Immune landscape and oncobiota in HPV-Associated Colorectal Cancer: an explorative study.

Worldwide more than 550,000 new patients suffering from malignant tumors are associated with human papillomaviruses (HPV) infection. However, only a small portion of patients infected progress to cancer, suggesting that other factors other than HPV may play a role. Some studies have investigated HPV infection in colorectal cancer (CRC) with discordant results; moreover, the role of HPV in CRC development is still unknown. We investigated HPV infection in 50 CRC from different regions, excluding the anal one, by immunohistochemistry (IHC), real-time PCR and RNA-seq. For each patient, we studied the tumor microenvironment in neoplastic and matched non-neoplastic samples, and we compared the tumor-infiltrating immune cell phenotypes among HPV-positive and negative samples. Finally, we compared the CRC-associated microbiota in HPV-positive and negative neoplastic samples by 16S rRNA sequencing. HPV infection was identified in 20% of CRC from the right side (caecum, ascending and transverse colon) and in 40% from the left side (descending colon and rectum). In all HPV-positive CRCs we found no expression of p53 and RB, thus suggesting HPV involvement in tumorigenesis. As far as the tumor microenvironment is concerned, in HPV-related cancers we observed a neoplastic environment with a reduced immune surveillance but an enhanced cytotoxic response by lymphocytes. HPV-positive and -negative CRC showed a different microbiota with lack of species normally found in CRC in the HPV-positive ones. Our results support the carcinogenic significance of HPV in CRC, suggesting a role of HPV in modulating the tumor immune microenvironment.

The Day-To-Day Practice of MMR and MSI Assessment in Colorectal Adenocarcinoma: What We Know and What We Still Need to Explore.

BACKGROUND: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy. SUMMARY: In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays. KEY MESSAGES: The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.

Paving the Path for Immune Enhancing Nutrition in Colon Cancer: Modulation of Tumor Microenvironment and Optimization of Outcomes and Costs.

INTRODUCTION: Published evidence suggests that immunonutrition has the potential to decrease postoperative complications and reduce length of stay in patients undergoing surgery for colorectal cancer. However, only a few studies have analyzed the effects of immunonutrition on tumor microenvironment and evaluated its prognostic impact. MATERIAL AND METHODS: This is a single center retrospective study enrolling 50 patients undergoing elective surgery for colorectal cancer managed with immunonutrition and 50 patients managed with standard nutrition for comparison. Tumor microenvironment was analyzed before (on the biopsy at the time of diagnosis) and after (on the matched surgical specimen) administration of immunonutrition. Immune function related indicators, including cytotoxic T-lymphocytes, helper T-cells, antigen presenting cells, natural killer cells, T-exhausted lymphocytes, T-regulatory cells, M1 and M2 tumor associated macrophages and PD-L1 expression were assessed by immunohistochemistry. For both groups, clinicopathological data were collected and a 5-year follow-up was available. RESULTS: We found that immunonutrition significantly activated the T-cell response against cancer, alter tumor microenvironment phenotype towards M2 polarization and inhibits the PD1/PD-L1 axis. A lower rate of postoperative complications and a shorter length of stay (p = 0.04) were observed in the immune nutrition group. Compared to standard nutrition group, patients managed wit immune nutrition showed a higher 5-year overall survival (p = 0.001). Finally, immune nutrition allowed to reduce the hospital care costs. CONCLUSIONS: Immunonutrition modulates tumor microenvironment by improving immune function and could prolong survival in patients undergoing elective surgery for colorectal cancer. Further studies are needed to optimize IN protocols and confirm their prognostic impact.

A national survey on the current status of minimally invasive gastric practice on behalf of GIRCG.

Italian Research Group for Gastric Cancer (GIRCG), during the 2013 annual Consensus Conference to gastric cancer, stated that laparoscopic or robotic approach should be limited only to early gastric cancer (EGC) and no further guidelines were currently available. However, accumulated evidences, mainly from eastern experiences, have supported the application of minimally invasive surgery also for locally advanced gastric cancer (AGC). The aim of our study is to give a snapshot of current surgical propensity of expert Italian upper gastrointestinal surgeons in performing minimally invasive techniques for the treatment of gastric cancer in order to answer to the question if clinical practice overcome the recommendation. Experts in the field among the Italian Research Group for Gastric Cancer (GIRCG) were invited to join a web 30-item survey through a formal e-mail from January 1st, 2020, to June 31st, 2020. Responses were collected from 46 participants out of 100 upper gastrointestinal surgeons. Percentage of surgeons choosing a minimally invasive approach to treat early and advanced gastric cancer was similar. Additionally analyzing data from the centers involved, we obtained that the percentage of minimally invasive total and partial gastrectomies in advanced cases augmented with the increase of surgical procedures performed per year (p = 0.02 and p = 0.04 respectively). It is reasonable to assume that there is a widening of indications given by the current national guideline into clinical practice. Propensity of expert Italian upper gastrointestinal surgeons was to perform minimally invasive surgery not only for early but also for advanced gastric cancer. Of interest volume activity correlated with the propensity of surgeons to select a minimally invasive approach.

Immunohistochemical Markers of the Epithelial-to-Mesenchymal Transition (EMT) Are Related to Extensive Lymph Nodal Spread, Peritoneal Dissemination, and Poor Prognosis in the Microsatellite-Stable Diffuse Histotype of Gastric Cancer.

Background: Although the prognostic value of the epithelial-to-mesenchymal transition (EMT) in gastric cancer has been reported in several studies, the strong association with the diffuse type may represent a confounding factor. Our aim is to investigate potential correlations among EMT status, tumor advancement, and prognosis in diffuse gastric cancer. Methods: Between 1997 and 2012, 84 patients with microsatellite-stable (MSS) diffuse-type tumors underwent surgery. The EMT phenotype was assessed with the E-cadherin, CD44, and zinc finger E-box binding homeobox 1 (ZEB-1) immunohistochemical markers. Results: Forty-five out of 84 cases (54%) were EMT-positive; more advanced nodal status (p = 0.010), pTNM stage (p = 0.032), and vascular invasion (p = 0.037) were observed in this group. The median numbers of positive nodes (13 vs. 5) and involved nodal stations (4 vs. 2) were higher in the EMT-positive group. The cancer-related survival time was 26 months in EMT-positive cases vs. 51 in negative cases, with five-year survival rates of 17% vs. 51%, respectively (p = 0.001). The EMT status had an impact on the prognosis of patients with <70 years, R0 resections, or treatment with adjuvant chemotherapy. Tumor relapses after surgery and peritoneal spread were significantly higher in the EMT-positive tumors. Conclusions: EMT status, when assessed through immunohistochemistry, identified an aggressive phenotype of MSS diffuse-type tumors with extensive lymph nodal spread, peritoneal dissemination, and worse long-term outcomes.

Peripancreatic paraganglioma: Lesson from a round table.

We described the case of a peripancreatic paraganglioma (PGL) misdiagnosed as pancreatic lesion. Surgical exploration revealed an unremarkable pancreas and a large well-defined cystic mass originating at the mesocolon root. Radical enucleation of the mass was performed, preserving the pancreatic tail. Histologically, a diagnosis of PGL was rendered. Interestingly, two previously unreported mutations, one affecting the KDR gene in exon 7 and another on the JAK3 gene in exon 4 were detected. Both mutations are known to be pathogenetic. Imaging and cytologic findings were blindly reviewed by an expert panel of clinicians, radiologists, and pathologists to identify possible causes of the misdiagnosis. The major issue was lack of evidence of a cleavage plane from the pancreas at imaging, which prompted radiologists to establish an intra-parenchymal origin. The blinded revision shifted the diagnosis towards an extra-pancreatic lesion, as the pancreatic parenchyma showed no structural alterations and no dislocation of the Wirsung duct. Ex post, the identified biases were the emergency setting of the radiologic examination and the very thin mesocolon sheet, which hindered clear definition of the lesion borders. Original endoscopic ultrasonography diagnosis was confirmed, emphasizing the intrinsic limit of this technique in detecting large masses. Finally, pathologic review favored a diagnosis of PGL due to the morphological features and immonohistochemical profile. Eighteen months after tumor excision, the patient is asymptomatic with no disease relapse evident by either radiology or laboratory tests. Our report strongly highlights the difficulties in rendering an accurate pre-operative diagnosis of PGL.

The Percentage of Signet Ring Cells Is Inversely Related to Aggressive Behavior and Poor Prognosis in Mixed-Type Gastric Cancer.

Background and Objectives: Only recently the percentage of signet ring cells (SRCs) in gastric cancer (GC) has been proposed as an independent predictor of survival. High amounts of SRCs have been related to lower recurrence and mortality rates, better prognosis, and favorable clinicopathological features in a poorly cohesive histotype. It is not known what the effect of SRC percentage in mixed-type GC is. We investigate the role of SRCs as a prognostic marker in mixed-histotype GC. Methods: A retrospective analysis was performed through a prospectively maintained database of patients with diagnosed "mixed-type" gastric carcinoma, defined according to 2019 WHO classification. These patients underwent surgery between 1995 and 2016, and their tissue samples were stored in a tissue bank. All slides were analyzed, and patients were divided into three groups according to the percentage of SRCs: "Group 1" (displaying ≤10% of SRCs), "Group 2" (displaying <90% but >10% of SRCs), and "Group 3" (displaying ≥90% of SRCs). We compared clinical and pathological features as well as prognostic factors between the different groups. Results: Among 164 enrolled patients, 68.9% were male and 31.1% were female (p = 0.612). The mean (±SD) age at diagnosis was 71.4 ± 9.6 years. Ninety-eight (59.7%) patients were classified as "Group 1", 66 (40.3%) as "Group 2", and none as "Group 3". Five-year overall survival was remarkably higher in Group 2 (73.8%) in comparison to Group 1 (35.4%), p < 0.001. Mortality risk was three times higher in patients with ≤10% SRC pattern compared to those with >10% [HR 2.70 (95% CI 1.72-4.24)]. After adjusting according to potential confounding factors, SRC percentage was still an independent predictor of survival. Conclusions: The proportion of SRCs is inversely related to aggressive behavior and poor prognosis in mixed-type GCs, highlighting the role of SRC amount as an independent predictor of survival.

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.

Surgeon-Pathologist Team Approach Dramatically Affects Lymph Nodes Detection and Improves Patients' Short-Term Outcome.

The downstaging of gastric cancer has recently gained particular attention in the field of gastric cancer surgery. The phenomenon is mainly due to an inappropriate sampling of lymph nodes during standard lymphadenectomy. Hence, collection of the maximum number of lymph nodes is a critical factor affecting the outcome of patients. None of the techniques proposed so far have demonstrated a real efficiency in increasing the number of identified lymph nodes. To harvest the maximum number of lymph nodes, we designed a protocol for on-site macroscopic evaluation and sampling of lymph nodes according to the Japanese Gastric Cancer Association protocol. The procedure was carried out by a surgeon/pathologist team in the operating room. We enrolled one hundred patients, 50 of whom belonged to the study group and 50 to a control group. The study group included patients who underwent lymph node dissection following the proposed protocol; the control group encompassed patients undergoing standard procedures for sampling. We compared the number and maximum diameter of lymph nodes collected in both groups, as well as some postoperative variables, the 30-day mortality and the overall survival. In the study group, the mean number of lymph nodes harvested was higher than the control one (p = 0.001). Moreover, by applying the proposed technique, we sampled lymph nodes with a very small diameter, some of which were metastatic. Noticeably, no difference in terms of postoperative course was identified between the two groups, again supporting the feasibility of an extended lymphadenectomy. By comparing the prognosis of patients, a better overall survival (p = 0.03) was detected in the study group; however, to date, no long-term follow-up is available. Interestingly, patients with metastasis in node stations number 8, 9, 11 or with skip metastasis, experienced a worse outcome and died. Based on our preliminary results, the pathologist/surgeon team approach seems to be a reliable option, despite of a slight increase in sfaff workload and technical cost. It allows for the harvesting of a larger number of lymph nodes and improves the outcome of the patients thanks to more precise staging and therapy. Nevertheless, since a higher number of patients are necessary to confirm our findings and assess the impact of this technique on oncological outcome, our study could serve as a proof-of-concept for a larger, multicentric collaboration.

A look towards the clonal origin of metastatic pulmonary carcinosarcoma: Report of a patient with an unexpected long-term survival.

INTRODUCTION: Pulmonary carcinosarcoma is a rare histological subtype of non-small cell lung cancer, defined by the combination of epithelial and mesenchimal elements. Prognosis is usually dismal, with a median survival of about 6 months. The use of immunotherapy by blockade of PD1/PD-L1 immune checkpoint signaling has been shown to improve patients' survival. However, local aggressiveness and distant metastases are frequent. Spread to the gastrointestinal tract is seldom reported. The genetic landscape of the disease has only recently begun to emerge, pointing at TP53, KRAS, EGFR and MET as the most common mutated genes. CASE DESCRIPTION: We describe the case of a metastatic patient with 37 months overall survival, treated by an aggressive multimodal approach combining surgery, chemotherapy, radiotherapy and immunotherapy. To shed new light on the molecular basis for sarcomatoid component in lung carcinoma, we performed next generation sequencing analysis of the squamous and sarcomatoid component by the two sites. We demonstrated a clonal origin and hypermutability of the sarcomatous elements that may account for the good response to immunotherapy. Moreover, we identified some mutations involving TP53 and EGFR genes, targetable by already available drugs. CONCLUSIONS: We depicted a model of how a squamous cell carcinoma can differentiate during its natural history into sub-clonal populations with different features and may ultimately result in a neoplasm (i.e. pulmonary carcinosarcoma) showing clonal heterogeneity. Our data might contribute to a better understanding of the pathogenesis and molecular mechanisms of this rare tumor and open new ways for a more tailored approach.

Signet ring cell percentage in poorly cohesive gastric cancer patients: A potential novel predictor of survival.

BACKGROUND AND OBJECTIVES: Signet ring cells (SRC) are widely acknowledged as a prognostically unfavorable histotype amongst poorly cohesive gastric cancer. In this study we evaluated the impact of SRC percentage on the clinical, pathological and prognostic features of these tumors according to the classification by the European Chapter of the IGCA. METHODS: We retrospectively reviewed records of patients with poorly cohesive gastric cancer that underwent surgery between 1995 and 2016, whose tissue specimens were available in a biological bank. All slides were put under revision, patients were reclassified into three groups according to the proportion of signet ring cells: "pure" SRC (containing ≥90% of SRCs), Poorly Cohesive-Not Otherwise Specified (PC-NOS) (containing ≤10% of SRCs), and PC-NOS/SRC (containing <90% but >10% of SRCs). The clinicopathological factors between different types were analyzed and prognostic differences were compared. RESULTS: Among 143 enrolled patients, 51% were male and 49% were female. The mean (±SD) age at diagnosis was 61 ± 13.9 years. Eighty-seven patients (60.8%) were reclassified as PC-NOS, 56 (39.2%) as PC-NOS/SRC and none as "pure" SRC. Five-years overall survival was significantly higher in PC-NOS/SRC group (63.3%) compared with PC-NOS group (12.7%). The increase in mortality risk was more than four-fold in patients with PC-NOS pattern compared to those with PC-NOS/SRC (HR 4.32 [95% CI 2.5-7.4]. After adjustment for potential confounding factors, SRC pattern was still an independent predictor of survival. CONCLUSIONS: The percentage of SRCs is inversely related to tumor aggressiveness, confirming the role of SRC pattern as an independent predictor of survival.

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.

Molecular Alterations in Gastric Preneoplastic Lesions and Early Gastric Cancer.

Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete (MUC2) and incomplete (MUC2, MUC5AC, and MUC6) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and MUC6 in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy.

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.

Preoperative oral immunonutrition in gastrointestinal surgical patients: How the tumour microenvironment can be modified.

BACKGROUND & AIMS: This study is focused on the impact of enteral immunonutrition on the cell-mediated immune response in the microenvironment of gastric and colorectal cancers. METHODS: This is a prospective pilot study approved by the local Ethics Committee. The immunophenotypic structure of the immune cells before (on the biopsy) and after (on the surgical sample) the administration of the immunonutrition in 16 patients is compared with 8 patients receiving regular diet. The samples of non-tumour tissue from sleeve-gastrectomy are used as non-neoplastic control. Antibodies were tested: CD4, CD8, PD-1, FOX-P3, CD68, CD163, CD80, CD21, CD56, PD-L1. We applied already well-known scoring systems for the evaluation of the immunohistochemistry and compared our data in the different groups by statistical analysis. RESULTS: In treated patients, we detected a modulation of the immune response with higher number of cytotoxic and helper T-lymphocytes in the tumour microenvironment of the surgical specimens compared to the pre-operative biopsy, and a lower number of lymphocytes presenting an exhausted (i.e. double positive CD8 and PD-1 lymphocytes) and regulatory (i.e. double positive CD4 and FOX-P3 lymphocytes) phenotype. Moreover we observed the M1 polarization with a lower number of CD163 positive macrophages and the inhibition of the PD-1/PD-L1 pathway in treated patients. CONCLUSIONS: The immunonutrition impacts on the tumoral microenvironment of gastric and colorectal cancer activating the inflammatory pathway, in terms of humoral and cellular response.

Pathological response and outcome after neoadjuvant chemotherapy with DOC (docetaxel, oxaliplatin, capecitabine) or EOF (epirubicin, oxaliplatin, 5-fluorouracil) for clinical T3-T4 non-metastatic gastric cancer.

PURPOSE: In this prospective observational study, we sought to compare the efficacy and safety of docetaxel + oxaliplatin + capecitabine (DOC) with epirubicin + oxaliplatin + 5-fluouracil (EOF) as neoadjuvant chemotherapy (NAC) for clinical T3 or T4 non-metastatic gastric cancer (GC) patients. METHODS: The DOC NAC consisted of docetaxel 35 mg/m2 (days 1-8), oxaliplatin 85 mg/m2 (day 1), and capecitabine 750 mg/m2 twice daily (days 1-14), every 3 weeks. The EOF NAC consisted of intravenous (IV) epirubicin 50 mg/m2 combined with IV oxaliplatin 130 mg/m2 on day 1 and continuous infusion 5-fluouracil 750 mg/m2 on days 1-5, every 3 weeks. After 4 cycles of NAC or upon progression during chemotherapy, patients underwent gastrectomy with standard D2 or D3 lymphadenectomy. Pathological complete response rate per Becker tumor regression grading system was the primary endpoint and the secondary endpoints included progression-free survival (2-yr PFS) and 2-year overall survival (2-yr OS) and tolerability. RESULTS: Overall, we identified 63 patients with T3-4 non-metastatic GC starting either NAC regimen between January 2010 and December 2017 at our Institution: 34 in the DOC group and 29 in EOF group. Thirty patients (88%) in the DOC group and 22 (76%) in the EOF group completed the 4 planned cycles of NAC. Fifty-seven patients received surgery. Results indicated no statistical significant differences between the two groups, and only a trend for some better data in favour of the DOC group. The R0 resection rate was 90.6% and 88.0% for the DOC and EOF cohorts, respectively. The pathological complete response rate was 6.2% in the DOC group and 4.0% in the EOF group. Becker 1-2 pathological response was found in 46.8% of the DOC cohort and 28.0% of the EOF cohort (p = .14). The 2-yr PFS rate was 54.1% for DOC vs. 41.4% for EOF (p = .14) and the 2-yr OS rate was 80.8% for DOC vs. 58.6% for EOF (p = .05). Neutropenia was the most common grade ≥3 toxicity and occurred in 8 (23.5%) patients of the DOC group and 10 (34.4%) patients of the EOF group (p = .33). CONCLUSIONS: These findings seem to confirm the feasibility of NAC for clinically T3 and T4 non-metastatic GC and, despite no statistical significant difference was documented, suggest a trend for better activity and tolerability for the docetaxel-based regimen (DOC) compared to the epirubicin-based combination (EOF).

Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases.

MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.

Occult malignancy underlying a case of "hyperacute" onset of severe pulmonary hypertension.

Investigations in a patient with new-onset pulmonary hypertension should include screening for undiagnosed malignancy http://bit.ly/2mrLmGM.