Emanuel Cavazzoni

Malignant ascites: pathophysiology and treatment

Malignant ascites (MA) accompanies a variety of abdominal and extra-abdominal tumors. It is a primary cause of morbidity and raises several treatment challenges. MA has several symptoms, producing a significant reduction in the patient’s quality of life: loss of proteins and electrolyte disorders cause diffuse oedema, while the accumulation of abdominal fluid facilitates sepsis. Treatment options include a multitude of different procedures with limited efficacy and some degree of risk. A Pubmed, Medline, Embase, and Cochrane Library review of medical, interventional and surgical treatments of MA has been performed. Medical therapy, primarily paracentesis and diuretics, are first-line treatments in managing MA. Paracentesis is widely adopted but it is associated with significant patient discomfort and several risks. Diuretic therapy is effective at the very beginning of the disease but efficacy declines with tumor progression. Intraperitoneal chemotherapy, targeted therapy, immunotherapy and radioisotopes are promising medical options but their clinical application is not yet completely elucidated, and further investigations and trials are necessary. Peritoneal–venous shunts are rarely used due to high rates of early mortality and complications. Laparoscopy and hyperthermic intraperitoneal chemotherapy (HIPEC) have been proposed as palliative therapy. Literature on the use of laparoscopic HIPEC in MA includes only reports with small numbers of patients, all showing successful control of ascites. To date, none of the different options has been subjected to evidence-based clinical trials and there are no accepted guidelines for the management of MA.

Successful palliation of malignant ascites from peritoneal mesothelioma by laparoscopic intraperitoneal hyperthermic chemotherapy.

A variety of options have been proposed to treat malignant ascites but most of them have failed to reach a significant impact in terms of palliation. Laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC) could represent a good therapeutic tool for patients in whom medical therapies have failed and peritoneovenous shunting is contraindicated. Here we present a case of a 49-year-old woman with malignant ascites secondary to peritoneal spreading of a right pleural mesothelioma. After failure of medical therapy, the patient underwent LHIPEC with Cisplatin 25 mg/m2/L and Doxorubicin 7 mg/m2/L. A dramatic reduction of ascites was documented in the postoperative period and the patient experienced complete abdominal symptom relief. Ascites did not recur during a follow-up period of 6 months. LHIPEC could be a good therapeutic option to palliate malignant ascites from mesothelioma in cases not eligible for a radical treatment. Further studies are needed to standardize dosage and perfusion parameters.

Prognostic value of the seventh AJCC/UICC TNM classification of non-cardia gastric cancer

BackgroundThe TNM staging criteria for gastric carcinoma have seen numerous revisions, the most recent of which are reflected in the seventh edition AJCC TNM cancer staging manual.MethodsA retrospective evaluation of the sixth and seventh TNM classification of gastric cancer on a prospective database, regarding patients operated on for primary gastric cancer, was conducted. The end point of the study was prognosis evaluation in terms of overall survival.Patients operated on for primary gastric cancer between September 2003 and March 2012 at our Department of Emergency and General Surgery, were consecutively retrieved in this study; a total of 114 patients were considered. Cardia gastric cancers, gastric lymphomas and gastrointestinal stromal tumors (GIST) were excluded. Median and mean follow-up periods were 22.5 and 27.7 months (range 15 days to 5 years). Both TNM6 and TNM7 were used to evaluate our patients. Overall survival and survival rates at different stages were analyzed using the Kaplan-Meier method and differences were determined using a log-rank test. Cox’s proportional hazard model was used to identify significant factors related to prognosis in a multivariate analysis.ResultsOverall survival between the sixth and seventh TNM classification was not significantly different. Both the Kaplan-Meier analysis and the multivariate analysis showed that the major negative prognostic factor was lymphovascular invasion (P < 0.001 in the univariate analysis and P = 0.035 to 0.048 in the multivariate analysis). Stage distribution and stage-related survival changed from the sixth to the seventh edition, especially in T3 stage where median survival for the sixth edition was 720 days versus 1,200 days for the seventh edition. Moreover, differences were shown in the survival rate of N1 versus N2 stages within the seventh TNM.ConclusionsEven though further studies are needed in order to increase the number of patients studied, the seventh edition seems to provide a more accurate prognosis, especially regarding N1 and N2 tumors, showing that the most important prognostic factor is lymphovascular invasion.

Mechanistic role of p38 MAPK in gastric cancer dissemination in a rodent model peritoneal metastasis.

Peritoneal dissemination is a highly frequent complication of poorly differentiated gastric cancers for which no effective therapies are available. Constitutive activation of mitogen-activated protein kinases (MAPKs) signaling cascades is recognized as a causative factor in the malignant transformation of several carcinoma cell types. In the present study we provide evidence that p38 MAPK inhibition protects against gastric cancer cells dissemination in a mouse model of peritoneal carcinomatosis. Administering mice with ML3403 and SB203580, potent and selective p38 MAPK inhibitors, attenuate the formation of neoplastic foci induced by intraperitoneal inoculation of gastric cancer cells. By gene array analysis we found that such a protective effect correlates with a robust downregulation in the expression of CXC chemokine receptor-4, Fms-related tyrosine kinase 4 (FLT4), the non-receptor spleen tyrosine kinase (SYK) and the collagen α2(IV) (COL4A2) in neoplasic foci. Inhibition of p38 MAPK in vivo increased the sensitivity of tumor cells to cisplatin and associated with a robust downregulation in the expression of the multidrug resistance (MDR)-1, a well defined marker of resistance to chemotherapy. In summary, p38 MAPK inhibition by a small molecule is beneficial in preventing the peritoneal dissemination of poorly differentiated gastric cancer cells by acting at multiple check-points in the process of attachment and diffusion of tumor cells in the peritoneum.

Epigenetic Modulation by Methionine Deficiency Attenuates the Potential for Gastric Cancer Cell Dissemination

IntroductionMethionine dependency occurs frequently in tumor cells. Here we have investigated the effect of methionine deficiency on metastatic potential of gastric cancer cells in vitro and in vivo.Materials and MethodsModel of peritoneal carcinomatosis and xenograft was generated by intraperitoneal or subcutaneous implantation of gastric cancer cells in NOD-SCID mice. In comparison to control medium, 3-day culture of MKN45, MKN74, and KATOIII cells in a methionine-deficient medium inhibited cell proliferation, increased the rate of cell apoptosis, and reduced cell adhesion and migration. In the xenograft model induced by implantation of MNK45 and MNK74 cells, two cycles of methionine-deficient diet reduced the tumor growth. Further on, a 10-day cycle of methionine-deficient diet reduced the number of peritoneal nodules in the model of peritoneal carcinomatosis induced by MKN45 cells injection. Finally, a microarray analysis of the methylation of promoter CpG islets demonstrated that methionine deficiency reduced the promoter methylation of E-cadherin whose expression was markedly increased in vivo and in vitro.ResultsIn summary, we have provided evidence that a methionine-deficient diet modulates the growth of gastric tumor cells and in vitro deficiency of methionine increased apoptosis and decreased cellular adhesion and migration associated to epigenetic change of E-cadherin gene, in vivo and in vitro.

Neoadjuvant chemotherapy in locally advanced gastric adenocarcinoma: our experience in the elderly

Background Gastric cancer is a neoplasm with a poor prognosis, often diagnosed in advanced stage of disease, specially in elderly patients. Neo-adjuvant chemotherapy may increase the possibility of complete surgical resection, improving progression-free and overall survival (five-years survival of 36% compared with 23% of patients treated by surgery alone) as shown in the MAGIC Trial by Cunningham et al.

Response to imiquimod 5% cream as treatment for condyloma and anal intraepithelial neoplasia in HIV-positive and HIV-negative patients

Treatments for anal intraepithelial neoplasia (AIN) include non-operative options and more invasive treatments, such as wide local excision.1 Unfortunately, recurrence rates remain high regardless of treatment and therefore surveillance is paramount.2 We performed a study of patients who underwent treatment of condyloma and AIN using imiquimod 5% cream and compared outcomes in those patients with and without HIV. We retrospectively reviewed patients who underwent anal cancer screening …

Simultaneous Delorme's procedure and inter-sphinteric prosthetic implant for the treatment of rectal prolapse and faecal incontinence: Preliminary experience and literature review

AIM Rectal prolapse is a distressing condition affecting mostly elderly patients and females. Delormes procedure is frequently performed since it offers good results and is burdened by a particularly low morbidity. Faecal Incontinence is associated with prolapse in a large percentage of patients, due to the sphincter damage caused by the prolapsed rectum through the anal canal. Prolapse resection is often ineffective in treating incontinence, and further specific procedures are frequently required. At present, no data are available on combined Delormes procedure with the implant of Bulking Agents for the simultaneous treatment of rectal prolapse and faecal incontinence. METHOD Three patients affected by complete external rectal prolapse underwent simultaneous Delormes procedure with application of six polyacrylonitrile prosthetic cylinders in the inter-sphinteric space (Gate Keeper™, THD, Correggio Italy). Follow up was at 3,6 and 12 months. RESULTS Gate Keeper procedure required a short operative time; no morbidity or complications were experienced. Prolapse was successfully treated in all patients and the mean Vaizeys incontinence score value dropped from pre-operative 19.3 to 9.3 after 3 months. All patients experienced a reduction of incontinence episodes and an improvement in daily activities and lifestyle. CONCLUSION Gate Keeper implant is feasible and safe when associated to surgical procedures like Delormes prolapse resection. Preliminary results are positive even if a study with a larger numbers of patients is needed to confirm the efficacy. A simultaneous treatment of faecal incontinence should be always considered when performing surgery for rectal prolapse. SHORT STATEMENT The present manuscript describes a simultaneous combination of two surgical techniques to treat rectal prolapse and faecal incontinence. To date, there are no published data on a similar approach. The paper underlies the importance of treating faecal incontinence when performing surgery for rectal prolapse.

Analysis of operative morbidity in a single center initial experience with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Background Peritoneal carcinomatosis has been traditionally considered a rapidly lethal disease and consequently managed by merely palliative options. In the last decade, the clinical interest in the condition has increased because encouraging results have been reported in association with a new treatment strategy that combines cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Relatively high rates of severe complications are generally associated to this complex procedure. Our aim was to analyze treatment-related morbidity in our institutional initial experience. Materials and Methods Since October 2006, 36 hyperthermic intraperitoneal chemotherapy plus cytoreductive surgery procedures have been carried out in our Department. Patients treated showed abdominal malignancies and ovarian cancer with peritoneal carcinomatosis. Only 9 patients were treated with prophylactic treatment for gastric cancer at high risk to develop peritoneal carcinomatosis. Results In 27 patients, a macroscopically complete cytoreduction was done. The overall morbidity was 75%. Grades IV and V represented only 11.1%. Conclusions Rigorous preoperative workup and strict selection criteria allowed a successful safe start of a new program of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a general surgery unit.

Evaluation of 153 Asymptomatic Subjects Using the Anopress Portable Anal Manometry Device

Background/Aims The Anopress device is a new portable manometry system. The aim of this study is to formulate normative data using this new device by recording the anorectal function of asymptomatic subjects. Patient comfort was also assessed. Methods Anorectal function was assessed in asymptomatic volunteers using the Anopress. All volunteers were examined in a standardized way in accordance with the study protocol. Normative values for the Anopress were obtained from the recorded data and patient comfort was assessed using a visual analogue scale. Results We recruited 153 healthy volunteers. Eighty were female (23 parous; median age 39.5 [interquartile range {IQR}, 28.75–53.00]) and 73 were male (median age 40.5 [IQR, 29.00–52.25]). For the female cohort, the following normal range (2.5–97.5 percentile) values were recorded across the whole anal canal: resting pressure 40.0–103.0 mmHg; squeeze increment 35.0–140.6 mmHg; endurance 1.3–9.0 seconds; involuntary squeeze 41.1–120.8 mmHg; and strain pressure 22.1–77.9 mmHg. Similarly, the following male normal range (2.5–97.5 percentile) values were recorded across the whole anal canal: resting pressure 38.3–99.6 mmHg; squeeze increment 42.5–154.8 mmHg; involuntary squeeze 40.0–123.6 mmHg; endurance 2.0–10.0 seconds; and strain pressure 11.0–72.1 mmHg. The median visual analogue scale scores for discomfort during the measurement was 0.0 (IQR, 0.00–0.00). Conclusions Normative values for the Anopress device have been calculated by this study. The Anopress appears to be a safe and well tolerated way of measuring pressures from the entire anal canal. Further comparisons with other standard and commonly used manometry tests are, however, required to verify its reliability.