Brain location and tumor biological markers in high- and low-grade gliomas.

BACKGROUND: Recent studies suggest gliomas location may be correlated with specific biological signatures. Our purpose was to focus on the possible correlation between MGMT metilation status and Ki67 positivity with patient age, glioma location and lateralization. METHODS: We performed a retrospective evaluation to assess the correlation between MGMT metilation status and Ki67 index positivity with patient age, glioma location and lateralization. RESULTS: The study included 174 supratentorial gliomas. Of these, 144 tumors were high grade gliomas (HGGs), and 30 tumors were low grade gliomas (LGGs). In HGG group we detected an association between tumor location and MGMT status. Those GBMs located in the frontal lobe were significantly associated with MGMT methylated status (MGMT+) and Ki67<30% than those GBMs located in other sites; while those GBMs located in the temporal lobe were associated with MGMT unmethylated (MGMT-) status. In anaplastic gliomas, we found an association between the involvement of the frontal lobe with MGMT+ status and Ki67<30%. In LGG group, our results showed that both frontal and temporal lobe were associated with a Ki67<30% and there was a predictive value for MGMT methylation status when patient age increased. CONCLUSIONS: Our findings suggest there is a high variability in anatomical distribution of biological glioma markers and this high heterogeneity may have a clinical role. Moreover, our study supports the idea that frontal lobe HGGs may be biologically favorable. Considering that as all glioma with lobar location are more amenable to radical surgical resection, it may be assumed that frontal tumor can have a better prognosis, and we have shown, to our knowledge for the first time, this is true both for HGG and for LGG.

Immunoglobulin G4-Related Disease of the Intestine: A Clinicopathological Entity to Be Considered.

Background and Objectives: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized immune-mediated, systemic condition of unknown etiology, associated with fibroinflammatory lesions. Diagnosis is set in the presence of IgG4-positive plasma cell infiltration of the involved tissue and elevated serum IgG4 levels. However, approximately 30% of patients have normal serum IgG4 levels. IgG4-RD may affect several organs, including the pancreas, bile ducts, mesentery, retroperitoneum, and salivary glands, but the involvement of the gastrointestinal tract is uncommon. Materials and Methods: The case series of 4 patients with IgG4-RD involving the intestinal tract was observed in the period of 2017-2022. Colorectal and ileal biopsy specimens were stained with hematoxylin and eosin and immunohistochemical techniques using monoclonal antihuman IgG4 primary antibody. Diagnosis of IgG4-RD was based on the presence of >50 cells/ HPF and IgG4/IgG ratio >40 confirmed by two pathologists. Results: IgG4-RD was set in patients previously diagnosed as affected by Crohn's disease. Conclusions: Systematic IgG4 immunohistochemical staining should be considered in the diagnostic workup of patients with gastrointestinal strictures, mimicking Crohn's disease. The exact prevalence of the condition is likely more frequent than reported and should be defined by a large series of consecutive patients.

Hypopharynx, oropharynx morphology and histology in severe Coronavirus 2 patients treated by noninvasive ventilation: comparison between full-face mask and helmet strategies.

BACKGROUND: Non-invasive ventilation may alter the morphology and histology of the upper airway mucosa. This study aimed to investigate the alterations of hypopharynx and oropharynx mucosa, identified during oro-tracheal intubation procedure via video-assisted laryngoscopy, in severe acute respiratory syndrome Coronavirus 2 related, treated by non-invasive ventilation via full-face mask or helmet. METHODS: Data of patients affected by Coronavirus 2 admitted to COVID Hospital of L'Aquila (Italy), presenting hypopharynx and oropharynx morphology alterations, requiring oro-tracheal intubation for invasive ventilation and initially treated with non-invasive ventilation were included in the study. The study aimed to investigate the upper airway mucosa alterations using oropharyngeal and hypopharyngeal images and biopsies taken during video-assisted-laryngoscopy. Data from the hypopharynx and oropharynx morphology and histology alterations between non-invasive ventilation via a full-face mask or helmet used during hospitalization were compared. RESULTS: From 220 data recorded, 60 patients were included in the study and classified into non-invasive ventilation full-face mask group (30/60) and via helmet group. Comparing data between groups, significant differences were found with respect to hyperemia (77% vs. 20%), laryngeal bleeding ulcerations (87% vs. 13%), and vocal cord edema with >50% narrowing of the tracheal lumen (73% vs. 7%), respectively. The histology examination revealed fibrin-necrotic exudate with extensive necrotic degenerative changes in the sample tissue of the groups. There were not any differences in the duration time of non-invasive ventilation, time from hospitalization and the start of ventilation between groups. CONCLUSIONS: The data from this research suggested that there were differences in airway mucosa damages among patients treated with a full-face mask or helmet. Further studies should be planned to understand which non-invasive ventilation support may mitigate upper airway mucosa damages when oro-tracheal intubation is requested for invasive respiratory support.

Cancer Three-Dimensional Spheroids Mimic In Vivo Tumor Features, Displaying "Inner" Extracellular Vesicles and Vasculogenic Mimicry.

The role of extracellular vesicles (EVs) as mediators of cell-to-cell communication in cancer progression is widely recognized. In vitro studies are routinely performed on 2D culture models, but recent studies suggest that 3D cultures could represent a more valid model. Human ovarian cancer cells CABA I were cultured by the hanging drop method to form tumor spheroids, that were moved to low adhesion supports to observe their morphology by Scanning Electron Microscopy (SEM) and to isolate the EVs. EVs release was verified by SEM and their identity confirmed by morphology (Transmission Electron Microscopy, TEM), size distribution (Nanoparticles Tracking Analysis), and markers (CD63, CD9, TSG-101, Calnexin). CABA I form spheroids with a clinically relevant size, above 400 µm; they release EVs on their external surface and also trap "inner" EVs. They also produce vasculogenic mimicry-like tubules, that bulge from the spheroid and are composed of a hollow lumen delimited by tumor cells. CABA I can be grown as multicellular spheroids to easily isolate EVs. The presence of features typical of in vivo tumors (inner entrapped EVs and vasculogenic mimicry) suggests their use as faithful experimental models to screen therapeutic drugs targeting these pro-tumorigenic processes.

Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status.

HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results.

Serum transglutaminase antibodies do not always detect the persistent villous atrophy in patients with celiac disease on a gluten-free diet.

BACKGROUND AND AIM: Serum transglutaminase antibodies (tTGs) are used for celiac disease screening and to monitor celiac disease patients on a gluten-free diet (GFD). The need for histology of duodenal biopsies to assess mucosal healing after a GFD is still a matter of debate. We evaluated whether tTGs are adequate to detect the persistence of histological lesions of duodenal mucosa in celiac patients after a GFD. METHODS: In total 253 patients with histological diagnosis of celiac disease according to Marsh criteria, both at the time of diagnosis (T0) and 18-24 months after starting a GFD (T2), were included. tTGs were evaluated both at T0 and T2; endomysial antibodies (EMAs) only at T0. RESULTS: At T0, 9.2% of patients had both tTG and EMA negative values, despite the evidence of duodenal lesions: 33.3% of Marsh 1, 14.3% of Marsh 2 and 5.2% of Marsh 3. At T2, tTGs were negative in 77.6% of patients: 82.2% of Marsh 0, 79.8% of Marsh 1, 70.0% of Marsh 2 and 59.1% of Marsh 3. At T2, approximately 60% of patients with the persistence of mucosal atrophy had negative tTGs. At T0, tTG median values were lower in patients with Marsh 1 and Marsh 2 than patients with Marsh 3 (P < 0.001), whereas no difference was found at T2 regardless of Marsh's grade (P = 0.4). CONCLUSIONS: The results of our study highlight how histologic evaluation of duodenal biopsies remains the gold standard for both celiac disease diagnosis and the evaluation of mucosal recovery after 18-24 months of a GFD.

Sporadic perivascular epithelioid cell tumor of the wall of the jejunum A case report.

BACKGROUND: Perivascular epithelioid cell tumors are rare mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. They are considered ubiquitous tumors and have been described in different organs, but gastro-intestinal PEComas are diseases of extreme rarity. METHODS: We report a case of a 51-year-old woman, without a medical history of tuberous sclerosis complex, affected by abdominal PEComa, adhering tightly to the jejunal loop and to the spleen. RESULTS: During the surgical operation, a large abdominal mass was found, and surgical resection was carried out. Definitive histologic and ultrastructural findings were consistent with PEComa. CONCLUSION: Given the rarity of GI-PEComas and the lack of cases reported in the literature, we want to emphasize the importance of conducting further studies in this regard, to better describe their biological behaviour. KEY WORDS: Gastro-intestinal tumor, PEComa, Perivascular epithelioid cell tumors.

Hypovolemic shock after pelvic radiotherapy. A rare combination leading to a devastating complication.

BACKGROUND: Radiotherapy currently plays a key role in pelvic malignancies' management. Excellent outcomes have been reported on its association with chemotherapy for the treatment of the anal carcinoma. Despite that, the combined use of chemo- and radiotherapy and the high doses administered seem to be strongly associated with early and late onset side effects. METHODS: We reported a case of a 72 years old woman, affected by anal squamous cell carcinoma. She underwent chemotherapy, and then radiotherapy, with good results. RESULTS: During a regular MR control, the patient developed anaphylactic reaction to Gadolinium, and after that a rectosigmoid ischemia with total necrosis of the posterior rectal wall was diagnosed and surgically treated with Hartmann procedure. CONCLUSION: In our case we faced with the rapid and severe degeneration of pelvic anatomy determined by the sum of vascular alterations following hypovolemic shock and pelvic tissues alteration after radiotherapy. It seems essential not to underestimate the exponential outcome of a similar unusual combination of events. KEY WORDS: Anal carcinoma, Hypovolemic shock, Pelvic radiotherapy, Rectal necrosis.

Intensive first-line FIr-C/FOx-C association of triplet chemotherapy plus cetuximab in RAS wild-type metastatic colorectal cancer patients: preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers.

BACKGROUND: Intensive triplet chemotherapy/bevacizumab significantly increased metastatic colorectal cancer (MCRC) outcome. This phase II study investigated the safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line RAS wild-type and the prediction of individual limiting toxicity syndromes (LTS) by pharmacogenomic biomarkers. METHODS: A Simon two-step design was used: p0 70%, p1 85%, power 80%, α5%, ß20%; projected objective response rate (ORR) I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-timed flat infusion 900 mg/m2 d1-2, 8-9, 15-16, 22-23; irinotecan (CPT-11) 160 mg/m2 d1 and 15, oxaliplatin 80 mg/m2 d8 and 22; CET 400mg/m2 then 250 mg/m2 d1, 8, 15, 22; every 28 days. Toxicity, and individual LTS were evaluated, compared by a Chi-square test; and activity/efficacy by log-rank. 5-FU/CPT-11 pharmacogenomic biomarkers, 5-FU degradation rate (5-FUDR), single nucleotide polymorphisms (SNPs) ABCB1, CYP3A4, DYPD, UGT1A1 were evaluated in patients with LTS and at a recommended dose. RESULTS: A total of 29 patients <75 years, with a primary/intermediate Cumulative Index Rating Scale were enrolled; the median age was 59 years; there were 7 young-elderly (yE; 24%). Recommended CPT-11/5-FU doses were 120/750 mg/m2. In the intent-to-treat analysis, the ORR was 58.6%. The primary endpoint was met in patients who received the planned three treatment cycles: the objective response (OR) was 14/18 (78%). At a median follow up of 18 months, progression-free survival (PFS) was 12, and overall survival (OS) was 23 months. At the recommended doses (received dose intensity >80%), grade 3-4 toxicities were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS 19 (65.5%), with 83% in yE patients. LTS prevalently multiple (ms) versus single site were 59% versus 7% (p = 0.006). The prevalence of reduced FUDR was 56%, SNPs CYP3A4 22%, UGT1A1 71%, and of >2 positive pharmacogenomics biomarkers was 78%, prevalently reported in patients who developed gastrointestinal LTS. CONCLUSIONS: FIr-C/FOx-C is highly active and tolerable at recommended doses in non-elderly RAS wild-type MCRC patients. LTS provided an evaluation of the toxicity burden in individual patients. Reduced FUDR, CYP3A4, and UGT1A1 SNPs may predict individual LTS-ms in patients at risk of limiting gastrointestinal toxicity. TRIAL REGISTRATION: The trial was registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009-016793-32.

Lymphangiomatosis of the ileum with perforation: A case report and review of the literature.

Lymphangiomatosis is a benign proliferation of lymph vessels. Lymphatic diseases can vary from small lymphangioma to generalized lymphangiomatosis, which is a rare condition and can have several clinical manifestations. The gastrointestinal tract may be affected, but the incidence in the intestinal wall is very low. We propose in our study a case of ileal lymphangiomatosis presenting with perforation, in which the diagnosis was made after the pathological analysis of the resected intestinal tract. Although rare and not described in the literature, intestinal lymphangiomatosis could manifest itself with acute abdomen and could be a surgical urgency. This disease should be considered when intestinal perforation is observed.

Weekly alternate intensive regimen FIrB/FOx in metastatic colorectal cancer patients: an update from clinical practice.

BACKGROUND: Several trials evaluated the role of intensive regimens, made of triplet chemotherapies plus bevacizumab, as first-line treatment for patients with metastatic colorectal cancer (mCRC). We previously reported, in a Phase II prospective study, the efficacy and the tolerability of FIrB/FOx regimen, reporting interesting results in terms of received dose intensities (rDIs) and safety. METHODS: We reported a retrospective update of 85 patients treated with FIrB/FOx, an intensive regimen of 5-fluorouracil, bevacizumab, and weekly alternate irinotecan and oxaliplatin, to confirm its feasibility in "real life". Subgroup analyses were performed, particularly among patients treated with standard and modified FIrB/FOx (based on age, performance status, and/or comorbidities). RESULTS: Overall, 3-month objective response rate (ORR) and 6-month ORR were 75.9% and 55.3%, respectively. Median progression-free survival (PFS) and median overall survival (OS) were 14.4 and 34.9 months, respectively. Among the patients treated with standard and modified regimens, 3-month ORR, PFS, and OS were 75.8% and 76% (P=1.0000), 14.4 and 14.4 months (P=0.8589), and 37.8 and 26.6 months (P=0.7746), respectively. Among the K/NRAS wild-type and K/NRAS mutant patients, 3-month ORR, PFS, and OS were 95.2% and 74.5% (P=0.0526), 15.3 and 14.4 months (P=0.8753), and 37.8 and 51.4 months (P=0.8527), respectively. The rDIs were ≥80% of full doses both in the standard and in the modified regimens subgroups. Cumulative G3/4 toxicities were neutropenia (14.1%), diarrhea (17.6%), asthenia (9.4%), vomiting (5.6%), and hypertension (16.5%). CONCLUSION: This update shows that intensive regimens such as FIrB/FOx are also feasible options for first-line treatment of mCRC patients in the "real-life" setting.

Looking for A Place for Dose-Dense TMZ Regimens in GBM Patients: An Experience with MGMT Exploratory Evaluation.

Prolonged exposure to temozolomide (TMZ) could improve clinical outcomes in recurrent glioblastoma multiforme (GBM) patients. We previously developed a dose-dense regimen of TMZ in a phase II study (180 mg/m2 from days 1 to 5 every two weeks). A retrospective analysis of patients with macroscopic residual GBM treated with "post-induction" dose-dense TMZ was conducted, adding an explorative subgroup analyses among patients with different O6-methylguanine DNA methyltransferase (MGMT) expressions (negative vs positive, < vs ≥ of 50 % of cells stained, < vs ≥ 70% of cells stained). Thirty-six patients were evaluated; after a median follow-up of 36 weeks, median Progression Free Survival (PFS) and median Overall Survival (OS) were 19 and 34 weeks, respectively. MGMT expression (70% cut-off) and sex were confirmed as independent predictors for disease control rate (DCR) at multivariate analysis. At univariate analysis ECOG-PS, Sex (female), extensive tumor resection was shown to be related to a longer PFS, while MGMT expression (cutoff 70%) to a shorter PFS. Multivariate analysis with Cox hazard regression confirmed only ECOGPS as an independent predictor for PFS. ECOG-PS showed to be significant related to a longer OS. Our analysis showed that dose-dense TMZ regimens are still an option for patients with recurrent GBM, but should be used for re-challenge treatments. MGMT immunohistochemistry high expression might be used as a "surrogate" negative predictor for DCR for dd-TMZ treatments.

Peri-prostatovesicular smooth muscle tumors of undetermined malignant potential: a case report.

INTRODUCTION: Smooth muscle tumors of undetermined malignant potential (STUMPs) are atypical smooth muscle tumors, most of which derived from uterine tissue. STUMPs of male genitourinary system and of the male pelvic organs are uncommon. CASE DESCRIPTION: In this report, we describe the first case of peri-prostatovesicular STUMP that was treated with laparoscopic excision, in a young asymptomatic man. CONCLUSIONS: In most cases, the definitive diagnosis can be made only after surgical resection and accurate histological examination. The usefulness of adjuvant chemotherapy remains unclear, and a standardized follow-up protocol has not been described.

Neoadjuvant chemotherapy in breast cancer: a dose-dense schedule in real life and putative role of PIK3CA mutations.

BACKGROUND: Dose-dense chemotherapy is one of the treatments of choice for neoadjuvant therapy in breast cancer (BC). Activating mutations in PIK3CA gene predict worse response to neoadjuvant chemotherapy for HER2-positive patients, while their role is less clearly defined for HER2-negative tumors. METHODS: We conducted a phase I/II study of neoadjuvant, sequential, dose-dense anthracycline/taxane chemotherapy, plus trastuzumab in HER2-positive patients and investigated the correlation of pre-treatment PIK3CA mutation status with pathologic complete response (pCR) and long-term outcome in a real-life setting. RESULTS: we established a dose-dense docetaxel recommended dose of 60 mg/m2 and 65 mg/m2, with or without trastuzumab, respectively, according to HER2-status, following dose-dense epirubicin-cyclophosphamide (90/600 mg/m2), every 2 weeks. The overall pCR rate was 21.4%; median disease-free survival (DFS) was 52 months and median overall survival (OS) was not yet reached. PIK3CA mutation status was not significantly associated with the pCR rate: 18% for both mutated and wild-type patients. The pCR rate was: 25% in the mutated and 24% in the wild-type (p 0.560) cohort of the HER2-positive subgroup; 33% both in the mutant and wild-type cohort of the triple-negative subgroup; no pCR neither in the mutant nor in the wild-type cohort of the HR-positive/HER2-negative subgroup. Among the HER2-positive population, a trend toward worse DFS was observed in case of mutation, as opposed to the triple negative population. CONCLUSIONS: This study proposes an effective and safe neoadjuvant dose-dense anthracycline/taxane schedule and suggests that PIK3CA mutation analysis can be usefully performed in real-life clinical practice.

KRAS, NRAS and BRAF mutations detected by next generation sequencing, and differential clinical outcome in metastatic colorectal cancer (MCRC) patients treated with first line FIr-B/FOx adding bevacizumab (BEV) to triplet chemotherapy.

BACKGROUND: First line triplet chemotherapy/BEV significantly improved clinical outcome of MCRC. KRAS/NRAS/BRAF mutations were evaluated by next generation sequencing (NGS) in MCRC patients treated with first line FIr-B/FOx. METHODS: KRAS exons 2-4 (KRAS2-4 ), NRAS2-4 , BRAF15 were evaluated in 67 tumours by ION Torrent platform. Mutation detection criteria: >500×sequence coverage (cov); >1% mutant allelic fraction (AF). Clinical outcomes were compared by log-rank. RESULTS: In 63 samples, KRAS2-4 /NRAS2-4 /BRAF15 wild-type (wt) were 14 (22.2%), mutant (mut) 49 (77.8%): KRAS2-4 42 (66.7%); NRAS2-4 11 (16.4%); BRAF15 5 (7.5%). Sixty mutations were detected, range 1-3 mut: 43 (71.7%) >1000×cov/>5% AF; 9 (15%) >500×cov/>5% AF; 8 (13.3%) >1000×cov/<5% AF. Mut distribution in KRAS2-4 /NRAS2-4 /BRAF15 : 40 (63.5%) >1000×cov/>5% AF, 8 (12.7%) >500×cov/>5% AF, 1 (1.6%) >1000×cov/<5% AF; BRAF15 1 (1.5%) >500×cov/>5% AF, 4 (6%) >1000×cov/<5% AF. Prevalence of ≥2 mut samples: KRAS2-4 /NRAS2-4 /BRAF15 8 (12.7%); KRAS2-4 7 (11.1%); NRAS2-4 5 (7.5%). BRAF15 mutant were all ≥2 mut (7.5%), atypical and associated to KRAS and/or NRAS mut: c.1405 G>A; c.1406 G>C; c.1756 G>A, 2 samples; c.1796 C>T. At 21 months (m) follow-up, clinical outcome wt compared to mut was not significantly different: in KRAS2-4 /NRAS2-4 /BRAF15 , progression-free survival (PFS) 18/12 m, overall survival (OS) 28/22 m; 1/≥2 mutations, PFS 14/11, OS 37/22. PFS was trendy worse in RAS/BRAF wt vs ≥2 mut genes (P 0.059). CONCLUSIONS: Most MCRC harboured KRAS2-4 /NRAS2-4 /BRAF15 mutations by NGS, often multiple and affecting few tumoral clones; 22% were triple wt. Clinical outcome is not significantly affected by KRAS2-4 /NRAS2-4 /BRAF15 genotype, trendy different in triple wt, compared with KRAS2-4 /NRAS2-4 /BRAF15 ≥2 mut.

Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer.

INTRODUCTION: Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. METHODS: Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m2/d 1-2, 8-9, 15-16, 22-23, with 100 mg/m2/d increase for dose level; DTX 50 mg/m2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. RESULTS: Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m2/d and 80 mg/m2, respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. CONCLUSIONS: First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.

KRAS and 2 rare PI3KCA mutations coexisting in a metastatic colorectal cancer patient with aggressive and resistant disease.

We describe a metastatic colorectal cancer patient, treated with first-line 5-fluorouracil, irinotecan, bevacizumab, and oxaliplatin (FIr-BFOx) therapy, with aggressive and resistant disease. KRAS, NRAS, BRAF, and PI3KCA were analyzed in primary tumor and liver metastasis. KRAS c.34G>A mutation was detected in primary tumor and liver metastasis, which additionally revealed 2 rare PI3KCA mutations (c.1633G>C and c.1645G>C). The c.1645G>C was never reported in colorectal cancer. Akt/p-AktSer473, phosphatase and tensin homolog, mismatch repair, and epidermal growth factor receptor expression was evaluated. Normal mismatch repair and epidermal growth factor receptor expression was detected. Akt was shown by primary tumor and liver metastasis, whereas p-AktSer473 was identified only in the latter, despite positive phosphatase and tensin homolog expression. Patient showed 7 months of progression-free survival and 15 months of overall survival, lower than median values reported in KRAS exon 2-mutant patients treated with the same therapy. Results lead to the hypothesis of a putative role of these mutations in worsening of the disease and are open to further confirmatory studies.

Subtypes of chronic gastritis in patients with celiac disease before and after gluten-free diet.

BACKGROUND: Celiac disease (CD) often manifests with dyspeptic symptoms and chronic gastritis is a common finding. AIM: To evaluate the frequency of lymphocytic gastritis (LG), chronic active gastritis (CAG), and chronic inactive gastritis (CIG) in patients with CD, before and after gluten-free diet (GFD). METHODS: A five-year prospective study including all consecutive patients with a new diagnosis of CD was conducted. Gastric and duodenal biopsy specimens taken both at the time of the CD diagnosis and at the first endoscopic control after 18-24 months on GFD were evaluated. RESULTS: 213 patients with CD were enrolled. At the time of the diagnosis, 42 patients (19.7%) showed normal gastric mucosa, 34 (15.9%) LG, 67 (31.5%) CAG, and 70 (32.9%) CIG. Out of the 34 patients with LG, all were Helicobacter pylori negative and the majority of them showed an improvement both of gastritis (94.1%) and duodenal lesions (82.3%) after GFD. GFD did not show significant effects on CAG and CIG. CONCLUSIONS: LG is present in 16% of CD patients, it is not associated with H. pylori infection, and it improves after GFD. Both CAG and CIG are also frequently associated with CD, but fail to respond to a GFD.

Systemic metastases from central nervous system ependymoma: case report and review of the literature.

Ependymal tumours in adults are rare, accounting for less than 4% of primary tumours of the central nervous system, and exceptionally metastasise outside the nervous system. In this study, we present a case of anaplastic ependymoma, which developed metastases outside the nervous system less than a year after its clinical onset. A healthy 65-year-old woman suddenly presented with drowsiness of unknown origin, accompanied by ingravescent fatigue, inability to maintain the upright posture, headache, nausea and vomiting. Computed tomography study performed in the emergency department showed the presence of an inhomogeneously hypodense area, with temporoparietal extension and median line deviation. After surgical excision, performed after two days, the bioptic examination demonstrated an anaplastic ependymoma with multiple areas of necrosis. The patient was submitted to adjuvant radiation therapy. At magnetic resonance imaging follow-up, performed three months after surgery, neither local recurrences nor typical 'drop metastases' to the spinal area were observed. Three months later, magnetic resonance imaging control revealed bone metastases and recurrences in the left insula and at the ipsilateral cerebellar hemisphere. Total body computed tomography examination showed metastases in the liver, vertebrae and pelvic bones, and involvement of paratracheal lymph nodes.