Michael Pitiakoudis

Early antivascular effects of bevacizumab anti-VEGF monoclonal antibody on colorectal carcinomas assessed with functional CT imaging.

Background:The complex effect on anti-VEGF (vascular endothelial growth factor) monoclonal antibodies on the tumor vasculature urges studies to identify the optimal time frames for the administration of such agents with chemotherapy and radiotherapy. Patients and Methods:Using CT scan functional imaging, we examined the perfusion changes of contrast medium induced 7 days following administration of bevacizumab (5 mg/kg iv) in 12 patients with colorectal cancer. Results:CT imaging 7 days after the administration of bevacizumab confirmed tumor shrinkage in 3 of 12 cases. The mean Haunsfield units after the injection of contrast medium were significantly lower 7 days following the administration of bevacizumab (P = 0.002). The “perfusion score” significantly decreased after the administration of bevacizumab (P = 0.01). In 5 of 12 cases the perfusion score was by 45% to 75% decreased, in 3 of 12 minor drop of the perfusion score was noted, in 1 of 12 a slight increase was noted, and in 3 of 12 remained unchanged. Conclusion:It is concluded that the antivascular effects of bevacizumab are evident within 7 days from administration in 40% of colorectal carcinomas. The mechanisms by which this early antivascular effect may favor the antitumor efficacy of radiotherapy and chemotherapy require further investigation.

Oxygen and glucose consumption in gastrointestinal adenocarcinomas: Correlation with markers of hypoxia, acidity and anaerobic glycolysis

This study gives an insight into tumor metabolic activity by investigating oxygen and glucose content, together with their metabolic products carbon dioxide and acids‐pH, in the arterial and venous blood of a tumor. Nineteen patients with gastrointestinal adenocarcinomas undergoing surgery were studied. Biochemical analysis showed that in a large subgroup of tumors, oxygen consumption was reduced while that of glucose was increased in malignant, as compared to normal tissues; these features were more evident in tumors overexpressing lactate dehydrogenase (LDH‐5) and hypoxia inducible factors (HIF1α/2α). An increase in carbon dioxide production in the tumor environment was linked with overexpression of carbonic anhydrase 9 (CA9). The simultaneous overexpression of CA9 and LDH‐5 was related to very low pH levels in the veins draining the tumor, suggesting an intense acidification of the tumor microenvironment in such cases. These in vivo data confirm the importance of HIFs and their downstream regulated genes in tumor metabolism, particularly in glycolysis and carbon dioxide buffering. (Cancer Sci 2006; 97: 1056 –1060)

Concurrent Liposomal Cisplatin (Lipoplatin), 5-Fluorouracil and Radiotherapy for the Treatment of Locally Advanced Gastric Cancer: A Phase I/II Study

PURPOSE Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. We investigated the feasibility of the combination of 5-fluorouracil/lecovorin-based radio-chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin). METHODS AND MATERIALS Lipoplatin was given at a dose of 120 mg/m(2)/week, 5-fluorouracil at 400mg/m(2)/week (Day 1), whereas radiotherapy was given through 3.5-Gy fractions on Days 2, 3, and 4. Two groups of 6 patients received four and five consecutive cycles, respectively. RESULTS Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3) was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or intestinal severe acute or late sequellae were documented, although the median follow-up of 9 months is certainly too low to allow safe conclusions. A net improvement in the performance status (from a median of 1 to 0) was recorded 2 months after the end of therapy. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles. CONCLUSIONS Lipoplatin radio-chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio-chemotherapy setting for the treatment of gastric cancer.

Development of primary malignant melanoma during treatment with a TNF-α antagonist for severe Crohn's disease: a case report and review of the hypothetical association between TNF-α blockers and cancer

It is recognized that immunosuppression may lead to reduced immune surveillance and tumor formation. Because of the immunosuppressive properties of tumor necrosis factor (TNF)-alpha (TNF-α) antagonists, it is plausible that these biologics may increase the risk of the occurrence of malignancies or the reactivation of latent malignancies. TNF-α antagonists have gained momentum in the field of dermatology for treating rheumatoid arthritis and psoriasis, and they have revolutionized the treatment of other inflammatory autoimmune diseases such as refractory Crohn’s disease. However, there is accumulating evidence that TNF-α inhibitors slightly increase the risk of cancer, including malignant melanoma (MM). The authors herein report the case of a 54-year-old female patient who developed a primary MM during treatment with adalimumab for severe Crohn’s disease resistant to successive medical therapies. The patient had been receiving this TNF-α blocker therapy for 3 years before the occurrence of MM. After wide surgical excision of the lesion and staging (based on Breslow thickness and Clark level), evaluation with a whole-body computed tomography scan was negative for metastatic disease. The long duration of the adalimumab therapy and the patient’s lack of a predisposition to skin cancer suggest an association between anti-TNF-α drugs and melanocytic proliferation. The authors also review the literature on the potential association between anti-TNF regimens and the occurrence of malignancies such as melanocytic proliferations. There is a substantial hypothetical link between anti-TNF-α regimens such as adalimumab and the potential for cancers such as melanoma. However, the risk of malignancy with biological therapy remains to be established, and most of the relevant studies have lacked the statistical power and randomization required for large clinical trials. Further long-term controlled clinical trials and registries are required to investigate this potentially serious association.

Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoArc) for rectal cancer: a Phase II study.

PURPOSE Bevacizumab has established therapeutic activity in patients with metastatic colorectal cancer, and anti-vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models. We assessed the feasibility and efficacy of preoperative radiochemotherapy combined with bevacizumab in patients with rectal cancer. METHODS AND MATERIALS Nineteen patients with radiologic T3 and/or N+ rectal carcinoma were treated with preoperative conformal hypofractionated accelerated radiotherapy (3.4 Gy in 10 consecutive fractions) supported with amifostine (500-1,000 mg daily), capecitabine (600 mg/m(2) twice daily, 5 days per week), and bevacizumab (5 mg/kg every 2 weeks for 2 cycles). Surgery followed 6 weeks after the end of radiotherapy. A cohort of 14 sequential patients treated with the same regimen without bevacizumab was available for comparison. RESULTS Grade 2 or 3 diarrhea was noted in 7 of 19 patients (36.8%), which was statistically worse than patients receiving the same regimen without bevacizumab (p = 0.01). A higher incidence of Grade 2 or 3 proctalgia was also noted (21.1%) (p = 0.03). Bladder and skin toxicity was negligible. All toxicities regressed completely within 2 weeks after the end of therapy. Pathologic complete and partial response was noted in 7 of 19 cases (36.8%) and 8 of 19 cases (42.1%). Within a median follow-up of 21 months, none of the patients has had late complications develop and only 1 of 18 evaluable cases (5.5%) has had locoregional relapse. CONCLUSIONS Bevacizumab can be safely combined with hypofractionated radiotherapy and capecitabine as a preoperative radiochemotherapy regimen for patients with rectal cancer. The high pathologic complete response rates urges the testing of bevacizumab in randomized studies.

The Effects of Apigenin on the Expression of Fas/FasL Apoptotic Pathway in Warm Liver Ischemia-Reperfusion Injury in Rats

Background. The aim of this experimental study was to investigate the role of apigenin in liver apoptosis, in an experimental model of hepatic ischemia-reperfusion in rats. Materials and Methods. Forty-eight Wistar rats (apigenin and control groups), 14 to 16 weeks old and weighing 220 to 350 g, were used. They were all subjected to hepatic ischemia by occlusion of the hepatic artery and portal vein for 45 minutes and reperfusion was followed for 60, 120, and 240 minutes. Apigenin was administrated intraperitoneally. Liver tissues were used for the detection of apoptosis by TUNEL assay and caspase 3 antibodies. Expression analysis of Fas/FasL genes was evaluated by real time PCR. Results. The expression analysis of Fas and FasL genes was increasing during reperfusion (significantly in the group of 240 minutes of reperfusion). It was in the same group that apigenin decreased Fas receptor levels and inhibited apoptosis as confirmed by TUNEL assay and caspase 3 antibodies. Conclusions. The effects of apigenin in the Fas/FasL mediated pathway of apoptosis, in the hepatic ischemia-reperfusion, seem to have a protective result on the hepatic cell.

Regenerated Nerve Defects with a Nerve Conduit Containing Dental Pulp Stem Cells in Pigs: An Immunohistochemical and Electrophysiological Evaluation

BACKGROUND Dental pulp stem cells (DPSCs) present an exciting new tool in the field of peripheral nerve regeneration due to their close embryonic origin. In this study, we examined their potential in pigs, using biodegradable collagen conduits filled with DPSCs. To our knowledge, this is the first time DPCSs are tested for peripheral nerve regeneration in such large animal model. MATERIALS AND METHODS The second lateral incisor was extracted from every animals lower jaw and stem cells were isolated and cultured. The collagen nerve conduits containing the DPSCs were subsequently transplanted into the transected fifth and sixth intercostal nerves, while the seventh intercostal nerve was used as a control and no stem cells were added on the respective collagen conduit. RESULTS A histological examination was performed on the 3rd and 6th postoperative months and showed the gradual development of neural tissue and immunohistochemical expression of neuron-specific enolase. An electrophysiological study was performed on the 6th postoperative month and showed similar potentials between the stem cell infusion region (5 ± 0.04 units) and their proximal stumps (5 ± 0.05 units) and slightly smaller potentials in the respective distal stumps (4 ± 0.045 units). CONCLUSION The nerves where DPSCs were injected exhibited morphological and functional recovery, in contrast to the control nerves where no recovery was detected; thus, there is a first evidence of the therapeutic potential of DPSCs in peripheral nerve regeneration.

Single-incision assisted laparoscopic surgery (SILS) in the treatment of an intussusception induced by a solitary hamartomatous polyp: a case report and review of the literature

IntroductionIn this case report, we describe the successful treatment of a small-bowel intussusception, which was caused by a 3cm solitary hamartomatous polyp, with single-incision laparoscopic surgery. Single-incision laparoscopic surgery is a minimally invasive surgical procedure with important advantages that allows the reduction of the intussusception and the resection of the polyp. This case report contributes to the medical literature by describing the advantages of this surgical technique that warrant its consideration as a treatment of choice in similar cases.Case presentationWe report a case of a 19-year-old Greek woman who complained about intermittent, non-specific abdominal pain in her left lateral abdomen. She had been admitted to the hospital because of incomplete obstructive ileus. Ultrasound and computed tomography were carried out, which revealed an intussusception of the small bowel. This pathogenic situation was treated by single-incision laparoscopic surgery. Her pathology report revealed a benign, hamartomatous excised polyp of the Peutz-Jeghers type. The patient had a quick recovery without any post-operative complications.ConclusionWe recommend single-incision laparoscopic surgery for the safe excision of solitary hamartomatous polyps and the management of their complications, as it represents a potential advance in minimally invasive approaches.

Does prophylactic administration of somatostatin decrease the rates of complications after pancreatic resection?: A clinical and electron microscopy study.

Objectives The postoperative morbidity after pancreatectomy remains high. The role of somatostatin and its analogs in reducing complications after pancreatic resection is controversial. The aim of the study was to evaluate the ability of somatostatin to influence pancreatic cell’s function with consequence the decrease of postoperative complications. Methods Between January 2006 and December 2009, 67 patients for which pancreatectomy was indicated were randomized into 2 groups. At surgery, biopsies of the pancreas were taken to be studied by electron microscopy and analyzed for ultrastructural morphometry. Results The total mortality was 4.4% (n = 3/67; 2 patients from the control group and 1 patient from the treatment group). The overall morbidity was 35.8% (n = 24/67). Eighteen patients in the control group (n = 18/32; 56.25%) and 6 patients in the treatment group (n = 6/35; 17.14%) developed postoperative complications (2-tailed Fisher exact test; P = 0.001). The most common complication was the presence of fistula (n = 6/67; 8.95%). Conclusions Perioperative administration of intravenous somatostatin at rates applied in this study was able to inhibit the exocrine pancreatic function. This finding supports the prophylactic effect of somatostatin on the early postoperative complications of pancreatic surgery shown in this study.

Oxidative stress in multi-port and single-port cholecystectomy

BACKGROUND This study was designed to analyze and compare plasma levels of 8-isoprostane (8-epiPGF2α), a biomarker of lipid peroxidation, and uric acid (UA), a marker of the antioxidant status, in standard laparoscopic (LC) and laparoendoscopic single-site cholecystectomy (LSSC). MATERIALS AND METHODS Forty patients with noncomplicated cholelithiasis were randomized to undergo either LSSC (n = 20) or LC (n = 20). The patients had body mass index <30, American Society of Anesthesiologists score I or II, and no previous upper gastrointestinal surgery. Blood samples were taken preoperatively and 6 h and 24 h postoperatively. Levels of 8-epiPGF2α were determined using enzyme-linked immunosorbent assay, whereas levels of UA were calculated using automated analyzer. RESULTS No significant differences were observed in operative data among the groups. Levels of 8-epiPGF2α were significantly higher in LSSC compared with LC at 6 h (P = 0.003) and 24 h (P < 0.001). 8-epiPGF2α levels showed significant changes over time in LC (LSSC: P = 0.720, LC: P < 0.001). UA levels were significantly higher in LC compared with LSSC, 24 h postoperatively (P = 0.021). No significant changes over time in the UA levels in both groups (LSSC: P = 0.056, LC: P = 0.205). CONCLUSIONS LSSC is associated with increased oxidative stress compared with LC. Further studies are needed to confirm these results.