Search

Background: Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC). Since response to radiotherapy (RT) is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve complete response (CR) is fundamental. Recently, an early tumour regression index (ERI) was introduced to predict pathological CR (pCR) after nCRT in LARC patients. The primary endpoints will be the increase of CR rate and the evaluation of feasibility of delta radiomics-based predictive MRI guided Radiotherapy (MRgRT) model. Methods: Patients affected by LARC cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0 without high risk features will be enrolled in the trial. Neoadjuvant CRT will be administered using MRgRT. The initial RT treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum and 45 Gy in 25 fractions on the drainage nodes. Chemotherapy with 5-fluoracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla MRI will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated: if ERI will be inferior than 13.1, the patient will continue the original treatment; if ERI will be higher than 13.1 the treatment plan will be reoptimized, intensifying the dose to the residual tumor at the 11th fraction to reach 60.1 Gy. At the end of nCRT instrumental examinations are to be performed in order to restage patients. In case of stable disease or progression, the patient will undergo surgery. In case of major or complete clinical response, conservative approaches may be chosen. Patients will be followed up to evaluate toxicity and quality of life. The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. Discussion: This clinical tri

N/A

Background: Peritoneal metastases carry the worst prognosis among all sites of colorectal cancer (CRC) metastases. In recent years, the advent of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival for selected patients with limited peritoneal involvement. We report the evolution of CRS and HIPEC for colorectal peritoneal metastases at a tertiary referral center over a 10-year period. Methods: Patients with colorectal peritoneal metastases undergoing CRS and HIPEC were included and retrospectively analyzed at a tertiary referral center from January 2006 to December 2015. Main outcomes included evaluation of grade III/IV complications, mortality rate, overall and disease-free survival, and prognostic factors influencing survival on a Cox multivariate analysis. Results: Sixty-seven CRSs were performed on 67 patients during this time for colorectal peritoneal metastases. The median patient age was 57 years with 55.2% being female. The median peritoneal carcinomatosis index (PCI) was 7, with complete cytoreduction achieved in 65 (97%) cases. Grade > 2 complications occurred in 6 cases (8.9%) with no mortality. The median overall survival for the entire cohort was 41 months, with a 3-year overall survival of 43%. In case of complete cytoreduction, median overall and disease-free survival were 57 months and 36 months respectively, with a 3-year disease-free survival of 62%. Complete cytoreduction and nonmucinous histology were key factors independently associated with improved overall survival. Conclusions: CRS and HIPEC for limited peritoneal metastases from CRC are safe and effective, with acceptable morbidity. In selected patients, it offers a highly favorable long-term outcomes.

Gastrointestinal stromal tumor management is extremely challenging, particularly the metastatic disease. The underlying mechanism in metastasis spread remains largely unknown. We aimed to characterize miRNAs involved in the metastatic process in gastrointestinal stromal tumor. Material & methods: Eight primary tumors and 18 synchronous metastases were analyzed through miRNA Taqman arrays or assays. Results: miRNAs profiles revealed similar expression in primary site and metastases. Pair-wise correlation coefficient between primary tumor and metastases was significant for each patient (p < 0.0001 for all profiled patients). Conclusion: Our study, the largest including primary tumors and metastases so far performed, highlighted perpetuation of miRNAs features in metastatic lesions and that the primary origin appears to be the main determinant of the metastases miRNA profile.

Background: Selection criteria and prognostic factors for patients with advanced gastric cancer (AGC) undergoing cytoreductive surgery (CRS) plus hyperthermic intra-operative peritoneal chemotherapy (HIPEC) have not been well defined and the literature data are not homogeneous. The aim of this study was to compare prognostic factors influencing overall (OS) and disease-free survival (DFS) in a population of patients affected by AGC with surgery alone and surgery plus HIPEC, both with curative (PCI, Peritoneal Carcinomatosis Index >1) and prophylactic (PCI=0) intent. Methods: A retrospective analysis of a prospectively collected database was conducted in patients affected by AGC from January 2006 to December 2015. Uni- and multivariate analyses of prognostic factors were performed. Results: A total of 85 patients with AGC were analyzed. Five-year OS for surgery alone, CRS plus curative HIPEC, and surgery plus prophylactic HIPEC groups was 9%, 27%, and 33%, respectively. Statistical significance was reached comparing both prophylactic HIPEC vs surgery alone group (p = 0.05), curative HIPEC vs surgery alone group (p = 0.03), and curative vs prophylactic HIPEC (p = 0.04). Five-year DFS for surgery alone, CRS + curative HIPEC, and surgery + prophylactic HIPEC groups was 9%, 20%, and 30%, respectively. Statistical significance was reached comparing both prophylactic HIPEC vs surgery alone group (p < 0.0001), curative HIPEC vs surgery alone group (p = 0.008), and curative vs prophylactic HIPEC (p = 0.05). Conclusions: Patients with AGC undergoing surgery plus HIPEC had a better OS and DFS with respect to patients treated with surgery alone.

N/A

N/A

Introduction: Gastrointestinal stromal tumors (GIST) are the best example of a targeted therapy in solid tumors. The introduction of tyrosine kinase inhibitors (TKIs) deeply improved the prognosis of this tumor. However, a degree of inter-patient variability is still reported in response rates and pharmacogenetics may play an important role in the final clinical outcome. Areas covered: In this review, the authors provide an updated overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST treatment efficacy and toxicity. Expert opinion: Besides the primary role of somatic DNA in dictating the clinical response to TKIs, several polymorphisms influencing their pharmacokinetics and pharmacodynamics have been identified as being potentially involved. In the last 10 years, many potential biomarkers have been proposed to predict clinical response and toxicity after TKI administration. However, the evidence is still too limited to promote a clinical translation. To date, the somatic mutational status represents the main player in clinical response to TKIs in GIST treatment; however, pharmacogenetics could still explain the degree of inter-patient variability observed in GIST patients. A combination of different theoretical approaches, experimental model systems, and statistical methods is clearly needed, in order to translate pharmacogenetics to clinical practice in the near future.

OBJECTIVE: Gastrointestinal schwannomas are rare benign mesenchymal tumors originating from Schwann cells, the nerve sheath belonging to the Auerbach’s plexus or, less frequently, to Meisser’s plexus. The esophagus is the least common site accounting for less than 2% of all esophageal tumors, and the upper to mid portion is usually involved. Esophageal schwannomas affect more frequently middle-aged Asian women. The most common symptom is dysphagia. Diagnosis requires histological and immunohistochemical studies and the standard of care is surgical resection. CASE REPORT: We present the case of a 22-year-old Caucasian male who was admitted to our hospital for progressive dysphagia and acute chest pain. An EGDS showed an elongated bulging of the lower esophagus with signs of a subcentimetric mucosal erosion. A CT-scan showed a lower esophageal ectasia and a huge postero-lateral wall mass measuring 37x28x70 mm. An endoscopic ultrasonography showed a hypoechoic heterogeneous mass with multiple anechoic areas and a fine needle biopsy was performed. Histological examination showed tissue made up of spindle cells with mild eosinophilic cytoplasm and rare nuclear atypia, which were intensively and diffusely positive for the S100 protein on immunohistochemical studies thus allowing pre-operative diagnosis of “ancient” schwannoma. after a multidisciplinary discussion, the patient underwent a surgical resection. Since the tumor had a transmural extension, a subtotal esophagectomy was performed to achieve complete resection with negative margins. CONCLUSIONS: This is the first case of a young Caucasian male patient with an “ancient” schwannoma of the lower esophagus, a benign but locally advanced lesion treated by subtotal esophagectomy.

Background and Objectives: The aim of this study was to determine whether the administration of neoadjuvant therapy (NAD) affects the incidence, timing, and pattern of recurrence in patients treated by curative gastrectomy. Methods: Sixty-nine patients undergoing NAD and R0 gastrectomy were compared with 198 patients undergoing upfront surgery using the propensity score matching (PSM) method. Disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS) analyses were conducted with a log-rank test and Cox regression. Risk factors for recurrence were assessed by logistic regression. Results: Among 69 patients with NAD, 28 (40.6%) experienced recurrence, and signet-ring cell (SRC) carcinoma was the only factor independently associated with recurrence. In the whole sample, NAD did not influence DFS, DSS, rate of recurrence, or PFS. After PSM, the variables associated with DFS were cN1, type of gastrectomy, the presence of SRCs, and the presence of lymphovascular invasion. Variables independently associated with recurrence were cN1, type of gastrectomy, and the presence of SRCs. Conclusions: NAD had no impact on DFS, DSS, or the pattern of recurrence in any patients with gastric cancer. To define a better treatment strategy, future studies should focus on subtypes that do not respond to the current neoadjuvant regimens.

Alterations in the transcriptional factor c-MYC could be involved in the anti-EGFR resistance in metastatic colorectal cancer (mCRC). The c-MYC expression was evaluated in 121 RAS and BRAF wild-type mCRC before treatment with anti-EGFR+Folfiri therapy and in 33 subsequent metastases collected during target therapy (TT) or in TT resistance phase. We analyzed the expression and the functional role of some c-MYC linked miRNAs (miR-31-3p, miR-143 and miR-145) in our patient group and in two CRC cell lines, also performing a c-MYC target PCR array. Patients with higher c-MYC expression (HME) showed a significant lower PFS and OS when compared to those with low c-MYC expression (LME). HME pattern was significantly more frequent in the metastases after TT and significantly associated to anti-EGFR molecular resistance alterations. We also found a significant correlation between the expression of the above-mentioned c-MYC linked miRNAs, c-MYC level and anti-EGFR resistance. Moreover, expression gene profiling pointed out the pivotal role of c-MYC in CRC-related cell-cycle, apoptosis, signal transduction and cell-growth pathways. c-MYC expression might distinguish patients with a lower PFS and OS in anti-EGFR treated mCRC. The individuation of some miRNAs involved in the c-MYC pathway regulation and the downstream c-MYC effector genes could provide a new possible target to overcome the anti-EGFR resistance in mCRC.

Gastroblastoma is a rare, distinctive gastric biphasic tumour affecting both sexes, with metastatic potential. To the best of our knowledge, 11 cases have been published so far, solidly supported by morphology, immunophenotype, and, in four instances, by identification of a characteristic MALAT–GLI1 fusion gene.1-6 A twelfth ‘gastroblastoma’, questionable because of the presence of cellular atypia significantly deviating from previous canonical examples, has been reported.7 A gastroblastoma‐like duodenal neoplasm has also been described.8 Finally, a series of six extragastric tumours harbouring GLI1 rearrangements has been published, showing focal cytokeratin positivity and scattered tubular structures in one case (bearing an ACTB–GLI1 fusion), leading to the proposal of an entity defined as ‘malignant epithelioid neoplasm with GLI1 fusions’.9 All reported canonical gastroblastomas occurred within the third decade of life, except for one in a patient aged 56 years. Grossly, gastroblastomas form multinodular/lobulated, often partly cystic/haemorrhagic, masses involving the gastric wall layers. Histologically, these tumours are biphasic, featuring spindle‐cell and epithelioid components, immature but non‐pleomorphic, with low mitotic activity. On immunohistochemistry, gastroblastoma variously expresses CD10, vimentin and cytokeratins, the former two prevailing in the spindle cells, and the latter prevailing in the epithelioid cells. The recently reported consistent finding of a MALAT1–GLI1 fusion gene in gastroblastoma allows a solid differential diagnosis with other biphasic neoplasms such as synovial sarcoma, carcinosarcoma, and teratoma. Intriguingly, the same genetic defect has been detected in some plexiform fibromyxomas, which are gastric mesenchymal tumours that are definitely benign, lack biphasic morphology and are most likely unrelated to gastroblastoma.6, 9 Table 1 summarises the features of the gastroblastomas published so far. Herein, we report a gas

Background: Despite their lethality and ensuing clinical and therapeutic relevance, circulating tumor cells (CTCs) from colorectal carcinoma (CRC) remain elusive, poorly characterized biological entities. Methods and findings: We perfected a cell system of stable, primary lines from human CRC showing that they possess the full complement of ex- and in-vivo, in xenogeneic models, characteristics of CRC stem cells (CCSCs). Here we show how tumor-initiating, CCSCs cells can establish faithful orthotopic phenocopies of the original disease, which contain cells that spread into the circulatory system. While in the vascular bed, these cells retain stemness, thus qualifying as circulating CCSCs (cCCSCs). This is followed by the establishment of lesions in distant organs, which also contain resident metastatic CCSCs (mCCSCs). Interpretation: Our results support the concept that throughout all the stages of CRC, stemness is retained as a continuous property by some of their tumor cells. Importantly, we describe a useful standardized model that can enable isolation and stable perpetuation of human CRC's CCSCs, cCCSCs and mCCSCs, providing a useful platform for studies of CRC initiation and progression that is suitable for the discovery of reliable stage-specific biomarkers and the refinement of new patient-tailored therapies. Fund: This work was financially supported by grants from “Ministero della Salute Italiano”(GR-2011-02351534, RC1703IC36 and RC1803IC35) to Elena Binda and from “Associazione Italiana Cancro” (IG-14368) Angelo L. Vescovi. None of the above funders have any role in study design, data collection, data analysis, interpretation, writing the project.

A 52-year-old woman presented with complaints of anal pain/ constipation/tenesmus for 3 months before being referred to our hospital. There were no relevant prior illnesses. Rectal digital examinationrevealeda6-cmsmoothelasticmassontherectalposteriorleft side 2 cm from the anal verge. Colonoscopy showed a rectal submucosalbulging.Computedtomography(CT)scanandmagneticresonanceimagingconfirmedthepresenceofasingle6-cmwell-delimited mass, compressing and infiltrating the wall of the medium to low rectum. The tumor was completely removed, although ruptured, by transanal excision to save the organ. The specimen (2- to 22-mm fragments) was almost entirely composed of tumor, highly cellular andwithnecrosis,consistingofspindlecellswithperinuclearvacuolizationandseveralmitoses(80/50high-powerfields;Fig1A,magnification 400). Scarce rectal wall smooth muscle was present (Fig 1B, left, magnification 100). The tumor stained for CD117 (Fig 1C, magnification 400), DOG1 (Fig 1D, magnification 400), CD34, and S100 (patchy cytoplasmic pattern); desmin, melan-A, and HMB45 were negative. The diagnosis was spindle-cell GI stromal tumor(GIST).Thepatient’sdiseasewasconsideredhigh-riskbecause ofthefragmentationduringremoval,morphology,andsite.1,2 Given thatasubsequentpositronemissiontomography/CTscanwasnegative,a conservativeapproachwasmaintained,leavingadditionalsurgeryasan option in case of relapse. By using polymerase chain reaction direct sequencing3-6onindependentDNAtemplatesfromfourdifferenttumor fragments, two mutations were consistently found: a 6-nucleotide– insertion GCCTAT between 1509-1510 nucleotides (CDS mutation: c. 1509_1510insGCCTAT)causinganinsertionoftwoaminoacids:alanine andtyrosine(p.Y503_F504insAY)inKITexon9(Fig2A;arrowindicates thestartpointoftheGCCTATinsertion),andapointmutation(A3Tat 2525)determiningaValforAspsubstitutionat842(D842V)ofexon18of platelet-derived growth factor receptor alpha (PDGFRA; Fig 2B; arrow indicatespointmutation).KITandPDGFRAwerewildtypeinthere

Background: Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the digestive tract. They have recently been recognized as a separate nosological entity and the literature on these stromal tumors has rapidly expanded. Materials and methods: The surgical records of 50 patients with primary GISTs treated at the Digestive Surgery Department of the Catholic University of Rome from January 1993 to December 2010 were reviewed and the prognostic factors were analyzed. Results: Surgery was performed in all patients with curative intent. The median age at presentation was 66.5 years (range, 28-81). Adjuvant therapy was administered in 26 (52%) cases. Median follow-up was 71 months (range, 5-208). There was an 8% recurrence rate. The actuarial 5-year overall and disease-free survival rates were 66.3% and 57.2%, respectively. High mitotic rate (P <0.001), tumor size greater than 10 cm (P = 0.007) and tumor rupture (P = 0.05) were the only prognostically significant negative factors for overall survival in multivariate analysis. Conclusions: The present study confirmed the important role of aggressive surgical management of GISTs to offer these patients the most appropriate treatment for long-term survival.

Background: Neoplastic microfoci have frequently been found in the mesorectum, with poor outcome. In this study, incidence and clinical significance of mesorectal microfoci (MMF) were analyzed in patients operated on for rectal cancer following neoadjuvant chemoradiation. Methods: A case series of 68 patients with extraperitoneal rectal cancer treated with neoadjuvant chemoradiation and surgery (including total mesorectal excision) were investigated for presence of neoplastic MMF. Results: MMF were found in 26 cases (38.2%). Increasing incidence of microfoci was statistically related to pathologic involvement of the bowel wall (P = 0.0006), Mandard's tumor regression grading (P = 0.0006), and pathologic neoplastic mesorectal involvement (P < 0.00001). None of the nine patients with complete tumor disappearance displayed both microfoci and lymph node metastasis. Only one local recurrence developed in a patient with multiple MMF. One out of nine pT0 or TRG1 patients (11.1%) had distant metastases compared with 15 out of 59 pT1-4 or TRG2-5 (25.4%, P = 0.70). Conclusions: A remarkable incidence of MMF was found following chemoradiation. However, when this therapy induced complete regression of primary tumor (pT0-TRG1), we found that node metastases and neoplastic MMF also disappeared. These features should be confirmed to assess the impact of these microfoci in treatment decision making in rectal cancers. © 2006 Society of Surgical Oncology.