Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy.

The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic polymorphisms in 16 genes relevant for treatment-associated pathways. Two polymorphisms were associated with TRG in a multivariate analysis: hOGG1-1245C > G, which can affect radiosensitivity and MTHFR-677C > T, which is involved in fluoropyrimidines action. Patients bearing at least one variant allele had a lower chance to get TRG ≤ 2 (OR = 0.46 95% CI 0.23-0.90, P = 0.024; and OR = 0.48 95% CI 0.24-0.96, P = 0.034; respectively). An association trend was observed for ABCB1-3435C > T, which is responsible for the multi-drug resistance (odds ratio (OR) = 1.96, 95% confidence interval (CI) 0.98-3.95, P = 0.057). Exploratory classification and regression tree (CART) analysis highlighted high-order gene-gene and gene-environment interactions and a genetic signature associated with differential response, with hOGG1-1245C > G as the most predictive factor. Other significant variables were: ABCB1-3435C > T, MTHFR-677C > T, ERCC1-8092C > A, ABCC2-1249G > A, XRCC1-28152G > A, XRCC3-4541A > G and patients gender. On the basis of CART results, patients were categorized into three groups according to tumor response probability: intermediate and high profiles had a higher probability to get TRG ≤ 2 as compared with low profiles (OR = 4.12 95% CI 1.46-11.65, P < 0.001 and OR = 12.44, 95% CI 5.52-28.04, P < 0.0001, respectively). This study evidences a major role of hOGG1-1245C > G and MTHFR-677C > T polymorphisms in the tumor response of rectal cancer patients treated with chemo-RT in neo-adjuvant setting, and shows the relevance of gene-gene and gene-environment interactions for complex phenotypes as tumor response.

Microsatellite instability and MLH1 and MSH2 germline defects are related to clinicopathological features in sporadic colorectal cancer.

Clinical and pathological features were evaluated to predict tumor microsatellite instability (MSI) and germline mutations in MLH1 and MSH2 DNA mismatch repair genes in two patient groups with sporadic colorectal cancer (CRC): 38 young patients (age /=60 years). Nine (25.7%) young patients out of 35 and five (16%) old patients out of 31 exhibited MSI in their cancers. MSI+ cancers were related to proximal cancer and mucinous carcinoma independently of the age at cancer onset. Three (7.9%) out of 38 young patients had mutations in MLH1 and MSH2 genes that led to truncated protein products; they were all at age <35 years and showed MSI in their tumors, with mucinous histotype in two cases. In conclusion, histopathological and clinical features of CRC allow identification of cancers showing DNA microsatellite instability. MSI in CRC at very early onset (age <35 years) appears useful to predict germline MMR gene defects.

[Usefulness of chromogranin A determination in the diagnosis of neuroendocrine neoplasia]. / Utilità del dosaggio della cromogranina A nella diagnosi delle neoplasie neuroendocrine.

Neuroendocrine gastroenteropancreatic tumor diagnosis is a very difficult and expensive procedure. This study compared Chromogranin A (CgA) to Neuron-specific enolase (NSE) in 55 patients affected by neuroendocrine tumors. Advanced local or metastatic neoplasia was found in 43 patients. Radical operation was performed in 12 patients. Seventeen cases of lung microcystoma, 23 cases of other intestinal tumors and 19 patients affected by irritable bowel syndrome were used as controls. CgA sampling demonstrated sensitivity of 73% and specificity of 66%, a positive predictive value of 77% and a negative predictive value of 61% while NSE sampling showed sensitivity of 100%, specificity of 36%, a positive predictive value of 15% and a negative predictive value of 100%. CgA values demonstrated a statistically significant difference between patients with neuroendocrine tumors and tumor-free resected patients (p = 0.0015), microcystoma patients (p = 0.0087), other types of neoplasia (p = 0.01) and irritable bowel syndrome patients (p = 0.0004). No significant difference was found among the same groups when NSE values were analyzed. The high diagnostic accuracy of CgA sampling renders it very useful in early neoplastic detection, even in cases of nonfunctioning neoplasms or absence of liver metastases. In addition, CgA sampling may be an effective screening test in patients with irritable bowel syndrome or with liver or lung metastases when there is no evidence of the primitive tumor.

Early gastric cancer: diagnosis, surgical treatment and follow-up of 45 cases.

AIMS AND BACKGROUND: The 5-year survival rate of early gastric cancer (EGC) is 85%-100% after "curative" resection, as compared to 20%-30% in advanced gastric cancer (AGC). Because of this relatively high cure rate, the interest in the diagnosis and therapy of EGC has been steadily increasing. The present study, based on 45 EGCs, is aimed at a critical evaluation of the diagnostic procedures and surgical options. METHODS AND RESULTS: Forty-five patients with early gastric cancer (27 men and 18 women; median age, 62 years; range, 28-84) were diagnosed and operated on. They represented 22.5% of all patients with gastric cancer (200) treated in the period July 1987 to January 1998. Forty-one patients were from the northeastern part of Italy. The most frequent symptom was epigastric pain (84%). Barium upper gastrointestinal radiography findings were strongly suggestive of malignancy in 41 cases (91%). Preoperative histopathological diagnosis of adenocarcinoma was performed in 43 cases (95.5%). In two cases (4.5%) severe epithelial dysplasia (associated with ulcer) was the first diagnosis, but the final diagnosis on the basis of the resected specimens was a well differentiated adenocarcinoma. The primary surgical procedure included i) subtotal distal resection (37 cases) with Billroth 11 (33) and Billroth I (4) reconstructions; ii) total gastrectomy (3) for proximal neoplastic extension; iii) proximal gastric resection (2) for cardial cancer; iv) degastro-total gastrectomy (3) for cancer of the stump. Two patients, previously treated with conservative surgery, underwent degastro-total gastrectomy for neoplastic microfocal extension to the margin of resection and for early anastomotic recurrence, respectively. Mural infiltration was limited to the mucosa and submucosa in 27 and 18 cases, respectively. Lymph node metastases were found in three mucosal and five submucosal tumor cases, involving either the first or the second echelon. No operative deaths or postsurgical complications occurred in this series. In the follow-up period (median, 36 months; range, 3-120) four patients died due to other causes; one developed liver metastases, another developed oropharyngeal cancer and two died of biopsy-proven lung cancer without evidence of gastric cancer recurrence. CONCLUSIONS: The clinical presentation of EGC is aspecific. Preoperative endoscopy with biopsy remains the most sensitive diagnostic procedure. For treatment, subtotal distal gastric resection with lymphadenectomy is the "gold standard" but in some instances total gastrectomy may be indicated. Accurate pathological examination establishes the depth of infiltration, as well as the superficial extension of tumors and the lymph node status. Although the prognosis of EGC is favorable, a medium-term follow-up should be planned.

Gastric cancer with bone marrow invasion at presentation: case-report and review of the literature.

A case of extensive bone marrow infiltration due to gastric cancer is reported. A 65-year old man with an acute episode of anemia (Hb 4.1 mg/dl) and dyspnea was admitted to the Medical Department of a general hospital. Bone marrow biopsy showed extensive paratrabecular infiltration of a poorly differentiated adenocarcinoma of gastric origin. The primary tumor in the stomach was confirmed, and the patient was referred to our Institute and treated with combination chemotherapy (FAMTX) for 6 cycles. Due to the disappearance of bone marrow infiltration, the patient was considered for curative resection of the primary gastric cancer. After 27 months the patient is alive and in clinical complete remission.

Primary gastric non-Hodgkin's lymphoma--does surgery still play any role?

36 patients with primary gastric non-Hodgkin's lymphoma (PGL) (stage Ie and IIe) were treated at the Comprehensive Cancer Center of Aviano (PN) Italy. The median follow-up time of the patients was 59 months (range 10 to 117). The pre-operative diagnosis of PGL was established by using endoscopy in 70% of the patients. There was understaging in non-invasive methods of diagnosis in comparison to laparotomy. Prognostic factors such as: stage, grade according to the Working Formulation, size, depth of penetration of the gastric wall and resectability of the tumor, were taken into consideration in the treatment plan. This consisted of surgical resection of the gastric lymphoma where feasible and according to the bad prognostic factors escalating adjuvant treatment was included: group I (n = 6) patients were treated only by surgery (S), II (n = 8) by S+radiotherapy (RT) (n = 5) or S+chemotherapy (CT) (n = 3), III (n = 17) by S+RT+CT and IV (n = 5) by non-resectable S+RT+CT. There were no statistically significant differences in the survival rate, calculated by Kaplan-Meier method, between the first three groups of patients. Only stage of disease (P = 0.048) and resectability of the lesion (P = 0.003) had a significant influence on survival. There were no serious complications observed in either S, RT or CT treatment. The estimated 5-year survival rate after management was 100%, 75% and 88%, respectively for stage Ie (n = 21), stage IIe (n = 15) and all together.

Primary lung melanoma.

A rare case of primary malignant melanoma of the lung in a 30 year-old female is reported. A chest x-ray and C.T. scan revealed a mass 3 cm in diameter. The patient underwent left lower lobectomy for cure.