Preoperative sequential short-course radiation therapy and FOLFOX chemotherapy versus long-course chemoradiotherapy for locally advanced rectal cancer: a multicenter, randomized controlled trial (SOLAR trial).

BACKGROUND: Preoperative (chemo)radiotherapy has been widely used as an effective treatment for locally advanced rectal cancer (LARC), leading to a significant reduction in pelvic recurrence rates. Because early administration of intensive chemotherapy for LARC has more advantages than adjuvant chemotherapy, total neoadjuvant therapy (TNT) has been introduced and evaluated to determine whether it can improve tumor response or treatment outcomes. This study aims to investigate whether short-course radiotherapy (SCRT) followed by intensive chemotherapy improves oncologic outcomes compared with traditional preoperative long-course chemoradiotherapy (CRT). METHODS: A multicenter randomized phase II trial involving 364 patients with LARC (cT3-4, cN+, or presence of extramural vascular invasion) will be conducted. Patients will be randomly assigned to the experimental or control arm at a ratio of 1:1. Participants in the experimental arm will receive SCRT (25 Gy in 5 fractions, daily) followed by four cycles of FOLFOX (oxaliplatin, 5-fluorouracil, and folinic acid) as a neoadjuvant treatment, and those in the control arm will receive conventional radiotherapy (45-50.4 Gy in 25-28 fractions, 5 times a week) concurrently with capecitabine or 5-fluorouracil. As a mandatory surgical procedure, total mesorectal excision will be performed 2-5 weeks from the last cycle of chemotherapy in the experimental arm and 6-8 weeks after the last day of radiotherapy in the control arm. The primary endpoint is 3-year disease-free survival, and the secondary endpoints are tumor response, overall survival, toxicities, quality of life, and cost-effectiveness. DISCUSSION: This is the first Korean randomized controlled study comparing SCRT-based TNT with traditional preoperative LC-CRT for LARC. The involvement of experienced colorectal surgeons ensures high-quality surgical resection. SCRT followed by FOLFOX chemotherapy is expected to improve disease-free survival compared with CRT, with potential advantages in tumor response, quality of life, and cost-effectiveness. TRIAL REGISTRATION: This trial is registered at Clinical Research Information under the identifier Service KCT0004874 on April 02, 2020, and at Clinicaltrial.gov under the identifier NCT05673772 on January 06, 2023.

Rebamipide for the Improvement of Gastric Atrophy and Intestinal Metaplasia: A Prospective, Randomized, Pilot Study.

BACKGROUND: The presence of atrophic gastritis (AG) and intestinal metaplasia (IM) is associated with an increased risk of gastric cancer (GC). Thus, the development of new strategies to improve AG/IM is essential for reducing the incidence of GC. AIMS: We aimed to evaluate the efficacy of rebamipide for improving AG/IM. METHODS: This was a prospective, randomized, pilot study from a single tertiary referral center. Fifty-three (rebamipide, n = 34 vs. placebo, n = 19) patients, who underwent endoscopic resection for gastric dysplasia or early GC, were analyzed. We obtained tissue samples from the antrum and corpus of the stomach, at the time of screening and 1-year later. The histologic grading of inflammation was performed by histopathologists RESULTS: The AG grade in the antrum improved significantly after rebamipide treatment (pre-administration, 1.870 ± 0.932 vs. post-administration, 1.430 ± 0.986; P = 0.013). Additionally, the severity of IM in the antrum was significantly improved (pre-administration, 1.750 ± 0.963 vs. post-administration, 1.370 ± 1.032; P = 0.038). The rebamipide subgroup analysis revealed that patients with no Helicobacter pylori (HP) infection showed significant improvements in AG in the antrum (pre-administration, 1.880 ± 1.040 vs. post-administration, 1.250 ± 0.894; P = 0.028) and IM in antrum (pre-administration, 1.840 ± 1.012 vs. post-administration, 1.180 ± 0.912; P = 0.020). CONCLUSIONS: This study demonstrated that the administration of rebamipide improves AG and IM in the antrum, especially in patients with HP non-infection (KCT0001915).

Prognostic Value of Venous Invasion Detected by Elastin Stain May Surpass Lymph Node Status in Colon Cancer.

BACKGROUND: Venous invasion is a poor prognostic factor in colon cancer but is often underreported with significant variability. OBJECTIVES: We aimed to determine the impact of an elastin stain on venous invasion detection in colon cancer and evaluate the value of venous invasion in predicting disease recurrence in combination with lymph node status and other prognostic factors. DESIGN: This is a retrospective analysis of a prospectively collected database. SETTING: This study was conducted at a tertiary cancer center. PATIENTS: A total of 418 patients who underwent curative resection for stage I to III colon cancer and routinely adopted an elastin stain were evaluated. MAIN OUTCOME MEASURES: Venous invasion detection rate after adopting elastin stain, prognostic factors influencing disease recurrences by multivariate Cox regression models, and survival were measured. The zones of lymph node metastasis were defined as LNZ1, LNZ2, and LNZ3, corresponding to metastases in the pericolic, intermediate, and apical nodes. RESULTS: Venous invasion detection rate increased from 11.3% to 35.4% compared with the previous period in which only hematoxylin and eosin stain was performed. Cox regression analysis showed venous invasion (HR, 3.856; 95% CI, 1.249-11.910; p = 0.019) and lymph node metastases (HR, 3.156; 95% CI, 1.094-9.108; p = 0.034) in all stages and LNZ 2, 3 (HR, 2.649; 95% CI, 1.244-5.640; p = 0.012) in stage III to be significantly associated with poor disease-free survival. When stratifying all patients by these 3 factors, patients with stage III [LNZ1/venous invasion (-)] had disease-free survival comparable with stage I, but significantly better disease-free survival than those with stage II [venous invasion (+)] (p = 0.018). Patients with stage II [venous invasion (+)] had better disease-free survival by using adjuvant chemotherapy (p < 0.001). LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Elastin stain contributed to a considerable increase in venous invasion detection. Venous invasion can be a powerful predictor of poor disease-free survival beyond lymph node metastases when limited to the pericolic area and is useful for deciding the use of adjuvant chemotherapy in stage II colon cancer. See Video Abstract at http://links.lww.com/DCR/B573. EL VALOR PRONSTICO DE LA INVASIN VENOSA DETECTADA POR LA TINCIN DE ELASTINA PUEDE SUPERAR EL ESTADO DE LOS GANGLIOS LINFTICOS EN EL CNCER DE COLON: ANTECEDENTES:Invasión venosa (IV) es un factor de mal pronóstico en el cáncer de colon, que frecuentemente no se informa con una variabilidad significativa.OBJETIVOS:Nuestro objetivo fue determinar el impacto de tinción de elastina en la detección de IV en el cáncer de colon y evaluar el valor de IV en la predicción de la recurrencia de la enfermedad en combinación con el estado de los ganglios linfáticos y otros factores pronósticos.DISEÑO:Este es un análisis retrospectivo de una base de datos recopilada prospectivamente.ENTORNO CLINICO:Este estudio se realizó en un centro oncológico de referencia de tercer nivel.PACIENTES:Se valoraron un total de 418 pacientes sometidos a resección curativa por cáncer de colon en estadio I-III utilizando de manera rutinaria una tinción de elastina.PRINCIPALES MEDIDAS DE VALORACION:Se midieron la tasa de detección de IV después de adoptar la tinción de elastina, los factores de pronóstico que influyen en las recurrencias de la enfermedad mediante modelos de regresión de Cox multivariados y la supervivencia. La zona de metástasis ganglionares se definió como, LNZ1, LNZ2 y LNZ3, correspondientes a las metástasis en los ganglios pericólicos, intermedios y apicales, respectivamente.RESULTADOS:La tasa de detección de IV aumentó de 11,3% a 35,4% en comparación con el período anterior en el que solo se realizó tinción con hematoxilina y eosina. El análisis de regresión de Cox mostró VI (razón de riesgo, 3.856; intervalo de confianza [IC] del 95%, 1.249-11.910, p = 0.019) y metástasis en los ganglios linfáticos (razón de riesgo, 3.156; IC del 95%, 1.094-9.108, p = 0.034) en todos los estadios y LNZ 2, 3 (cociente de riesgo, 2.649; IC del 95%, 1.244-5.640, p = 0.012) en el estadio III se asociaron significativamente con una pobre supervivencia libre de enfermedad. Al estratificar a todos los pacientes según estos tres factores, los pacientes con estadio III [LNZ1 / VI (-)] tuvieron una sobrevivencia sin enfermedad (SSE) comparable con el estadio I, pero una supervivencia libre de enfermedad significativamente mejor que aquellos con estadio II [VI (+)] (p = 0,018). Pacientes en estadío II [VI (+)] tuvieron una mejor supervivencia sin enfermedad mediante el uso de quimioterapia adyuvante (p <0,001).LIMITACIONES:Estudio limitado por su diseño retrospectivo.CONCLUSIÓN:La tinción de elastina contribuyó a un aumento considerable en la detección de IV. IV puede ser un poderoso predictor de supervivencia sin enfermedad deficiente más allá de las metástasis de los ganglios linfáticos cuando se limita al área pericólica y es útil para decidir el uso de quimioterapia adyuvante en el cáncer de colon en estadío II. Consulte Video Resumen en http://links.lww.com/DCR/B573. (Traducción-Dr. Adrian Ortega).

Dual Clarithromycin and Metronidazole Resistance Is the Main Cause of Failure in Ultimate Helicobacter pylori Eradication.

BACKGROUND/AIM: Antimicrobial resistance significantly affects the cure rate of Helicobacter pylori (H. pylori) eradication. We evaluated the risk factor of failure in ultimate H. pylori eradication and assessed the efficacy of current regimens to overcome antibiotic resistance. METHODS: Patients with H. pylori infection were prospectively enrolled in a single center. They were classified into 3 groups according to the previous history of H. pylori eradication, and antibiotic susceptibility was evaluated by culture and minimum inhibitory concentrations (MICs). RESULTS: Ninety-seven patients were successfully cultured for H. pylori and 81 (83.5%), 7 (7.2%), and 9 (9.3%) were classified into primary resistance, 1st eradication failure, and 2nd or more eradication failure groups; the resistance to clarithromycin (CLA), metronidazole (MET), and levofloxacin increased in the 1st eradication failure (85.7, 57.1, and 42.9%) and 2nd or more eradication failure (88.9, 88.9, and 55.6%) groups. The prevalence of MDR was 21.0% (17/81), 57.1% (4/7), and 88.9% (8/9) in the primary, 1st eradication failure, and 2nd or more eradication failure groups, respectively. In multivariate analysis, dual CLA/MET resistance (CLA/MET-R) (OR = 31.432, 95% CI: 3.094-319.266, p = 0.004) was an independent risk factor for ultimate H. pylori eradication failure. In patients with dual CLA/MET-R, the eradication ratio of concomitant therapy was 57.1% (4/7), whereas that of bismuth-containing quadruple therapy was 27.3% (3/11) (p = 0.350). CONCLUSIONS: Dual CLA/MET-R was the main cause of failure in ultimate H. pylori eradication, and 7-day bismuth quadruple or concomitant regimen would not be suitable for H. pylori eradication in the dual CLA/MET-R group.

Initial experience of preoperative short-course radiotherapy followed by oxaliplatin-based consolidation chemotherapy for locally advanced rectal cancer.

PURPOSE: We analyzed the safety and feasibility of preoperative short-course radiotherapy (SCRT) followed by consolidation chemotherapy for patients with locally advanced rectal cancer (LARC). METHODS: From April 2018 to May 2019, 19 patients with LARC were treated with SCRT followed by three cycles of consolidation chemotherapy with leucovorin, fluorouracil, and oxaliplatin (FOLFOX6) before surgery. Adjuvant chemotherapy relied on oxaliplatin. Tumor response, patient compliance, and toxicities were analyzed. RESULTS: The median age was 60 years (range 44-71), and 16 of the patients were male. The median tumor height was 5 cm (range 0-9) from anal verge. All patients received a total dose of 25 Gy in five fractions. The number of cycles of FOLFOX6 before surgery was three in 17, four in one, five in one. Five patients required dose reductions in consolidation chemotherapy. The median interval between initiation of SCRT and surgery was 10.6 weeks (range 8.6-16.4). A pathologic complete response was seen in two patients (11%). Grade III toxicities to the preoperative treatment were seen in five patients (26%): diarrhea in two, a decreased white blood cell count in one, and anemia in two. Postoperative complications arising within 30 days developed in five patients (26%). During the median follow-up period of 20.4 months, there was no tumor recurrence. CONCLUSION: Preoperative SCRT followed by oxaliplatin-based consolidation chemotherapy showed acceptable toxicity and feasibility in patients with LARC. Prospective randomized trials are warranted to verify the efficacy and safety of this treatment strategy compared with conventional long-course concurrent chemoradiotherapy.

S122: impact of fluorescence and 3D images to completeness of lateral pelvic node dissection.

BACKGROUND: Lateral pelvic lymph node dissection (LPND) is a technically demanding procedure. Consequently, there is a possibility of incomplete dissection of lateral pelvic lymph nodes (LPNs). We aimed to identify metastatic LPNs intraoperatively in real-time under dual guidance of fluorescence imaging and 3D lymphovascular reconstruction, and then to remove them completely. METHODS: Rectal cancer patients who were scheduled to undergo LPND after preoperative chemoradiotherapy (CRT) were prospectively enrolled. We traced changes in suspected metastatic LPNs during preoperative CRT and defined them as index LPNs on post-CRT imaging studies. For fluorescence imaging, indocyanine green (ICG) at a dose of 2.5 mg was injected transanally around the tumor before the operation. For 3D reconstruction images, each patient underwent preoperative axial CT scan with contrast (0.6 mm slice thickness). These images were then manipulated with OsiriX. Index LPNs and essential structures in the pelvic sidewall, such as the obturator nerve, were reconstructed with abdominal arteries from 3D volume rendering. All surgical procedures were performed via laparoscopic or robotic approach. RESULTS: From March to July 2017, ten rectal cancer patients underwent total mesorectal excision with LPND after preoperative CRT under dual image guidance. Bilateral LPND was performed in five patients. All index LPNs among ICG-bearing lymph nodes were clearly identified intraoperatively by matching with their corresponding 3D images. Pathologic LPN metastasis was confirmed in four patients (40.0%) and in five of the 15 dissected pelvic sidewalls (33.0%). All metastatic LPNs were identified among index LPNs. Four (80.0%) of the five metastatic LPNs were located in the internal iliac area. CONCLUSION: Index LPNs among ICG-bearing lymph nodes in pelvic sidewall were clearly identified and completely removed by matching with their corresponding 3D reconstruction images. Further studies and long-term oncologic outcomes are required to determine the real impact of dual image guidance in LPND.

Development and Validation of an Easy-to-Implement, Practical Algorithm for the Identification of Molecular Subtypes of Gastric Cancer: Prognostic and Therapeutic Implications.

BACKGROUND: Gastric cancer (GC) is a heterogeneous disease, and substantial efforts have been made to develop a molecular biology-based classification system for GC. Analysis of the genomic signature is not always feasible, and thus, we aimed to (i) develop and validate a practical immunohistochemistry (IHC)- and polymerase chain reaction (PCR)-based molecular classification of GC and (ii) to assess HER2 status according to this classification. MATERIALS AND METHODS: A total of 894 consecutive patients with GC from two individual cohorts (training, n = 507; validation, n = 387) were classified using Epstein-Barr virus (EBV) in situ hybridization, microsatellite instability (MSI) testing, and IHC for E-cadherin and p53. RESULTS: We were able to classify patients into five groups in the training cohort: group 1 (MSI+), group 2 (EBV-, MSI-, non-epithelial-mesenchymal transition [non-EMT]-like, p53-), group 3 (EBV+), group 4 (EBV-, MSI-, non-EMT-like, p53+), and group 5 (EBV-, MSI-, EMT-like). In the training cohort, each group showed different overall survival (OS) after gastrectomy (p < .001); group 1 had the best prognosis, and group 5 showed the worst survival outcome. The significant impact of the classification system on OS was also verified in the validation cohort (p = .004). HER2 positivity was observed in 6.5% of total population, and most of HER2-positive cases (93.1%) were included in groups 2 and 4. CONCLUSION: We developed and validated a modified IHC- and PCR-based molecular classification system in GC, which showed significant impact on survival, irrespective of stage or other clinical variables. We also found close association between HER2 status and non-EMT phenotype in our classification system. IMPLICATIONS FOR PRACTICE: Molecular classification of gastric cancer suggested by previous studies mostly relies on extensive genomic data analysis, which is not always available in daily practice. The authors developed a simplified immunohistochemistry- and polymerase chain reaction-based molecular classification of gastric cancer and proved the prognostic significance of this classification, as well as the close association between HER2 status and certain groups of the classification, in the largest consecutive cohort of gastric cancer. Results of this study suggest that this scheme is a cost-effective, easy-to-implement, and feasible way of classifying gastric cancer in daily clinical practice, also serving as a practical tool for aiding therapeutic decisions and predicting prognosis.

Factors to improve the interobserver agreement for gastric atrophy and intestinal metaplasia: consensus of definition and criteria.

AIMS: Intestinal metaplasia and atrophy of the gastric mucosa are associated with Helicobacter pylori infection and are considered premalignant lesions. The updated Sydney system is used for these parameters, but experienced pathologists and consensus processes are required for interobserver agreement. We sought to determine the influence of the consensus process on the assessment of intestinal metaplasia and atrophy. METHODS AND RESULTS: Two study sets were used: consensus and validation. The consensus set was circulated and five gastrointestinal pathologists evaluated them independently using the updated Sydney system. The consensus of the definitions was then determined at the first consensus meeting. The same set was recirculated to determine the effect of the consensus. The second consensus meeting was held to standardise the grading criteria and the validation set was circulated to determine the influence. Two additional circulations were performed to assess the maintainance of consensus and intraobserver variability. Interobserver agreement of intestinal metaplasia and atrophy was improved through the consensus process (intestinal metaplasia: baseline κ = 0.52 versus final κ = 0.68, P = 0.006; atrophy: baseline κ = 0.19 versus final κ = 0.43, P < 0.001). Higher interobserver agreement in atrophy was observed after consensus regarding the definition (pre-consensus: κ = 0.19 versus post-consensus: κ = 0.34, P = 0.001). There was improved interobserver agreement in intestinal metaplasia after standardisation of the grading criteria (pre-standardisation: κ = 0.56 versus post-standardisation: κ = 0.71, P = 0.010). CONCLUSIONS: This study suggests that interobserver variability regarding intestinal metaplasia and atrophy may result from lack of a precise definition and fine criteria, and can be reduced by consensus of definition and standardisation of grading criteria.

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein-Barr virus-associated gastric cancer.

BACKGROUND: This study investigated the clinical relevance and prognostic impact of the overall expression of programmed cell death protein ligand-1 (PD-L1) and programmed cell death protein ligand-2 (PD-L2), in patients with Epstein-Barr virus-associated gastric cancer (EBVaGC). METHODS: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, the expression status of PD-L1 and PD-L2 in 120 patients with EBVaGC identified by EBV-encoded RNA in situ hybridisation was retrospectively analysed using immunohistochemistry (IHC). For each IHC marker, positivity was separately in intraepithelial tumour cells (iTu-) and immune cells in the tumour stroma area (str-). RESULTS: Among 116 eligible patients, 57 (49.1%) and 66 patients (56.9%) were determined as iTu-PD-L1-positive and str-PD-L1-positive, respectively, whereas 23 (21.6%) and 45 patients (38.8%) were determined as iTu-PD-L2 positive and str-PD-L2 positive, respectively. Intraepithelial tumour cell PD-L1 positivity was found to be significantly associated with lymph node (LN) metastasis (P=0.012) and a poor disease-free survival (DFS) (P=0.032), yet not overall survival (P=0.482). In a multivariate analysis, iTu-PD-L1 positivity was independently associated with a poor DFS (P=0.006, hazard ratio=12.085). In contrast, str-PD-L2-positivity was related to a lower T category (P=0.003), absence of LN metastasis (P=0.032) and perineural invasion (P=0.028). Intraepithelial tumour cell and str-PD-L2 positivity showed a trend towards an improved DFS, although not significant (P=0.060 and P=0.073, respectively). CONCLUSIONS: Intraepithelial tumour cells PD-L1 expression can be used to predict a poor outcome in patients with EBVaGC and can represent a rational approach for PD-1/PD-L pathway-targeted immunotherapy.

Comparative analysis of the EGFR, HER2, c-MYC, and MET variations in colorectal cancer determined by three different measures: gene copy number gain, amplification status and the 2013 ASCO/CAP guideline criterion for HER2 testing of breast cancer.

BACKGROUND: The purpose of this study was to explore gene copy number (GCN) variation of EGFR, HER2, c-MYC, and MET in patients with primary colorectal cancer (CRC). METHODS: Dual-colour silver-enhanced in situ hybridization was performed in tissue samples of 334 primary CRC patients. The amplification status (GCN ratio ≥2) and GCN gain (average GCN ≥4) data for the EGFR, HER2, c-MYC and MET genes were obtained. GCN variation was also assessed by the criterion of the 2013 ASCO/CAP guidelines for HER2 testing. RESULTS: Amplification of EGFR, HER2, c-MYC and MET was detected in 8 (2.4%), 20 (6.0%), 29 (8.7%), and 14 (4.2%) patients, respectively. Of 66 patients with at least one amplified gene, five exhibited co-amplification of genes studied (HER2-MET co-amplification: two patients; HER2-c-MYC co-amplification: two patients; EGFR-c-MYC co-amplification: one patient). There were 109 patients with GCN gains of one or more genes (EGFR: 11/334, HER2: 29/334, c-MYC; 60/334, MET: 48/334) and 32.1% (35/109) had multiple GCN gains. When each GCN was assessed by the criterion of the ASCO/CAP 2013 guideline for HER2 testing, 116 people showed positive or equivocal results for one or more genes. The cumulative amplification status had no association with patients' outcome. However, the cumulative results of the GCN gain and GCN status determined according to the ASCO/CAP guideline had a significant prognostic correlation in the univariate analysis (P values of 0.006 and 0.022, respectively). In the multivariate analysis, GCN gain and GCN status were independent prognostic factors (P values of 0.010 and 0.017, respectively). CONCLUSIONS: In this study, we evaluated GCN variation of four genes in a large sample of Korean CRC patients. The amplification status was not related to patient outcome. However, the GCN gain and GCN status according to the ASCO/CAP 2013 guideline were independent prognostic factors.

Clinicopathologic and Molecular Pathology of Collecting Duct Carcinoma and Related Renal Cell Carcinomas.

Collecting duct carcinoma (CDC) and related tumors [ie, renal medullary carcinoma (RMC)] are rare types of highly aggressive renal cell carcinomas (RCC) with poor prognosis. Because of the rarity and diagnostic uncertainty of them, their molecular pathology and significance have not yet been fully elucidated. CDC, RMC, fumarate hydratase-deficient RCC (including hereditary leiomyomatosis and RCC-associated RCC HLRCC-RCC), and recently reported anaplastic lymphoma kinase (ALK)-rearrangement RCC have significant morphologic overlaps, but they are separately distinct entities having different molecular pathway and clinical settings. CDC is more likely to occur in middle to old age population with immunoreactivity for PAX8 and integrase interactor-1 proteins (INI-1). Various chromosomal and genomic alterations have been reported with inconsistent results. In contrast, RMC is more likely to occur in younger patients with sickle cell trait. In RMC, loss of INI-1 expression and OCT3/4 expression are distinguished compared with other RCCs. Finally, ALK-rearrangement RCC seems to have 2 different clinical settings, one with sickle cell trait (VCL-ALK fusion) and the other without (other fusions such as TPM3-ALK, EML4-ALK, and STRN-ALK fusions). Interestingly, VCL-ALK fusion was found in pediatric patients with sickle cell trait, whereas other fusions were detected in adolescent or adult without sickle cell trait. Taken together, CDC and related tumors such as RMC, fumarate hydratase-deficient RCC (including hereditary leiomyomatosis and RCC-associated RCC), and ALK-rearrangement RCC are the distinct entities and their recognition is important for the development of future personalized therapeutic options. This review updates the clinicopathologic features of these tumors with overlapping morphology and outcome.

Modified 3-Point MRI-Based Tumor Regression Grade Incorporating DWI for Locally Advanced Rectal Cancer.

OBJECTIVE: The purpose of this study was to evaluate the prognostic relevance of a modified 3-point MRI-based tumor regression grading system incorporating DWI for patients with locally advanced rectal cancer after preoperative chemoradiotherapy (CRT). MATERIALS AND METHODS: Between March 2012 and September 2013, 118 consecutively registered patients with middle or lower locally advanced rectal cancer who underwent CRT followed by surgery were enrolled in this retrospective study. Two radiologists in consensus assessed MRI tumor regression grade (mrTRG) based on T2-weighted images and high b value DW images (0 and 1000 s/mm2) using the following grades: 0, complete regression (no obvious tumor); 1, intermediate regression (dominant fibrosis, regression > 50%); 2, poor regression (dominant tumor, regression ≤ 50%). Multivariate analysis with a Cox regression model was performed to evaluate the association between modified mrTRG and 3-year disease-free survival (DFS) rate. A Kaplan-Meier method with a log-rank test was used to compare the DFS rate between responder (grades 0 and 1) and nonresponder (grade 2) groups. RESULTS: Both the accuracy (72.9% vs 38.1%; p < 0.001) and the interreader agreement (κ = 0.580 vs 0.338; p < 0.001) of modified 3-point mrTRG were improved over the established 5-point mrTRG. Modified mrTRG (adjusted hazard ratio, 2.505; 95% CI, 1.231-5.100) was independently associated with 3-year DFS rate (p = 0.011). There was also a significant difference in the 3-year DFS rate between responders (73.8%; 95% CI, 64.2-81.3%) and nonresponders (41.7%; 95% CI, 10.9-70.8%) (p = 0.028). CONCLUSION: In patients with middle or lower locally advanced rectal cancer, the modified 3-point mrTRG incorporating DWI was independently associated with the 3-year DFS rate after CRT followed by surgery. The grading scale may be used as a surrogate for expected prognosis of preoperative CRT. Further prospective trials are warranted.

Expression of breast cancer stem cell markers as predictors of prognosis and response to trastuzumab in HER2-positive breast cancer.

BACKGROUND: Breast cancer stem cells (BCSCs) have been suggested to have clinical implications for cancer therapeutics because of their proposed role in chemoresistance. The aim of this study was to investigate the impact of BCSC marker expression on clinical outcome and trastuzumab response in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: We analysed the expression of BCSC markers, CD44+/CD24- and aldehyde dehydrogenase 1 (ALDH1), and clinical outcomes in three sets of breast cancer cases: Set 1, 242 HER2-positive primary breast cancers treated by various modalities; Set 2, 447 HER2-positive primary breast cancers treated with surgery and chemotherapy plus adjuvant trastuzumab; Set 3, 112 metastatic HER2-positive breast cancers treated with trastuzumab. RESULTS: Expression of CD44+/CD24- and ALDH1 was detected in 30.7% and 10.0%, respectively, of the Set 1 cases, and was associated with hormone receptor negativity. In survival analyses, expression of CD44+/CD24-, but not ALDH1, was found to be an independent prognostic factor for poor disease-free and overall survival in whole patients and also in the subgroup not receiving adjuvant trastuzumab. In Set 2 cases treated with adjuvant trastuzumab, CD44+/CD24- expression was an independent prognostic factor for poor disease-free survival, but not for overall survival; expression of ALDH1 had no impact on disease-free or overall survival. In metastatic disease treated with trastuzumab (Set 3 cases), CD44+/CD24- and ALDH1 expression had no effect on trastuzumab response or survival. CONCLUSIONS: These results suggest that the CD44+/CD24- phenotype can be used as a prognostic factor for clinical outcome and a predictive factor of trastuzumab response in patients with HER2-positive primary breast cancer.

Clinical influence of cancer stem cells on residual disease after preoperative chemoradiotherapy for rectal cancer.

We evaluated the clinical influence of cancer stem cells (CSCs) on residual disease after preoperative chemoradiotherapy (CRT) in patients with rectal cancer. The surgical specimens of 145 patients with residual rectal cancer after preoperative CRT were assessed. To identify CSCs, immunohistochemistry was performed using their surrogate makers (CD44 and aldehyde dehydrogenase 1 [ALDH1]) in full section tissues. Of the 145 cases, ALDH1 and CD44 positivity was found in 80.0 % (n = 116) and 47.6 % (n = 69), respectively; ALDH1 positivity showed weakly positive correlation with CD44 (r s = 0.269, P = 0.002). ALDH1 and CD44 positivity was related to lower tumor regression grade (TRG) (P = 0.009 and 0.003, respectively). Additionally, ALDH1 positivity was associated with positive circumferential resection margin (P = 0.019). However, ALDH1 and CD44 positivity showed no relationship with KRAS or BRAF mutation. In univariate analysis, ALDH1 positivity was associated with short recurrence-free survival (RFS) (P = 0.005) and rectal cancer-specific survival (RCSS) (P = 0.043), but not CD44 positivity (RFS, P = 0.725; RCSS, P = 0.280). In multivariate analysis, ALDH1 positivity was an independent prognostic factor for poor RFS (P = 0.039; hazard ratio = 2.997; 95 % confidence interval = 1.059-8.478), but not RCSS (P = 0.571). The expression of ALDH1 assessment independently predicts RFS in patients with residual disease after CRT. These results suggest that targeting CSCs could be an effective therapeutic approach to rectal cancer patients receiving preoperative CRT.

Clinical significance of fibroblast growth factor receptor 2 expression in patients with residual rectal cancer after preoperative chemoradiotherapy: relationship with KRAS or BRAF mutations and MSI status.

This study was designed to determine the prognostic impact and clinical significance of FGFR2 in residual disease after preoperative chemoradiotherapy (CRT) in patients with rectal cancer. The surgical specimens of 145 patients with residual rectal cancer after preoperative CRT were analyzed. To evaluate FGFR2 expression, immunohistochemistry was performed on whole section tissues. KRAS exon 2 (codon 12 and 13), BRAF V600E mutational status, and microsatellite instability (MSI) were determined using polymerase chain reactions. Of the eligible 141 patients, FGFR2 over-expression was observed in 75.9 % (n = 107) and was correlated with perineural invasion (P = 0.005) and inferior tumor regression grading (TRG) (P = 0.009). However, FGFR2 expression had no relationship with KRAS and BRAF mutation results or with MSI results. On univariate analysis, FGFR2 over-expression was significantly associated with worse rectal cancer-specific survival (RCSS) (P = 0.005) and disease-free survival (DFS) (P = 0.035). However, multivariate analysis revealed that FGFR2 over-expression was not independently associated with RCSS and DFS (all P > 0.05). Although FGFR2 over-expression did not independently influence patient outcome, FGFR2 over-expression was associated with worse prognosis and inferior TRG. Our data may aid in understanding the therapeutic approaches targeting FGFR2 in patients with residual rectal cancer after preoperative CRT.

Correlations between molecular subtypes and pathologic response patterns of breast cancers after neoadjuvant chemotherapy.

BACKGROUND: The relationship between the pathologic response patterns after neoadjuvant chemotherapy (NAC) and specific subtypes of breast cancer is unclear. METHODS: This study retrospectively analyzed 351 tumors from 348 women with breast cancer who received anthracycline and taxane-based NAC and subsequent surgery. Various histopathologic factors were assessed in the pretreatment biopsy and surgery specimens based on molecular subtypes defined by immunohistochemistry. RESULTS: The tumors without a pathologic complete response in each subtype retained their morphologic features after NAC. Lymphocytic infiltration was higher in the hormone receptor-negative (HR-) tumors than in the HR+ tumors. The HR- tumors showed more necrosis and histiocytic infiltration in the tumor bed than the HR+ tumors. The overall (including in situ carcinoma) and invasive pathologic cancer sizes were similar for the triple-negative tumors only. Although all the subtypes showed significantly reduced tumor size after NAC, the difference between the pre-NAC magnetic resonance imaging (MRI) tumor size and the overall pathologic cancer size was significantly smaller for the HR+/human epidermal growth factor receptor 2-negative (HER2-) subgroup than for the triple-negative subgroup. The triple-negative tumors showed the highest correlation between post-NAC tumor size measured by MRI and overall or invasive pathologic tumor size. CONCLUSION: The molecular subtypes of breast cancer have characteristic pathologic patterns of response to NAC.

Serum VEGF-A and Tumor Vessel VEGFR-2 Levels Predict Survival in Caucasian but Not Asian Patients Undergoing Resection for Gastric Adenocarcinoma.

BACKGROUND: Clinical trials of agents targeting the vascular endothelial growth factor A (VEGF-A) pathway in gastric adenocarcinoma (GA) suggest that these therapies may have varying efficacy in different races. METHODS: VEGF-A in serum and/or VEGF receptor 2 (VEGFR-2) in CD31-positive tumor vessels (VEGFR-2/CD31) were measured in 118 Caucasians and 263 Asians who underwent gastric resection at two institutions and correlated with overall survival (OS). Blood was drawn before any treatment. Patients receiving neoadjuvant treatment were excluded from VEGFR-2 analysis. RESULTS: Compared with Asians, Caucasians were older (mean age 66-73 vs 59-62 years), had more proximal tumors, and had more advanced TNM stage. In the VEGF-A cohort, Caucasians had a median VEGF-A level that was 95 % higher than that of Asians and a much higher standard deviation (88 ± 6.206 vs 45 ± 76 pg/ml, p < 0.001). The 5-year OS for patients with low versus high VEGF-A levels was 72 versus 43 % in Caucasians (p = 0.001) and 86 versus 77 % in Asians (p = 0.236). In the VEGFR-2 cohort, OS was worse in Caucasians with high VEGFR-2/CD31 levels (49 vs 73 %, p = 0.038), while there was no significant difference in OS in Asians (80 vs 90 %, p = 0.119). On multivariate analyses of significant prognostic factors (excluding treatment factors and margin status), serum VEGF-A and tumor VEGFR-2/CD31 levels were independent predictors of OS only in Caucasians. CONCLUSIONS: In patients with resectable GA, VEGF-A and VEGFR-2/CD31 levels are independent predictors of OS in Caucasians but not in Asians, suggesting varying importance of this pathway in GA progression among different races.

Clinical and prognostic value of MET gene copy number gain and chromosome 7 polysomy in primary colorectal cancer patients.

We aimed to explore the clinical and prognostic influence of numeric alterations of MET gene copy number (GCN) and chromosome 7 (CEP7) CN in colorectal cancer (CRC) patients. MET GCN and CEP7 CN were investigated in tissue arrayed tumors from 170 CRC patients using silver in situ hybridization (SISH). MET GCN gain was defined as ≥4 copies of MET, and CEP7 polysomy was prespecified as ≥3 copies of CEP7. Additionally, MET messenger RNA (mRNA) transcription was evaluated using mRNA ISH and compared with MET GCN. MET GCN gain was observed in 14.7 % (25/170), which correlated with advanced stage (P = 0.037), presence of distant metastasis (P = 0.006), and short overall survival (OS) (P = 0.009). In contrast, CEP7 polysomy was found in 6.5 % (11/170), which was related to tumor location in the left colon (P = 0.027) and poor OS (P = 0.029). MET GCN positively correlated with CEP7 CN (R = 0.659, P < 0.001) and mRNA transcription (R = 0.239, P = 0.002). Of note, MET GCN gain and CEP7 polysomy were also associated with poor OS (P = 0.016 and P < 0.001, respectively) in stage II/III CRC patients (n = 123). In multivariate analysis, CEP7 polysomy was an independent prognostic factor for poor OS in all patients (P = 0.009; hazard ratio [HR], 2.220; 95 % confidence interval [CI], 1.233-3.997) and in stage II/III CRC patients (P < 0.001; HR, 20.781; 95 % CI, 4.600-93.882). MET GCN gain and CEP7 polysomy could predict a poor outcome in CRC patients, especially CEP7 polysomy has the most powerful prognostic impact in stage II/III CRC patients.