Cholestatic HCV Cryoglobulinemia: A New Clinical and Pathological Entity before and after Direct-Acting Antiviral Therapies-A Case-Control Study.

Twenty-nine patients with HCV infection (HCV+) and mixed cryoglobulinemia (MC+) were retrospectively selected and matched for age and sex with 31 HCV+ MC- patients. Biomarkers of cholestasis (direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase), HCV-RNA and genotype, and plasma cryoprecipitates were measured before and after virus eradication; liver histology and plasma cells (aggregation and distribution), observed blinded by two pathologists, were analyzed. Sixty participants (mean age: 56.5; range: 35-77, males: 50%) with HCV infection were enrolled. Cholestasis (≥2 pathologically increased cholestasis biomarkers) was significantly higher in the MC group (p = 0.02) and correlated with cryoglobulinemia (OR 6.52; p = 0.02). At liver histological assessment, plasma cells were significantly increased in the MC+ group (p = 0.004) and tended to form aggregates more than the control group (p = 0.05). At multivariate analysis with MC, age, HCV-RNA, HBV diabetes, and cirrhosis, cholestasis was only significantly correlated to MC (OR 8.30; p < 0.05). In 25% patients, MC persisted after virus eradication with new antiviral treatment. Our study identified for the first time an association between MC, cholestasis, and an increased number of intrahepatic plasma cells in chronic hepatitis C (CHC) patients before virus eradication. Future studies are required to understand how MC contributes to liver damage and how its persistence affects the patients' follow-up after antiviral therapies.

hERG1 Potassium Channel Expression in Colorectal Adenomas: Comparison with Other Preneoplastic Lesions of the Gastrointestinal Tract.

Preneoplastic lesions represent a useful target for early diagnosis and follow-up of gastrointestinal malignancies. hERG1 channel expression was tested by immunohistochemistry (IHC) in a cohort of colorectal adenoma samples belonging to Italian subjects. Overall, hERG1 was expressed in 56.5% of cases with both high staining intensity and a high percentage of positive cells. Moreover, hERG1 was expressed in a higher percentage of dysplastic adenomas with respect to hyperplastic lesions, and the proportion of positive samples further increased in patients with high-grade dysplasia. Comparing hERG1 expression in other preneoplastic lesions of the GI tract (gastric dysplasia and Barrett's esophagus), it emerged that in all the conditions, hERG1 was expressed with a diffused pattern, throughout the cell, with variable staining intensity within the samples. The highest expression was detected in gastric dysplasia samples and the lowest in Barrett's esophagus at similar levels observed in colorectal adenomas. Our results show that hERG1 is aberrantly expressed in human preneoplastic lesions of the gastrointestinal tract and has a different pattern of expression and role in the different sites. Overall, the detection of hERG1 expression in preneoplastic lesions could represent a novel diagnostic or prognostic marker of progression in the gastrointestinal tract.

Poorly Cohesive Gastric Cancers Showing the Transcriptomic Hallmarks of Epithelial-Mesenchymal Transition Behave Aggressively.

HYPOTHESIS: Poorly cohesive (PC) gastric cancer (GC) exhibits variable clinical behavior, being extremely aggressive in most cases but more indolent at times. We hypothesized that the integrative genomic and gene expression characterization of a PC GC series could help identifying molecular subtypes with potential clinical implications. MATERIALS AND METHODS: 64 PC GCs were assessed for alterations in 409 genes and 30 cases were subjected to transcriptomic profiling of 20,815 genes. RESULTS: A median of 8.2 mutations per Mb (interquartile range 6.9-10.4) was found and a tumor mutational load >10 muts/Mb was significantly associated with patients' worse survival ( P =0.0024). The most frequent mutated genes were CDH1 and TP53 (each 32.8%) followed by PIK3CA (10.9%). In 15 samples (23.4%), at least 1 chromatin remodeling gene was mutated: KMT2D (5 cases); ARID1A and BAP1 (4 cases each); EZH2 , KMT2A , PBRM1 (1 case each). Eight samples (12.5%) had fusion genes involving CLDN18 gene. Gene expression profiling identified 4 different clusters: cluster A associated with epithelial to mesenchymal transition (EMT) signature; cluster B associated to proliferative signature and EMT; cluster C correlated to hedgehog signaling; cluster D showing no enrichment for any of the previous signatures. Notably, cluster A and B showed a worse prognosis compared with clusters C and D ( P =0.0095). CONCLUSION: integrated genomic and transcriptomic analysis suggest the existence of 4 molecular subtypes of PC GC with prognostic significance where EMT features are associated with a worse outcome.

Early Gastric Cancer: identification of molecular markers able to distinguish submucosa-penetrating lesions with different prognosis.

BACKGROUND: Early Gastric Cancer (EGC) reaches 25% of the gastric cancers surgically treated in some areas of Northeastern Italy and is usually characterized by a good prognosis. However, among EGCs classified according to Kodama's criteria, Pen A subgroup is characterized by extensive submucosal invasion, lymph node metastases and worse prognosis, whereas Pen B subgroup by better prognosis. The aim of the study was to characterize the differences between Pen A, Pen B and locally advanced gastric cancer (T3N0) in order to identify biomarkers involved in aggressiveness and clinical outcome. METHODS: We selected 33 Pen A, 34 Pen B and 20 T3N0 tumors and performed immunohistochemistry of mucins, copy number variation analysis of a gene panel, microsatellite instability (MSI), TP53 mutation and loss of heterozygosity (LOH) analyses. RESULTS: Pen A subgroup was characterized by MUC6 overexpression (p = 0.021). Otherwise, the Pen B subgroup was significantly associated with the amplification of GATA6 gene (p = 0.002). The higher percentage of MSI tumors was observed in T3N0 group (p = 0.002), but no significant differences between EGC types were found. Finally, TP53 gene analysis showed that 32.8% of Pen tumors have a mutation in exons 5-8 and 50.0% presented LOH. Co-occurrence of TP53 mutation and LOH mainly characterized Pen A tumors (p = 0.022). CONCLUSIONS: Our analyses revealed that clinico-pathological parameters, microsatellite status and frequency of TP53 mutations do not seem to distinguish Pen subgroups. Conversely, the amplification of GATA6 was associated with Pen B, as well as the overexpression of MUC6 and the TP53mut/LOH significantly characterized Pen A.

The amount of signet ring cells is significantly associated with tumour stage and survival in gastric poorly cohesive tumours.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate whether the amount of signet ring cells (SRCs) affects clinicopathological characteristics and prognosis of poorly cohesive (PC) gastric tumours. STUDY DESIGN: One hundred seventy-three patients with PC tumours treated at three European centres from 2004 to 2014 were reclassified in three categories: (a) pure SRC cancers (SRC1) (≥90% SRCs); (b) PC carcinoma with SRC component (SRC2) (>10%, <90% SRCs); (c) PC carcinoma not otherwise specified (SRC3) (≤10% SRCs). RESULTS: The percentage of SRCs was inversely related to the pT stage (Spearman's ρ = -0.174, P < .001) and the number of positive nodes coded as a continuous variable (P = .009). Five year cancer-related survival was significantly higher (58%, 95% confidence interval [CI]: 36%-75%) in SRC1 compared with SRC2 (39%, 95% CI: 28%-50%) and SRC3 (38%, 95% CI: 22%-53%), (P = .048). In multivariable analysis, the impact of PC categories on cancer-related survival was significant when controlling for sex, age, pT, pN, and curativity (hazard ratio [HR] of sSRC2 vs SRC1 = 2.08, 95% CI: 1.01-4.29, P = .046; HR of SRC3 vs SRC1 = 2.38, 95% CI: 1.05-5.41, P = .039). CONCLUSION: The percentage of SRCs was inversely related to tumour aggressiveness, with long-term survival significantly higher in SRC1 compared with SRC2 and SRC3 tumours.

Early Gastric Cancer: Clinical Behavior and Treatment Options. Results of an Italian Multicenter Study on Behalf of the Italian Gastric Cancer Research Group (GIRCG).

BACKGROUND: Early gastric cancer (EGC) generally has a good prognosis. However, the current definition of EGC includes various subgroups of patients with different pathological characteristics and different prognoses, some of whom have aggressive disease with a biological behavior similar to that of advanced carcinoma. MATERIALS AND METHODS: We retrospectively evaluated 1,074 patients with EGC who had undergone surgery between 1982 and 2009. The cumulative incidence function of cancer-specific mortality and competing mortality were estimated using the Fine and Gray method. RESULTS: The median follow-up period was 193 months (range 1-324). Five hundred and sixty-two (52.3%) patients died, 96 (8.9%) from EGC. The 5-, 10-, and 15-year cumulative incidence rates for mortality of all causes were 20.5% (95% confidence interval [CI] 18.0-22.9), 37.1% (95% CI 34.7-40.7), and 52.6% (95% CI 49.1-56.0), respectively; for cancer-specific mortality, 6.0% (95% CI 4.5-7.6), 9.9% (95% CI 7.9-11.9), and 11.1% (95% CI 8.8-13.3), respectively; and for mortality of other causes, 14.4% (95% CI 12.1-16.6), 27.2% (95% CI 24.2-30.2), and 41.5% (95% CI 38.1-43.3), respectively. A significant increase in the risk of cancer-specific mortality was observed for lesions >2 cm (adjusted hazard ratio [HR] = 1.44, 95% CI 1.07-1.94), Pen A-type disease (adjusted HR = 1.73, 95% CI 1.15-2.61), and node-positive cancers (adjusted HR = 2.28, 95% CI 1.61-3.21). CONCLUSION: Patients with EGC with tumors >2 cm, Pen A-type disease according to Kodama, or lymph node metastases show a poorer prognosis and an increased risk of cancer-specific mortality. IMPLICATIONS FOR PRACTICE: Early gastric cancer generally has a good prognosis, and some patients can be treated radically by endoscopic resection. However, the current definition of early gastric cancer includes subgroups of patients with an aggressive disease. In particular, patients with lymph node metastases and Pen A-type tumors according to Kodama's classification need a more invasive treatment, such as subtotal or total gastrectomy with an extended D2 lymphadenectomy, plus eventual adjuvant chemotherapy.

The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015.

This article reports the guidelines for gastric cancer staging and treatment developed by the GIRCG, and contains comprehensive indications for clinical management, including radiological, endoscopic, surgical, pathological, and oncological paths.

Sonographic diagnosis of acute cholecystitis in patients with symptomatic gallstones.

PURPOSE: The aim of the retrospective study was to assess the diagnostic ultrasound (US) criteria for acute cholecystitis in patients admitted for symptomatic gallbladder stones. METHODS: The medical records of 186 patients who had undergone cholecystectomy within 24 hours after an US examination were reviewed. Acute cholecystitis was defined on the basis of pathology findings. The correlation between standardized US signs and final diagnosis of acute cholecystitis was assessed with univariate and multivariate analyses. The diagnostic values of US based on the correlated signs were then calculated. RESULTS: The prevalence of acute cholecystitis was 52.7% (95% confidence interval [CI], 42.8-64.2). Three US signs were found to be predictive of acute cholecystitis: gallbladder distension, wall edema, and pericholecystic fluid collection. When none of the US signs were registered, sonography proved to have a 72.4% (95% CI, 59.1-83.3) negative predictive value. When registering two or three signs, sonography had positive predictive values of 78% (95% CI, 56.3-92.5) and 100% (95% CI, 58.9-100), respectively. With just one sign, the positive predictive value was 57.6% (95% CI, 47.2-67.4), and such a finding was furthermore observed in only 53.2% of the cases. CONCLUSIONS: The sonografic diagnosis of acute cholecystitis may be achieved by registering only three standardized US signs. Nevertheless, in patients admitted for symptomatic gallstones, US is of some utility in less than half of those patients.

High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers.

BACKGROUND: There is still no widely accepted molecular marker available to distinguish between gastric high-grade intraepithelial neoplasia (HG-IEN) and invasive early gastric cancer (EGC). METHODS: HG-IEN and EGC lesions coexisting in the same patient were manually microdissected from a series of 15 gastrectomies for EGC; 40 ng DNA was used for multiplex PCR amplification using the Ion AmpliSeq Cancer Panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes. RESULTS: Of the 15 EGCs, 12 presented at least one somatic mutation among the 50 investigated genes, and 6 of these showed multiple driver gene somatic mutations. TP53 mutations were observed in 9 cases; APC mutations were identified in 3 cases; and ATM and STK11 were mutated in 2 cases. Seven HG-IEN lesions shared an identical mutational profile with the EGC from the same patient; 13 mutations observed in APC, ATM, FGFR3, PIK3CA, RB1, STK11, and TP53 genes were shared by both HG-IEN and ECG lesions. CDKN2A, IDH2, MET, and RET mutations were observed only in EGC. TP53 deregulation was further investigated in an independent series of 75 biopsies corresponding to all the phenotypic lesions occurring in the EGC carcinogenetic cascade. p53 nuclear immunoreaction progressively increased along with the dedifferentiation of the lesions (P < 0.001). Overall, 18 of 20 p53-positive lesions showed a TP53 mutated gene. DISCUSSION: Our results support the molecular similarity between HG-IEN and EGC and suggest a relevant role for TP53 in the progression to the invasive phenotype and the use of immunohistochemistry as a surrogate to detect TP53 gene mutations.

Influence of Tumor Stroma on the Aggressiveness of Poorly Cohesive Gastric Carcinoma.

Tumor-stroma crosstalk promotes the adaptation of cancer cells to the local microenvironment and sustains their growth. We assessed the quantitative and qualitative impact of intralesional stroma on clinic-pathological features and the prognosis of poorly cohesive gastric cancer (PCGC) variants. Tissue microarrays including 75 PCGC specimens were immunostained for cytokeratin 8/18 and α-smooth muscle actin to assess the relative proportion of neoplastic cells versus stromal components and the cases were subsequently divided into stroma-rich (SR) and stroma-poor (SP) tumors. Stromal status is significantly associated with the depth of tumor invasion. Patient survival rate was found to be higher in the SP compared to the SR tumor group and, hence, abundant stroma was identified as a significant risk factor in univariable analysis but had no independent prognostic impact. We also investigated the mRNA levels of KRT8 and the associated transcriptional signatures using the molecular data of 82 PCGC cases divided into KRT8-high and KRT8-low groups. KRT8-high tumors were enriched in proteins localized in the extracellular compartment and their expression levels correlated with longer survival in the KRT8-high group and shorter overall survival in the KRT8-low group. Comprehensively, we find that relative intralesional stromal content is a marker of aggressiveness in PCGC tumors and that extracellular proteins characterize functionally and clinically different PCGC subgroups.

Neoadjuvant therapy with weekly docetaxel and cisplatin, 5-fluorouracil continuous infusion, and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long-lasting pathological complete response: a phase 2 study.

BACKGROUND: This phase 2 study was aimed at defining the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion (c.i.) of 5-fluorouracil (5-FU) and concomitant radiotherapy (RT) in untreated stage II-III adenocarcinoma and squamous cell carcinoma of mid-distal thoracic esophagus. METHODS: The schedule consisted of a first phase of chemotherapy alone and of a second phase of concurrent chemoradiation. Doses were as follows: docetaxel 35 mg/m(2) and cisplatin 25 mg/m(2) on days 1, 8, 15, 29, 36, 43, 50, and 57 plus 5-FU c.i. (180 mg/m(2) on days 1-21 and 150 mg/m(2) on days 29-63); RT (50 Gy) started at day 29. Surgery was planned 6 to 8 weeks after the completion of chemoradiation. RESULTS: A total of 74 patients were enrolled; pathological complete remission (pCR) was found in 47% (35 of 74) and near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) (pnCR) in 15% of the patients (11 of 74). Grade 3-4 neutropenia, nonhematological toxicity, and toxic deaths occurred in 13.5%, 32.4%, and 4% of the patients, respectively. Median follow-up was 55 months (range, 3-108 months). Median survival of all 74 patients was 55 months, whereas it was not reached in the pCR subset. The 3- and 5-year survival rates were, respectively, 83% and 77% for pCR, 73% and 44% for pnCR, and 21% and 14% for Residual Tumor subsets (P < .001). CONCLUSIONS: This study shows that 1) this intensive weekly schedule produced a high pathological response rate, 2) responders had high and long-term durable survival rates.

Endoscopic submucosal dissection in the treatment of gastric submucosal tumors: results from a retrospective cohort study.

BACKGROUND: A submucosal tumor (SMT) of the stomach, which is an occasional finding during routine upper gastrointestinal endoscopy, may pose diagnostic and therapeutic challenges. METHODS: To assess whether endoscopic submucosal dissection (ESD) is a feasible approach to definitively cure SMTs, the authors performed a retrospective cohort study with two endoscopic italian centers. RESULTS: The study consisted of 20 patients with SMTs who underwent ESD. The patients underwent ESD and were followed up by endoscopy. We analyzed complete resection rate, frequency of complications, and survival. The overall rate of R0 resection was 90 % (18/20), with two endoscopic failures, one for a submucosal tumor and one for a neoplasm deeply infiltrating the proper muscle layer. The median procedure time was 119.1 min (range 40-240 min). The median size of the resected specimens was 29 mm (range 15-60 mm). Perforation occurred in 3 patients; all were treated conservatively. There were no cases of severe bleeding. Based on histopathological findings, 6 cases of ectopic pancreas, 1 of ectopic spleen, 3 of leiomyoma, and 10 of gastrointestinal stromal tumor (GIST) were diagnosed. Complete resection was obtained in all GIST cases. Among the 10 GIST cases treated by ESD, no death occurred: the 5-year disease-specific survival rate was 100 %. CONCLUSIONS: The high success rate of 90 % and the low incidence of complications should indicate ESD is the correct diagnostic and definitive treatment in selected patients.

Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab.

Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon's two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies.

Clinical Features of Gastric Signet Ring Cell Cancer: Results from a Systematic Review and Meta-Analysis.

BACKGROUND: Conflicting results about the prognostic relevance of signet ring cell histology in gastric cancer have been reported. We aimed to perform a meta-analysis focusing on the clinicopathological features and prognosis of this subgroup of cancer compared with other histologies. METHODS: A systematic literature search in the PubMed database was conducted, including all publications up to 1 October 2021. A meta-analysis comparing the results of the studies was performed. RESULTS: A total of 2062 studies referring to gastric cancer with signet ring cell histology were identified, of which 262 studies reported on its relationship with clinical information. Of these, 74 were suitable to be included in the meta-analysis. A slightly lower risk of developing nodal metastases in signet ring cell tumours compared to other histotypes was found (especially to undifferentiated/poorly differentiated/mucinous and mixed histotypes); the lower risk was more evident in early and slightly increased in advanced gastric cancer. Survival tended to be better in early stage signet ring cell cancer compared to other histotypes; no differences were shown in advanced stages, and survival was poorer in metastatic patients. In the subgroup analysis, survival in signet ring cell cancer was slightly worse compared to non-signet ring cell cancer and differentiated/well-to-moderately differentiated adenocarcinoma. CONCLUSIONS: Most of the conflicting results in signet ring cell gastric cancer literature could be derived from the lack of standardisation in their classification and the comparison with the different subtypes of gastric cancer. There is a critical need to strive for a standardised classification system for gastric cancer, fostering clarity and coherence in the forthcoming research and clinical applications.

Correlations between Molecular Alterations, Histopathological Characteristics, and Poor Prognosis in Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.

MET mutations in cancers of unknown primary origin (CUPs).

Cancer of unknown primary origin (CUP) defines metastatic disease of unknown origin, accounting for 3-5% of all cancers. Growing evidence demonstrates that inappropriate execution of a genetic program named "invasive growth," driven by the MET oncogene, is implicated in the metastatic process. MET activation in cancers is mainly consequent to overexpression, whereas mutations are rarely found. We reasoned that the occurrence of MET somatic mutations might sustain premature occult dissemination of cancer cells, such as that observed in CUPs. We sequenced MET in genomic DNA obtained from 47 early metastatic cancers. By extensive immunohistochemical analysis a primary site was afterward postulated in 24 patients, whereas 23 cases remained of unknown primary (CUPs). MET somatic mutations were found in seven cases, all belonging to the CUP cohort. Mutational incidence (30%) was thus significantly higher than the expected one (4%), in the absence of high mutational background. Several nucleotide changes were novel and clustered either in the kinase domain or in the extracellular semaphorin domain. Mutated receptors were functional and sustained the transformed phenotype, suggesting that MET activating mutations are genetic markers associated with the CUP syndrome.

Influence of myocardial fibrosis on left ventricular hypertrophy in patients with symptomatic severe aortic stenosis.

AIM: It was the aim of our study to determine whether myocardial fibrosis influences physiologic or non-physiologic left ventricular (LV) hypertrophy in severe aortic stenosis. METHODS: Myocardial fibrosis was evaluated using specimens taken from the ventricular septum in 79 patients submitted to aortic valve replacement because of symptomatic aortic stenosis. Patients were considered to have physiologic LV hypertrophy if end-systolic wall stress, evaluated by echocardiography, was <90 kdyn/cm(2), while those with end-systolic wall stress >90 kdyn/cm(2) were considered to have non-physiologic hypertrophy. RESULTS: Fibrosis tissue mass index was significantly inversely related with LV fractional shortening and directly related with LV diastolic and systolic diameter and LV mass index (LVMI). Patients with non-physiologic hypertrophy (n = 24) had a higher LVMI due to larger LV diastolic and systolic diameters with thinner wall, resulting in lower relative wall thickness. These patients had a higher fibrosis tissue mass index and impaired LV systolic and diastolic functions, as suggested by lower LV fractional shortening and higher mean wedge pressure. At follow-up of 7.4 ± 2.1 months, the LVMI and New York Heart Association class remained higher in patients with non-physiologic hypertrophy. CONCLUSIONS: Our study suggests a different quality of hypertrophies in patients with aortic stenosis, where myocardial fibrosis seems to be the critical abnormality that differentiates adaptive from maladaptive response to increased afterload.

The presence of poorly differentiated clusters predicts survival in stage II colorectal cancer.

In stage II colorectal carcinoma (CRC), adjuvant chemotherapy is reserved to cases at high risk of adverse outcome. This study aims to investigate the prognostic value of tumor budding (TB) and poorly differentiated clusters (PDC) in this setting. In a cohort of 149 patients with surgically resected stage II CRC not undergoing neoadjuvant or adjuvant treatments, we assessed the prognostic value of several clinical-pathological variables, including PDC and TB, on cancer-specific survival (CSS). Rectal location, lymphovascular invasion, and a number of lymph nodes < 12 confirmed to be significant and independent predictors of shorter CSS. A total of 117 CRCs were graded as PDC-G1 (0-4 PDCs), 19 as PDC-G2 (5-9 PDCs), and 13 as PDC-G3 (> 9 PDCs). Ninety-eight cases had PDC absent. TB foci were found in 91 CRCs; 121 were classified Bd1, 16 were Bd2, and 12 were Bd3. PDC-G2/G3 was significantly prognostic of shorter CSS (P < 0.0001). Among PDC-G1 cases, the presence of PDC was significantly associated with reduced CSS (P < 0.0001). Moreover, in the whole 149 CRCs, it had higher sensitivity and specificity to identify high-risk patients, compared to PDC grade, and it was independently associated with shorter CSS at multivariate analysis. High TB grade (Bd3) was significantly associated with shorter CSS (P = 0.0001), but it lost prognostic value at multivariate analysis. These findings suggest that the presence of PDC in stage II CRCs might be added to the pool of high-risk factors, warranting the use of adjuvant chemotherapy.

Validating a nodal regression system for gastric cancer: An ancillary cohort study of the GASTRODOC trial.

BACKGROUND: To validate a nodal regression system for gastric cancer and to verify its impact on prognosis. METHODS: This is an ancillary study which included 47 patients of the GASTRODOC trial. The dedicated pathologists of each Institute were invited to revise all the lymph nodes included in the surgical specimens in order to classify the regression according to the grading system proposed by Tsekrekos et al. The association of the nodal regression system and the clinico-pathological characteristics and prognosis were investigated. RESULTS: According to the classification of Tsekrekos et al., there were 19 (40.4%) patients with grade a, 14 (29.8%) with grade b and 14 (29.8%) with grade c nodal regression. This regression system showed significant statistical associations with pathological N status (p < 0.001), residual tumor classification (p = 0.003) and Becker regression system (p = 0.011). At multivariable analysis only Tsekrekos' grading regression system was significantly associated with the PFS (HR 10.1, 95% CI 1.3-75.5; p = 0.025). CONCLUSIONS: The analyzed nodal regression system is significantly associated with Becker's regression system and it has a strong correlation with prognosis.

The Prognostic Impact of Histology in Esophageal and Esophago-Gastric Junction Adenocarcinoma.

Stage significantly affects survival of esophageal and esophago-gastric junction adenocarcinomas (EA/EGJAs), however, limited evidence for the prognostic role of histologic subtypes is available. The aim of the study was to describe a morphologic approach to EA/EGJAs and assess its discriminating prognostic power. Histologic slides from 299 neoadjuvant treatment-naïve EA/EGJAs, resected in five European Centers, were retrospectively reviewed. Morphologic features were re-assessed and correlated with survival. In glandular adenocarcinomas (240/299 cases-80%), WHO grade and tumors with a poorly differentiated component ≥6% were the most discriminant factors for survival (both p < 0.0001), distinguishing glandular well-differentiated from poorly differentiated adenocarcinomas. Two prognostically different histologic groups were identified: the lower risk group, comprising glandular well-differentiated (34.4%) and rare variants, such as mucinous muconodular carcinoma (2.7%) and diffuse desmoplastic carcinoma (1.7%), versus the higher risk group, comprising the glandular poorly differentiated subtype (45.8%), including invasive mucinous carcinoma (5.7%), diffuse anaplastic carcinoma (3%), mixed carcinoma (6.7%) (CSS p < 0.0001, DFS p = 0.001). Stage (p < 0.0001), histologic groups (p = 0.001), age >72 years (p = 0.008), and vascular invasion (p = 0.015) were prognostically significant in the multivariate analysis. The combined evaluation of stage/histologic group identified 5-year cancer-specific survival ranging from 87.6% (stage II, lower risk) to 14% (stage IVA, higher risk). Detailed characterization of histologic subtypes contributes to EA/EGJA prognostic prediction.