Giuseppe Modica

60KDa chaperonin (HSP60) is over-expressed during colorectal carcinogenesis.

The aim of the present study was to evaluate the expression of the heat shock protein 60 (HSP60), a mitochondrial matrix-associated protein belonging to the chaperonin family, in colorectal adenomas and cancers, comparing them to normal colonic tissues and hyperplastic polyps. We performed both immunohistochemistry and Western blot analysis for HSP60. Immunohistochemistry resulted positive in all tubular adenomas and infiltrating adenocarcinomas. By contrast, normal tissues and hyperplastic polyps were negative. Quantitative analysis showed that tubular adenomas with different levels of dysplasia did not present statistical differences concerning HSP60 positivity. In addition, carcinomas always showed the highest expression. Western blot analysis confirmed these observations. These data suggest that HSP60 over-expression is an early event in carcinogenesis. We suspect that HSP60 plays a different role in colorectal carcinogenesis with respect to that in normal cells, which foresees its possible use as diagnostic and prognostic tools.

BRAFV600E mutation, TIMP-1 upregulation, and NF-κB activation: closing the loop on the papillary thyroid cancer trilogy

BRAF(V600E) is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-κB have been shown to play an important role in thyroid cancer. In particular, TIMP-1 binds its receptor CD63 on cell surface membrane and activates Akt signaling pathway, which is eventually responsible for its anti-apoptotic activity. The aim of our study was to evaluate whether interplay among these three factors exists and exerts a functional role in PTCs. To this purpose, 56 PTC specimens were analyzed for BRAF(V600E) mutation, TIMP-1 expression, and NF-κB activation. We found that BRAF(V600E) mutation occurs selectively in PTC nodules and is associated with hyperactivation of NF-κB and upregulation of both TIMP-1 and its receptor CD63. To assess the functional relationship among these factors, we first silenced BRAF gene in BCPAP cells, harboring BRAF(V600E) mutation. We found that silencing causes a marked decrease in TIMP-1 expression and NF-κB binding activity, as well as decreased invasiveness. After treatment with specific inhibitors of MAPK pathway, we found that only sorafenib was able to increase IκB-α and reduce both TIMP-1 expression and Akt phosphorylation in BCPAP cells, indicating that BRAF(V600E) activates NF-κB and this pathway is MEK-independent. Taken together, our findings demonstrate that BRAF(V600E) causes upregulation of TIMP-1 via NF-κB. TIMP-1 binds then its surface receptor CD63, leading eventually to Akt activation, which in turn confers antiapoptotic behavior and promotion of cell invasion. The recognition of this functional trilogy provides insight on how BRAF(V600E) determines cancer initiation, progression, and invasiveness in PTC, also identifying new therapeutic targets for the treatment of highly aggressive forms.

Heat Shock Protein 60 Levels in Tissue and Circulating Exosomes in Human Large Bowel Cancer Before and After Ablative Surgery

Heat shock protein 60 (Hsp60) is a chaperonin involved in tumorigenesis, but its participation in tumor development and progression is not well understood and its value as a tumor biomarker has not been fully elucidated. In the current study, the authors presented evidence supporting the theory that Hsp60 has potential as a biomarker as well as a therapeutic target in patients with large bowel cancer.

Hsp10: anatomic distribution, functions, and involvement in human disease

There is growing evidence that molecular chaperones/heat shock proteins are involved in the pathogenesis of a number of human diseases, known as chaperonopathies. A better molecular understanding of the pathogenetic mechanisms is essential for addressing new strategies in diagnostics, therapeutics and clinical management of chaperonopathies, including those in which Hsp10 is involved. This chaperonin has been studied for a long time as a member of the mitochondrial protein-folding machine. However, although in normal cells Hsp10 is mainly localized in the mitochondrial matrix, it has also been found during and after stress in other subcellular compartments, such as cytosol, vesicles and secretory granules, alone or in combination with other proteins. In these extramitochondrial locales, Hsp10 plays an active role in cell signalling. For example, cancer cells often show altered levels of Hsp10, compared to normal cells. Hsp10 may also be found in the extracellular space and in the bloodstream, with a possible immunomodulatory activity. This minireview focuses on some studies to date on the involvement of Hsp10 in human disease pathogenesis.

Weekly docetaxel as II line therapy in non-small cell lung cancer: an interim analysis of a phase II study

To evaluate the efficacy and toxicity of weekly docetaxel (D) as II line treatment in non-small cell lung cancer (NSCLC), in November 1999, we started a phase II study on advanced (stages IIIB-IV) NSCLC patients pre-treated with at least one platinum-based chemotherapy regimen with or without radiotherapy. The schedule consisted of D 40 mg/m(2), weekly for 6 weeks, followed by a rest period of 2 weeks, for three cycles or until progression. Eligibility criteria were: histopathologic diagnosis of NSCLC; age <or=75 years; evaluable or measurable progressive lesions; PS (ECOG) 0-2; adequate haematology and biochemistry parameters; no serious concurrent diseases; no symptomatic brain lesions; and informed consent. The end points were assessment of overall response rate, toxicity and quality of life (QoL). Patients were re-evaluated at the end of every cycle. An interim analysis of 18 patients (16 M) was performed. Weekly courses were 132; 16 of 18 patients were evaluable for response and 17 of 18 for toxicity. Two of the 16 patients (12.5%) had a partial response (95% CI: 10.5-14.7%). Haematological toxicity was very mild: grade 1-2 neutropenia occurred in four patients, grade 3 neutropenia in two patients; grade 1-2 anaemia in four patients; and grade 1-2 thrombocytopenia in two patients. Non-haematological toxicity was also very mild, with the exclusion of asthenia (grade 1-2 in ten patients and grade 3 in five patients) and alopecia (grade 1-2 in seven patients and grade 3 in eight patients). No cases of grade 4 toxicity were observed. No QoL evaluations were reported in this interim analysis. In conclusion, these preliminary data confirm that weekly D results in tolerable toxicity in pre-treated NSCLC. Myelo-suppression, the dose-limiting toxicity of every 3 week schedules, is not a clinically relevant problem when D is administered weekly. G-CSF was used only sporadically in four patients, and no febrile neutropenia was reported. Patients were pre-treated with dexamethasone and no allergic reactions were seen. Although the therapeutic activity appears to be comparable to that of every 3 week schedules, more data are necessary before definite conclusions can be drawn. Accrual of patients is still ongoing.

Endoscopic Resection of a Large Colonic Lipoma: Case Report and Review of Literature

Colonic lipomas are uncommon, benign, submucosal adipose tumors that are usually asymptomatic. Large lipomas can cause symptoms such as constipation, abdominal pain, rectal bleeding and intussusception. We report the case of a 60-year-old man with a history of lower abdominal pain and pseudoobstructive symptoms. Colonoscopy revealed a large polypoid sessile lesion in the sigma. We used a standardized technique of polypectomy, preceded by submucosal injection of dilute 5 ml polygelin with epinephrine 1:10,000 solution, to fully resect large colonic lipomas. The lipoma size was 3.5 cm. No bleeding or perforation developed. Histology showed the polyp to be a submucosul lipoma. On follow-up, there was no residual lesion. Colonic lipomas larger than 2 cm can be safely and efficaciously removed using electrosurgical snare polypectomy technique. The technique of submucosal injection before resection and using an electrocautery snare appears to be safe and reduces the risk of perforation reported in the literature.

Asymptomatic Bone Cement Pulmonary Embolism after Vertebroplasty: Case Report and Literature Review

Introduction. Acrylic cement pulmonary embolism is a potentially serious complication following vertebroplasty. Case Report. A 70-year-old male patient was treated with percutaneous vertebroplasty for osteoporotic nontraumatic vertebral collapse of L5-S1. Asymptomatic pulmonary cement embolism was detected on routine postoperative chest radiogram and the patient was treated with enoxaparin, amoxicillin, and dexamethasone. At the followup CT scan no further migration of any cement material was reported; and the course was uneventful. Discussion. The frequency of local leakage of bone cement is relatively high (about 80–90%), moreover, the rate of cement leakage into the perivertebral veins (seen in up to 24% of vertebral bodies treated) with consequent pulmonary cement embolism varies from 4.6 to 6.8% (up to 26% in radiologic studies); the risk of embolism is increased with the liquid consistency of the cement and with the treatment of some malignant lesions. Patients may remain asymptomatic and develop no known long-term sequelae. Conclusions. Our ancedotal case illustrates the need for close monitoring of patients undergoing percutaneous vertebroplasty and emphasizes the importance of prompt and correct diagnosis and treatment, even if actually there is no agreement regarding the therapeutic strategy.

Ultrasonography-guided central venous catheterisation in haematological patients with severe thrombocytopenia

BACKGROUND Cannulation of the internal jugular vein (CVC) is a blind surface landmark-guided technique that could be potentially dangerous in patients with very low platelet counts. In such patients, ultrasonography (US)-guided CVC may be a valid approach. There is a lack of published data on the efficacy and safety of urgent US-guided CVC performed in haematological patients with severe thrombocytopenia. MATERIALS AND METHODS We retrospectively studied the safety of urgent CVC procedures in haematological patients including those with severe thrombocytopenia (platelet count <30×10(9)/L). From January 1999 to June 2009, 431 CVC insertional procedures in 431 consecutive patients were evaluated. Patients were included in the study if they had a haematological disorder and required urgent CVC insertion. Patients were placed in Trendelenburgs position, an 18-gauge needle and guide-wire were advanced under real-time US guidance into the last part of the internal jugular vein; central venous cannulation of the internal jugular vein was performed using the Seldinger technique in all the procedures. Major and minor procedure-related complications were recorded. RESULTS All 431 patients studied had haematological disorders: 39 had severe thrombocytopenia, refractory to platelet transfusion (group 1), while 392 did not have severe thrombocytopenia (group 2). The general characteristics of the patients in the two groups differed only for platelet count. The average time taken to perform the procedure was 4 minutes. Success rates were 97.4% and 97.9% in group 1 and group 2, respectively. No major complications occurred in either group. DISCUSSION US-guided CVC is a safe and effective approach in haematological patients with severe thrombocytopenia requiring urgent cannulation for life support, plasma-exchange, chemotherapy and transfusion.

Herpes simplex esophagitis in immunocompetent host: a case report.

Introduction. Herpes simplex esophagitis is well recognized in immunosuppressed subjects, but it is infrequent in immunocompetent patients. We present a case of HSE in a 53-year-old healthy man. Materials and Methods. The patient was admitted with dysphagia, odynophagia, and retrosternal chest pain. An esophagogastroduodenoscopy revealed minute erosive area in distal esophagus and biopsies confirmed esophagitis and findings characteristic of Herpes Simplex Virus infection. Results. The patients was treated with high dose of protonpump inhibitor, sucralfate, and acyclovir, orally, with rapid resolution of symptoms. Discussion. HSV type I is the second most common cause of infectious esophagitis. The majority of symptomatic immunocompetent patients with HSE will present with an acute onset of esophagitis. Endoscopic biopsies from the ulcer edges should be obtained for both histopathology and viral culture. In immunocompetent host, HSE is generally a self-limited condition. Conclusions. HSE should be suspected in case of esophagitis without evident cause, even if the patient is immunocompetent. When the diagnosis of HSE is confirmed, careful history and assessment for an immune disorder such as HIV infection is crucial, to look for underlying immune deficiency.

Surgical treatment of coledochal cyst associated with an aberrant posterior hepatic duct: report of a case and brief literature review.

Choledochal cysts (CCs) are rare congenital cystic or fusiform dilatations of the biliary tree that can involve the extrahepatic and/or intrahepatic biliary tree. We report a case of huge type I CC associated with an aberrant posterior hepatic duct. A 52-year-old man presented with a 3-week history of upper right abdominal pain and jaundice and serologic sign of obstructive jaundice. Ultrasonography (US), magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography were performed with the diagnosis of CC type I according to the classification of Alonso-Lej and Todani-Watanabe. The indication for surgical resection was posed. The cyst was completely resected and the biliary tract was reconstructed with a double hepatico-jejunostomy using the same Roux limb, since during the surgical dissection a before unrecognized anatomical variation of the right biliary tree (aberrant posterior hepatic duct at VI–VII segment) was identified. The diagnosis of CC is often difficult and US and magnetic resonance cholangiopancreatography are necessary to definite biliary dilatation. Endoscopic retrograde cholangiopancreatography should be the most definitive and reliable procedure for the diagnosis and treatment of bilio-pancreatic disorders. Gold standard treatment is surgery (bilio-jejunostomy) and frozen-section histology should be performed to rule out the presence of cancer. In conclusion, surgery is the gold standard for the treatment of CC type I and does not depend on the age of patients, based on a substantial lifetime risk of developing cholangiocarcinoma. Preoperative study is mandatory to assess the biliary tree morphology and to research any anatomical variation.