Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping.

This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m2, and capecitabine 2000 mg/m2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3-4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.

HER Family Protein Expression in a Greek Population with Gastric Cancer. A Retrospective Hellenic Cooperative Oncology Group Study.

BACKGROUND: Gastric cancer is a relatively common malignancy. Recently, the presence of the human epidermal growth factor receptor 2 (HER2) was identified as a molecular target in a proportion of patients who benefited from the addition of appropriate anti-HER2 treatments. Our study explored the clinical and prognostic role of known HER family members, human epidermal growth factor receptor 1 (EGFR or HER1), HER2, HER3 and HER4. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 249 gastric cancer patients were studied by immunohistochemistry for protein expression of EGFR, HER2, HER3 and HER4. RESULTS: Of the 249 evaluable patients, 32 did not have complete data of treatment details and/or follow-up and were excluded from the survival analyses. Of the 217 patients with complete treatment and follow-up data, 178 were operated and treated for early disease (group 1), while 39 for advanced disease (group 2). The frequency of positive EGFR, HER2, HER3 and HER4 protein expression in all patients was 17.5%, 11.8%, 14.8% and 32.9%, respectively. There were no differences in protein expression of any of the markers between the two groups. There were, however, statistically significant associations between HER4 and all other HER family members, as well as between HER2 and HER3 expression. Of note, EGFR-positive membranous protein expression was significantly associated with the presence of lymphovascular invasion (p=0.027) and HER3 and HER4 negative cytoplasmic protein expression with well/moderately-differentiated tumors (p=0.030 and p=0.014, respectively). None of the HER family members were of prognostic value for OS in univariate analysis. CONCLUSION: The present study confirmed the known protein expression frequencies of HER family members in gastric cancer in a Greek population. Several associations were observed among the HER family members and between clinicopathological characteristics and HER family members. Further research is needed on their exact prognostic role, as well as their therapeutic targeting.

The prognostic significance of WNT pathway in surgically-treated colorectal cancer: ß-catenin expression predicts for disease-free survival.

BACKGROUND: The wingless-type MMTV integration site family of proteins (WNT) pathway is highly involved in colorectal cancer development. The aim of this study was to explore the prognostic significance and clinicopatological correlations of this pathway in a cohort of surgically-treated patients with non-metastatic colorectal cancer in relation to the site of expression of pathway proteins. MATERIALS AND METHODS: Immunohistochemical expression of nuclear cyclin D1, membranous E-cadherin and P-cadherin, membranous and nuclear ß-catenin in the invasive front (IF), the tumor center (TC), as well as their mean, were assessed in 106 paraffin-embedded tissue samples. Adenomatous Polyposis Coli (APC), Axin-2 (AXIN2), cyclin-D1 (CCND1), Matrix Metalloproteinase-7 (MMP7), Secreted Frizzled Related Protein (SFRP) 1, 2 and 4 and WNT5A were evaluated by RT PCR. RESULTS: Membranous ß-catenin expression was statistically reduced in the IF. Cyclin-D1 was reduced in tumors arising closer to the rectum. Reduced nuclear expression of cyclin-D1 in the IF was associated with lymphatic, venous and perineural invasion. Loss of membranous ß-catenin in the TC was more common among N2 tumors. Higher SFRP4 mRNA was associated with advanced T stage. In univariate analysis, membranous expression of ß-catenin in TC and IF, and their mean, was associated with longer disease-free survival (DFS). In multivariate analysis, tumor stage and mean ß-catenin expression were prognostic for longer DFS (hazard ratio=0.33; p=0.01). ß-Catenin expression in the IF remained significant when the mean expression was not included in the multivariate analysis (hazard ratio=0.41; p=0.028). CONCLUSION: Mean membranous expression of ß-catenin, as well as that in the IF, is prognostic for longer DFS in patients with non metastatic colorectal cancer.

Metachronous early gastric adenocarcinoma presenting coinstantaneously with complete remission of stage IV gastric MALT lymphoma.

Adenocarcinoma and lymphoma represent the two most common malignant tumours of the stomach, with both neoplasms being associated with infection by Helicobacter pylori. However, the presence of lymphoma and adenocarcinoma in the same patient is a rare entity with synchronous neoplasms being more common than metachronous types. We report a case of stage IV gastric MALT lymphoma of the gastric angle with infiltration of the bone marrow successfully treated with chemotherapy and the occurrence of metachronous early gastric adenocarcinoma of the fundus presenting 1 year after the diagnosis of the lymphoma.

Pseudomyxoma retroperitonei: report of 2 cases and review of the literature.

Pseudomyxoma peritonei is a rare clinical condition that is characterized by the presence of mucinous ascitis. It is believed to originate predominately from a mucinous neoplasm of the appendix including a heterogeneous group of tumours ranging from indolentto malignant. It was first described in the late 19th century. Pseudomyxoma retroperitonei is extremely rare with only 33 cases having been reported since the first description in the middle of the 20th century. We report two additional cases of pseudomyxoma retroperitonei and present a review of the literature.

Multiple desmoid tumors in a patient with familial adenomatous polyposis caused by the novel W421X mutation.

Familial adenomatous polyposis (FAP) is a rare syndrome characterized by the presence of hundreds to thousands of colorectal adenomas and is responsible for less than 1% of all colorectal cancers. The syndrome is also characterized by extra-colorectal features including amongst others upper gastrointestinal tract polyps and desmoid tumors. The syndrome is inherited by an autosomal dominant gene, the adenomatous polyposis coli (APC) gene. We present the physical history, clinical presentation, diagnosis and treatment of a patient with a novel germline APC mutation, the W421X mutation, which resulted in FAP presenting with about a hundred colorectal polyps, gastric hyperplastic polyps and multiple aggressive intra-abdominal and extra-abdominal desmoid tumors.

Recurrent small intestine intussusception in a patient with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome is a rare hereditary autosomal dominant disease caused by a mutation of the tumor suppressor gene serine/threonine kinase 11 located in chromosome 19p13.3. It is characterized by the presence of extensive mucocutaneous pigmentation, especially of the lips and the occurrence of hamartomatous polyps throughout the gastrointestinal tract. Gastrointestinal hamartomas occur predominantly in the small intestine and can become symptomatic leading usually to intestinal obstruction and abdominal pain.We present a case of recurrent intestinal obstruction caused by small bowel intussusception treated by reduction, enterotomy and polypectomy and followed by intraoperative enteroscopy and endoscopic polypectomy.

Pathologic Rupture of the Spleen as the Presenting Symptom of Primary Splenic Non-Hodgkin Lymphoma.

Pathologic splenic rupture is defined as the spontaneous rupture of a diseased spleen and is quite rare. It is usually associated with oncologic, infectious, and hematologic diseases and more seldom with other rare causes. Pathologic splenic rupture related to hematologic malignancy seems to be rare with only 136 cases reported from 1861 until 1996 and a few cases thereafter. Non-Hodgkin lymphoma and acute myeloid leukemia are most frequently reported followed by chronic myeloid leukemia and lymphoblastic acute leukemia. However, even in cases of non-Hodgkin lymphoma, pathologic splenic rupture as the presenting symptom of the disease is rare as is the presence of primary splenic lymphoma. Conservative treatment is not an option, while operative intervention and emergency splenectomy is the only feasible treatment. We present a very rare case of pathologic rupture of primary splenic lymphoma which was the presenting symptom of the disease.

Emphysematous cellulitis of the left thigh caused by sigmoid diverticulum perforation.

Necrotizing fasciitis and gas gangrene of the lower extremities are two life-threating emergencies and are the most common causes of gas presence in the lower extremity. Rarely the gas presence is secondary to a perforated viscus and especially the colon. Large bowel diverticula are a quiet common disease in western countries and their prevalence increases with age. Also, the possibility of complications is greater in older patients. However, perforated colonic diverticulum seldom presents only with the presence of gas in the lower extremity. We report a case of emphysematous cellulitis of the left thigh caused by a sigmoid diverticulum perforation in a patient with peritoneal carcinomatosis.

Acute respiratory failure caused by neglected giant substernal nontoxic goiter / Insuficiência respiratória aguda resultante de bócio atóxico mergulhante gigante negligenciado

Substernal goiter is usually defined as a goiter in which the thyroid mass has descended the plane of the thoracic inlet or if more than 50 percent of the thyroid mass is located below the thoracic inlet. Substernal goiters may be asymptomatic or may present with symptoms caused by compression of adjacent organs. Acute respiratory failure is rare in cases of substernal goiter. In cases of symptomatic substernal goiter the treatment is surgical by thyroidectomy. We present a rare case of a giant substernal nontoxic goiter which caused acute respiratory failure which was treated by urgent thyroidectomy through a T-incision.

Geralmente se define o bócio mergulhante como o bócio em que a massa da tireoide descende ao plano da cavidade torácica ou mais do que 50 por cento da massa tireoidiana se localiza abaixo da cavidade tireoidiana. O bócio mergulhante pode ser assintomático ou apresentar sintomas resultantes da compressão de órgãos adjacentes. A insuficiência respiratória aguda é rara nos casos de bócio mergulhante. Nos casos de bócio mergulhante sintomático, o tratamento indicado é cirúrgico, por tireoidectomia. Nesse relato, descreveu-se um caso raro de bócio atóxico mergulhante gigante negligenciado que resultou em insuficiência respiratória aguda e foi tratado com tireoidectomia de emergência com incisão em T.

Giant bilateral symptomatic adrenal myelolipomas associated with congenital adrenal hyperplasia.

Adrenal myelolipoma is an uncommon, benign, biochemically non-functioning and endocrinologically inactive tumor composed of variable amounts of mature adipose tissue and scattered islands of haemopoietic elements, including erythroid, myeloid and lymphoid series, as well as megakaryocytes. Diagnosis of myelolipomas is based on imaging, with ultrasonography, CT and MRI being effective in more than 90% of cases. Differential diagnosis includes other containing fat adrenal masses such as teratoma, lipoma and liposarcoma. The optimal treatment depends on the size and symptoms of the myelolipoma. For incidentally discovered, asymptomatic adrenal myelolipomas smaller than 4 cm surveillance seems to be enough while symptomatic, complicated, hormonally active and larger than 7 cm myelolipomas, should be surgically removed. We present a case of giant bilateral symptomatic adrenal myelolipomas associated with congenital adrenal hyperplasia. A 34 year old female, with congenital adrenal hyperplasia because of 21-hydroxylase deficiency, presented with diffuse abdominal pain and vomiting. Physical examination revealed hirsutism, pronounced virilization and palpable masses both on the right and left abdominal area. The abdominal CT demonstrated bilateral large masses in the anatomical position of the adrenal glands with densities indicating adipose tissue. The differential diagnosis was between myelolipoma and liposarcoma. For diagnostic and also therapeutical reasons, as the masses were large and symptomatic and causing pressure to the surrounding structures, the patient was submitted to laparotomy for bilateral excision. Histopathological examination established the diagnosis of adrenal myelolipoma.

Expression of a molecular marker panel as a prognostic tool in gastric cancer patients treated postoperatively with docetaxel and irinotecan. A study of the Hellenic Cooperative Oncology Group.

INTRODUCTION: This study evaluated the prognostic role of vascular epidermal growth factor (VEGF), thymidylate synthase (TS), topoisomerase I (Topo-I), topoisomerase IIalpha (Topo-IIalpha) and E-cadherin (E-cadh) tumor expression, in patients with resectable gastric cancer, who were treated postoperatively with the docetaxel/irinotecan combination. PATIENTS AND METHODS: Forty-five patients with resectable gastric cancer were treated with 6 cycles of docetaxel 30 mg/m2 and irinotecan 110 m/m2 on day 1 and d8 every 21 days. All specimens were examined by using immunohistochemistry (IHC) for the expression of VEGF, TS, Topo-I, Topo-IIalpha and E-cadh. RESULTS: Positivity for TS was significantly correlated with age and for VEGF with diffuse histological type and good PS. No significant correlation was observed among Topo-I, Topo-IIalpha and E-cadh positivity with any of the clinicopathological parameters studied. Median overall survival (OS) was 31.7, and disease-free survival (DFS) 26 months, respectively. None of the above-investigated molecular markers were significantly associated with OS and DFS. Finally, according to the univariate analysis for survival, only advanced stages (III, IV) of the disease implied risk of death, mainly due to lymph node involvement and, to a lesser extent, tumor size. None of the studied molecular markers were found to be independent prognostic markers. CONCLUSION: These results should be interpreted very cautiously, due to the limited number of patients studied, as well as the limitations of the IHC technique.