small sample size.

Neoadjuvant treatment for advanced esophageal cancer: response assessment before surgery and how to predict response to chemoradiation before starting treatment.

Patients with advanced esophageal cancer (T3-4, N) have a poor prognosis. Chemoradiation or chemotherapy before esophagectomy with adequate lymphadenectomy is the standard treatment for patients with resectable advanced esophageal carcinoma. However, only patients with major histopathologic response (regression to less than 10% of the primary tumor) after preoperative treatment will have a prognostic benefit of preoperative chemoradiation. Using current therapy regimens about 40% to 50% of the patients show major histopathological response. The remaining cohort does not benefit from this neoadjuvant approach but might benefit from earlier surgical resection. Therefore, it is an aim to develop tools for response prediction before starting the treatment and for early response assessment identifying responders. The current review discusses the different imaging techniques and the most recent studies about molecular markers for early response prediction. The results show that [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) has a good sensitivity but the specificity is not robust enough for routine clinical use. Newer positron emission tomography detector technology, the combination of FDG-PET with computed tomography, additional evaluation criteria and standardization of evaluation may improve the predictive value. There exist a great number of retrospective studies using molecular markers for prediction of response. Until now the clinical use is missing. But the results of first prospective studies are promising. A future perspective may be the combination of imaging technics and special molecular markers for individualized therapy. Another aspect is the response assessment after finishing neoadjuvant treatment protocol. The different clinical methods are discussed. The results show that until now no non-invasive method is valid enough to assess complete histopathological response.

Serum microRNA profiles as prognostic/predictive markers in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction.

Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis of locally advanced adenocarcinomas of the gastroesophageal junction. This study aimed to asses if serum microRNA profiles are useable as response indicators in this therapeutic setting. Fifty patients with locally advanced adenocarcinomas of the gastroesophageal junction were included in the study. All patients received neoadjuvant therapy and subsequently underwent surgical resection. Histomorphologic regression was defined as major histopathological response when resected specimens contained less than 10% vital residual tumor cells. Circulating RNA was isolated from pretherapeutic/post-neoadjuvant blood serum samples. RNA from nine patients was applied to PCR microarray analyses Based on these findings possible predictive miRNA markers were validated by quantitative RT-PCR analyses. Depending on the histomorphologic regression, a differential serum microRNA profile was identified by microarray analyses. Based on the divergent miRNA pattern, miR-21, miR-192, miR-222, miR-302c, miR-381 and miR-549 were selected for further validation. During neoadjuvant therapy, there was a significant increase of miR 222 and miR-549. Although on an expanded patient cohort, the six microRNAs could not be validated as markers for therapy response, there was a significant correlation between a high miR-192 and miR-222 expression with a high T-category as well as miR-302c and miR-222 expression significantly correlated with overall survival. Comprehensive miRNA profiling showed a differential microRNA expression pattern depending on the histomorphologic regression in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction. Moreover, using single RT-PCR analyses a prognostic impact of miR-222 and miR-302c was detected.

ERCC1 expression and tumor regression predict survival in esophageal squamous cell carcinoma patients receiving combined trimodality therapy

PurposeCombined trimodality therapy with neoadjuvant chemoradiation followed by surgery has shown promising results for locally advanced operable esophageal cancer. DNA repair proteins may affect treatment efficacy through repairing DNA damage induced by chemotherapy and radiation therapy. We evaluated the associations of XRCC1, ERCC1 and MGMT expression with histopathologic response and survival in patients with locally advanced operable esophageal squamous cell carcinoma (ESCC) who received neoadjuvant chemoradiation. MethodsParaffin-embedded pre-treatment tissue samples, collected by endoscopic biopsy from patients treated with cisplatin-based neoadjuvant chemoradiation followed by surgery, were immunohistochemically stained for XRCC1, ERCC1 and MGMT expression. ResultsOf the 44 patients, major histopathologic response was noted in 26 (59.1%) patients. 68.8% of patients with ERCC1-negative tumors had major histopathologic response, compared to 53.6% of those who expressed positive ERCC1, though the difference was not statistically significant (P=0.361). The patients with ERCC1-negative tumor presented much better overall survival than those positive for ERCC1 expression (P=0.018). Patients with major histopathologic response had a 3-year survival rate of 96.2% versus those with minor response, with a 3-year survival rate of 41.5% (P=0.000). Multivariate analysis showed that ERCC1 expression and histopathologic response were independent predictive factors of overall survival in patients with locally advanced operable ESCC receiving neoadjuvant chemoradiation. ConclusionPatients with ERCC1-negative tumors show a benefit from neoadjuvant chemoradiation, ERCC1 expression and tumor regression are useful predictive markers in patients with locally advanced operable ESCC receiving neoadjuvant chemoradiation followed by surgery.

Interim endoscopy results during neoadjuvant therapy for gastric cancer correlate with histopathological response and prognosis

Neoadjuvant chemotherapy for locally advanced gastric cancer leads to major histopathological response in less than 30% of patients. Data on interim endoscopic response assessment do not exist. This exploratory prospective study evaluates early endoscopy after 50% of the chemotherapy as predictor for later response and prognosis. Forty-seven consecutive patients were included (45 resected; 33 R0 resections). All patients received baseline endoscopy and CT scans, after 50% of their chemotherapy (EGD-1, CT-1) and after completion of chemotherapy (EGD-2, CT-2). Interim endoscopic response (EGD-1) was assessed after having received 50% (6weeks) of the planned 12weeks of neoadjuvant chemotherapy. Post-chemotherapy response was clinically assessed by a combination of CT scan (CT-2) and endoscopy (EGD-2). Histopathological response was determined by a standardized scoring system (Becker criteria). Endoscopic response was defined as a reduction of >75% of the tumor mass. Twelve patients were responders at EGD-1 and 13 at EGD-2. Nine patients (19.1%) were clinical responders and 7 patients (15.6%) were histopathological responders after chemotherapy. Specificity, accuracy, and negative predictive value of the interim EGD-1 for subsequent histopathological response were 31/38 (82%), 36/47 (76%), and 31/33 (93%); and for recurrence or death, 28/30 (93.3%), 38/47 (80.9%), and 28/35 (80.0%). Response at EGD-1 was significantly associated with histopathological response (p=0.010), survival (p<0.001), and recurrence-free survival (p=0.009). Interim endoscopy after 6weeks predicts response and prognosis. Therefore, tailoring treatment according to interim endoscopic assessment could be feasible, but the findings of this study should be validated in a larger patient cohort.

MicroRNA profiling in locally advanced esophageal cancer indicates a high potential of miR‐192 in prediction of multimodality therapy response

To identify possible predictive markers, our study aimed to characterize microRNA (miRNA) profiles of responder and nonresponder in the multimodality therapy of locally advanced esophageal cancer. Initially, a microarray-based approach was performed including eight patients with esophageal cancer. Patients received neoadjuvant chemoradiation followed by surgical resection. Major histopathological response was defined if resected specimens contained less than 10% vital tumor cells (major/minor response: 4/4 patients). Intratumoral RNA was isolated from both, pretherapeutic tissue biopsies in addition to corresponding surgical specimens. The profile of 768 miRNAs was analyzed in 16 specimens (preneoadjuvant and postneoadjuvant therapy). Selected miRNAs were than analyzed on pretherapeutic and post-therapeutic biopsies of 80 patients with esophageal cancer, who underwent multimodality therapy (major/minor response: 30/50 patients). Comprehensive miRNA profiling identified miRNAs in pretherapeutic biopsies that were significantly different between major/minor responders. Based on the microarray results, miR-192, miR-194 and miR-622 were selected and the dysregulated miRNAs were studied on an extended series of esophageal cancer patients. The expression of miR-192, miR-194 and miR-622 was significantly reduced after neoadjuvant therapy confirming the array profiling data. Importantly, the pretherapeutic intratumoral expression of miR-192 and miR-194 was significantly associated with the histopathologic response of esophageal squamous cell carcinoma to multimodal therapeutic treatment. Therefore, in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiation followed by esophagectomy, miR-192 and miR-194 in pretherapeutic biopsies are considered as indicators of major histopathologic regression.

β-catenin and Her2/neu expression in rectal cancer: association with histomorphological response to neoadjuvant therapy and prognosis

Neoadjuvant treatment strategies have been developed to improve survival of patients with advanced rectal cancer. Since mainly patients with major histopathological response benefit from this therapy, predictive and prognostic markers are needed. We examined the association of β-catenin and Her2/neu protein expression with histopathologic response to neoadjuvant radiochemotherapy and prognosis in patients with locally advanced rectal cancer. Fifty-four patients (33 male; 21 female; median age 60.4 years) with locally advanced rectal cancer were included in this study. All patients received a neoadjuvant radiochemotherapy (50.4 Gy, 5-FU) followed by surgical resection. Histomorphologic regression was evaluated by Dworak and Cologne staging system. Major response was defined by Dworak classification when resected specimens contained less than 50% vital tumor cells (n = 14) and by Cologne grading system when resected specimens contained less than 10% vital tumor cells (n = 15). Intratumoral β-catenin (nuclear/membranous) and Her2/neu (cytoplasmatic/membranous) expression was determined by immunohistochemistry in pre- and post-therapeutic specimens and correlated with clinicopathologic parameters. A significant association was detected between pre-therapeutic membranous β-catenin levels and response: patients with a lower β-catenin protein expression showed significantly more often a major response compared with patients having high intratumoral protein levels (p = 0.011). In addition, patients with a higher Her2/neu protein expression showed a significant survival benefit compared with patients having low intratumoral protein levels (5-year survival rate: 81% vs. low 41%; p = 0.023). The pre-therapeutic β-catenin and Her2/neu protein expression seem to be valuable predictive and prognostic markers in the multimodality treatment of advanced rectal cancer.

Impact of ABCB1 C3435T Polymorphism on Lymph node Regression in Multimodality Treatment of Locally Advanced Esophageal Cancer

Neoadjuvant treatment strategies have been developed to improve the survival of patients with locally advanced esophageal cancer. Since patients with major histopathological response are the ones who mainly benefit from this therapy, we are looking for causes of nonresponse. The multidrug resistance protein ABCB1 belongs to the ATP-binding cassette superfamily of membrane transporters. By exporting positively charged drugs it plays a role in the acquisition of resistance in anticancer therapy. We examined the ABCB1 gene polymorphism C3435T to predict response and prognosis to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil and 36 Gy) in locally advanced esophageal cancer patients. A total of 262 patients (216 male; 46 female; median age: 62 years) with locally advanced esophageal cancer (squamous cell cancer: n = 116, adenocarcinoma: n = 146) were included in this study. All patients received a neoadjuvant radiochemotherapy (36.0 Gy, 5-fluorouracil, cisplatin) followed by surgery. Histomorphologic regression was classified according to the Cologne Regression Grade with major response being classifed as having less than 10% vital tumor cells (n = 107) and minor response when 10% or more vital tumor cells (n = 155) were detected in the surgical specimen. Genomic DNA was extracted from paraffin-embedded tissues of all study patients. Allelic genotyping was performed for ABCB1 rs1045642 by real-time PCR using two allele-specific TaqMan(®) probes in competition. Allelic genotyping was correlated with therapy response and prognosis. Allelic discrimination revealed a TT genotype in 27%, a CC in 19% and a CT genotype in 54% of the study patients. This SNP was not predictive for response of the primary tumor to neoadjuvant radiochemotherapy. The ABCB1 genotype CC was associated with lymph node formation (p = 0.012) and distant metastases (p = 0.019). Patients with a TT genotype exhibited a significantly less positive lymph node status (ypN1 35%) after chemoradiation compared with patients with a CC (ypN1 = 60%) or CT (ypN1 = 46%) genotype. Moreover, patients bearing the TT genotype exhibited no distant metastasis, while five patients with a CC and two patients with CT genotype had distant metastases. In Kaplan-Meier curves, adenocarcinoma patients with a CC genotype showed a worse survival rate than patients with TT or CT (p = 0.048). Our data supports the impact of ABCB1 on effectiveness of esophageal cancer treatment. SNPs of ABCB1 could be helpful in predicting lymph node regression in the multimodality treatment of locally advanced esophageal cancer.

Impact of PET‐CT on Primary Staging and Response Control on Multimodal Treatment of Esophageal Cancer

The predictive value of positron emission tomography-computed tomography (PET-CT) in primary staging and response control in patients with esophageal carcinoma (EC) is under discussion. In the present study initial staging and metabolic response of PET-CT was correlated with tumor regression and survival in patients with multimodal treatment of EC. The authors conducted a retrospective analysis on a prospective database for 83 patients with EC (42 squamous cell, 39 adenocarcinoma, 2 anaplastic carcinoma) undergoing PET-CT for primary staging. Twenty-four of the patients underwent primary esophagectomy, 9 had palliative treatment, and 50 neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil; 50.4 Gy). The PET-CT study was repeated 6 weeks after induction of chemotherapy and compared with endoscopic ultrasound (EUS). For response control, the metabolic response (tumor standardized uptake value [SUV] reduction) was correlated with histopathologic (ypT0-4) and histomorphologic response (tumor regression) and survival. At primary staging 81 of 83 EC (97.5%) showed an increased SUV uptake correlating with the EUS tumor stage. Suspicious lymph nodes were detected in 51 (61.4%) patients by PET-CT and 66 (79.5%) were detected by EUS. Fifteen patients had additional findings on PET-CT examination leading to a change in therapy in 9 patients (10.3%). Of 50 patients receiving a second PET-CT study, a SUV reduction >50% correlated with major histomorphologic response (tumor regression grade 4, <10% vital tumor cells) and histopathologic response (ypT0 ypN0). Furthermore, these patients showed a significantly increased survival (33.1 ± 3.5 months) compared to non-responders (21.7 ± 3.3 months; p = 0.02) and patients after primary surgery (29 ± 3.2 months; p = 0.05). The present study shows that PET-CT is a valuable tool for primary staging and response control in multimodal treatment of patients with EC.

X-Ray Cross-Complementing Group 1 and Thymidylate Synthase Polymorphisms Might Predict Response to Chemoradiotherapy in Rectal Cancer Patients

5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series. A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m(2)/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG) as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5). The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR_C677 and MTHFR_A1298 expression. XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.

Chimioradiothérapie préopératoire des adénocarcinomes du pancréas : évaluation anatomopathologique de l’efficacité thérapeutique

Purpose Several phase II studies have shown the feasibility of neoadjuvant chemoradiation regimens for resectable localized pancreatic adenocarcinoma. However, there is to date no completed phase III study to validate this approach and treatment effects evaluation still remains an active area of investigation. From the mature results of the SFRO-FFCD 9704 trial, we explored the antitumoral effect of a 5-fluoro-uracil and cisplatin-based preoperative chemoradiation regimen, with a special highlight on the histopathological response and performed a literature review. Patients and methods Treatment consisted of concurrent radiotherapy (50 Gy within five weeks) and chemotherapy with 5-fluoro-uracil (300 mg/m 2/day, five days/week, weeks 1–5) and cisplatin (20 mg/m 2/day, days 1–5 and 29–33), followed by surgical resection of the pancreatic tumour in patients without progression. Results In all, 41 patients were enrolled, 26 patients (63%) underwent surgical resection with curative intent and 21 (80.7%) had R0 resection. A total of 13 of 26 specimens (50%) presented a major pathologic response (≥ 80% of severely degenerative cancer cells), with one complete pathologic response. The local recurrence and two-year survival rates were 4 and 32%, respectively, for the 26 operated patients. Conclusion Our results suggest that preoperative chemoradiation provides antitumoral effect associated with major histopathological response in 50% of patients and a high R0 resection rate. Evaluation of histopathological response to neoadjuvant chemoradiation may serve as a surrogate marker for treatment efficacy and further research is needed to determine new prognostic and predictive factors of treatment response.

Pancreatic surgery in France

In 2006, French cancer registries showed that pancreatic cancer was ranked 14th for estimated incidence (8.7/100,000) and mortality 11.4/100,000) for men, and 12th for women (5.1/100,000 and 7.4/100,000) (age-standardized rate). Long-term survival after pancreatectomy has become a reality, albeit in only a small number of patients. A series of 30 patients who survived more than 5 years postoperatively was collected from three French institutions and was published in 2008. The results of a trial using preoperative chemoradiation in potentially resectable pancreatic adenocarcinoma (French phase II FFCD 9704-SFRO trial) suggested that some tumors are chemoradiosensitive. It further suggested that preoperative chemoradiation provides an antitumor effect, which is associated with a major histopathological response in 50% of patients. Since the quality of assessment is of major concern for surgeons and for national health authorities, there is a current prospective evaluation of the role of resection margins and lymph node invasion (with precise identification of the status of superior mesenteric artery lymph nodes and nerve plexus), and the adequacy of the surgical procedure and prognosis that is ongoing in France. The objectives of this trial are to define and standardize quality criteria for surgical resection and histopathological examination of surgical specimens.