A prognostic model comprising pT stage, N status, and the chemokine receptors CXCR4 and CXCR7 powerfully predicts outcome in neoadjuvant resistant rectal cancer patients.

Despite the optimization of the local treatment of advanced rectal cancer (LARC), combination of preoperative chemoradiotherapy (CRT) and surgery, approximately one third of patients will develop distant metastases. Since the chemokine receptor CXCR4 has been implicated in metastasis development and prognosis in colorectal cancer, the role of the entire axis CXCR4-CXCL12-CXCR7 was evaluated to identify high relapse risk rectal cancer patients. Tumor specimens of 68 LARC patients undergoing surgery after neoadjuvant-CRT were evaluated for CXCR4, CXCR7, and CXCL12 expression through immunohistochemistry. Multivariable prognostic model was developed using classical prognostic factors along with chemokine receptor expression profiles. High CXCR4 correlated with a shorter relapse-free survival (RFS) (p = 0.0006) and cancer specific survival (CSS) (p = 0.0004). Concomitant high CXCR4-negative/low CXCR7 or high CXCR4-negative/low CXCL12 significantly impaired RFS (p = 0.0003 and p = 0.0043) and CSS (p = 0.0485 and p = 0.0026). High CXCR4/N+ identified the worst prognostic category for RFS (p < 0.0001) and CSS (p = 0.0003). The optimal multivariable predictive model for RFS was a five-variable model consisting of gender, pT stage, N status, CXCR4, and CXCR7 (AUC = 0.92, 95% CI = 0.77-0.98). The model is informative and supportive for adjuvant treatment and identifies CXCR4 as a new therapeutic target in rectal cancer.

Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid--short Radiotherapy--rectum 3rd trial).

BACKGROUND: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. METHODS/DESIGN: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT. DISCUSSION: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01898104.

Integrated strategies for allogeneic blood saving in major elective surgery.

BACKGROUND: Large use of allogeneic red blood cell concentrates (RBCc), albeit necessary in major surgery, may influence patients' outcome. DESIGN AND METHODS: We introduced an integrated strategy including patients' evaluation and supplementation associated with autologous blood collection and saving to support major elective surgery at our hospital since 2008. After 2 years of stabilization of this approach, we analyzed the results obtained in 2010 in terms of allogeneic blood usage and reduction of transfusion of stored RBCc. RESULTS: Analyzing 2010 results we found that usage of total autologous RBCc units was increased by 2.2 folds, of "not stored" autologous RBCc units by 2.4 folds and of allogeneic RBCc unit transfusion reduced by 65%. The significant reduction in the number of transfused allogeneic RBCc units associated with the use of "fresher" blood could prevent patients' complications due to immunomodulation and biologic/metabolic disregulation.

Gastric schwannoma misdiagnosed as GIST: A case report with immunohistochemical and molecular study.

Schwannomas are tumors derived from Schwann cells. Generally, they are benign and their typical site of origin is the subcutaneous tissue of the distal extremities or of the head and neck region. Gastrointestinal localization of schwannomas is extremely rare, and the stomach is the prevalent site. The present study describes the case of a gastric schwannoma in a 61-year-old male who underwent subtotal gastrectomy following a clinical diagnosis of a gastrointestinal stromal tumor (GIST). A histological, immunohistochemical and molecular study was performed to exclude the misdiagnosis of GIST. The histomorphological features of the lesion and absence of c-Kit and PDGFRA mutations indicated the diagnosis of gastric schwannoma.

Critical role of bevacizumab scheduling in combination with pre-surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: Results of the BRANCH trial.

BACKGROUND: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy. PATIENTS AND METHODS: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate. RESULTS: The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade ≥ 3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%-89%) and 85% (95%CI, 69%-93%), respectively, for the sequential-schedule. CONCLUSIONS: These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.

Duodenal gangliocytic paraganglioma, a rare entity among GEP-NET: a case report with immunohistochemical and molecular study.

Gastroenteropancreatic neuroendocrine tumors are the most incident neuroendocrine tumors. In the new WHO classification (2010) the embryological derivation of each neoplastic entity is one of the most important parameters. Gangliocytic Paraganglioma is a tumor originating in the hindgut, a rare neoplasm, generally affecting the second portion of the duodenum, the majority of which are benign.Cases of gangliocytic paraganglioma with local metastasis or local recurrence have also been reported.We describe a GP in a 48-year-old caucasian male with an unusual site (4th portion of duodenum) and an interesting immunohistochemical and molecular pattern. In particular, we examined the expression of some neuroendocrine markers and a marker of neuronal differentiation, NeuroD1, whose expression can help to better understand the nature of this neoplasia. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3720959161096807.

De-hospitalization of the pediatric day surgery by means of a freestanding surgery center: pilot study in the Lazio Region.

BACKGROUND: Day surgery should take place in appropriate organizational settings. In the presence of high volumes, the organizational models of the Lazio Region are represented by either Day Surgery Units within continuous-cycle hospitals or day-cycle Day Surgery Centers. This pilot study presents the regional volumes provided in 2010 and the additional volumes that could be provided based on the best performance criterion with a view to suggesting the setting up of a regional Freestanding Center of Pediatric Day Surgery. METHODS: This is an observational retrospective study. The activity volumes have been assessed by means of a DRG (Diagnosis Related Group)-specific indicator that measures the ratio of outpatients to the total number of treated patients (freestanding indicator, FI). The included DRGs had an FI exceeding the 3rd quartile present in at least a health-care facility and a volume exceeding 0.5% of the total patients of the pediatric surgery and urology facilities of the Lazio Region. The relevant data have been provided by the Public Health Agency and relate to 2010. The best performance FI has been used to calculate the theoretical volume of transferability of the remaining facilities into freestanding surgery centers. Patients under six months of age and DRGs common to other disciplines have been excluded. The Chi Square test has been used to compare the FI of the health-care facilities and the FI of the places of origin of the patients. RESULTS: The DRG provided in 2010 amounted to a total of 5768 belonging to 121 types of procedures. The application of the criteria of inclusion have led to the selection of seven final DRG categories of minor surgery amounting to 3522 cases. Out of this total number, there were 2828 outpatients and 694 inpatients. The recourse of the best performance determines a potential transfer of 497 cases. The total outpatient volume is 57%. The Chi Square test has pointed to a statistically significant difference of the facilities and to a non-significant difference of inferiority of the regional places of origin with respect to the city of Rome. CONCLUSIONS: The activity volumes would seem to support the setting up of a Freestanding Regional Center of Pediatric Day Surgery. This Center represents the healthcare facility that is most likely to allow a de-hospitalization process. Subsequent studies will be required to confirm the validity of this pilot study.

Willingness to pay for one-stop anesthesia in pediatric day surgery.

BACKGROUND: This study assesses the parents' Willingness To Pay (WTP) for One Stop Anesthesia (OSA). OSA is part of a free screening procedure that determines the timing of the anesthesiological assessment. In OSA-positive patients, the preoperative assessment is carried out on the same day as the surgery. The OSA allows patients who have to undergo surgery in a pediatric day surgery to avoid accessing the pre-admission clinic. METHOD: This is a descriptive cohort study. A sample of 106 parents were interviewed directly by means of a questionnaire. The questionnaire builds a hypothetical scenario where the interviewee has a chance to buy the OSA health service with the WTP. The WTP values are distributed in classes and are contingent to the market built in the questionnaire. The Chi Square and Cramer's V tests evaluate the WTP dependence on the parents' place of origin and occupation. RESULTS: The approximate average of the WTP classes is €87.21 per family. The Chi Square test relative to the WTP classes and the places of origin is statistically significant (p < 0.05). The Cramer's V test is 0.347 and points to a positive association between the two demographics. The Cramer's V test of the WTP classes and the types of job is 0.339 and indicates a positive association. CONCLUSION: Nearly 90% of pediatric patients who were screened for timing the preoperative assessment are true positives to OSA. This allows doing away with the pre-hospitalization, with definite advantages for the families. This screening is a health service that families would be hypothetically willing to pay.