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Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are currently the most accepted treatment for peritoneal metastases from colorectal cancer. Restrictive selection criteria are essential to obtain the best survival benefits for this complex procedure. The most widespread score for patient selection, the peritoneal surface disease severity score (PSDSS), does not include current biological factors that are known to influence on prognosis. We investigated the impact of including RAS mutational status in the selection criteria for these patients. Methods: We studied the risk factors for survival by multivariate analysis using a prospective database of consecutive patients with carcinomatosis from colorectal origin treated by CRS and HIPEC in our unit from 2009 to 2017. The risk factors obtained were validated in a multicentre, international cohort, including a total of 520 patients from 15 different reference units. Results: A total of 77 patients were selected for local análisis. Only RAS mutational status (HR: 2.024; p = 0.045) and PSDSS stage (HR: 2.90; p = 0.009) were shown to be independent factors for overall survival. Early PSDSS stages I and II associated to RAS mutations impaired their overall survival with no significant differences with PSDSS stage III overall survival (p > 0.05). These results were supported by the international multicentre validation. Conclusions: By including RAS mutational status, we propose an updated RAS-PSDSS score that outperforms PSDSS alone providing a quick and feasible preoperative assessment of the expected overall survival for patients with carcinomatosis from colorectal origin undergone to CRS + HIPEC.

La noma e un’infezione gangrenosa che puo causare una grave deturpazione del viso. Colpisce quasi esclusivamente i bambini piccoli che vivono nei paesi in via di sviluppo con una mortalita elevata. Per i bambini che sopravvivono, le sequele sono spesso talmente mutilanti, da metterli ai limiti della societa. I fattori di rischio sono noti (malnutrizione, malattie debilitanti), ma l’eziologia rimane parzialmente sconosciuta. Il reparto di chirurgia plastica e ricostruttiva degli Ospedali universitari di Ginevra (Svizzera) ha piu di 30 anni di esperienza nella chirurgia delle sequele da noma. I pazienti con lesioni meno gravi sono operati direttamente nelle missioni chirurgiche, mentre quelli che richiedono una ricostruzione piu complessa vengono trasferiti. Dopo aver descritto le peculiarita degli effetti della noma e le difficolta incontrate nella gestione di questi pazienti, gli autori analizzano le principali tecniche chirurgiche utilizzate per la ricostruzione. I problemi riscontrati durante il follow-up a lungo termine di questi pazienti hanno contribuito all’evoluzione delle tecniche chirurgiche utilizzate: utilizzo di lembi liberi per la ricostruzione dei tessuti molli della guance, per diminuire il rischio elevato di recidiva di costrizione mandibolare (lembo muscolocutaneo di gran dentato), ricostruzione delle perdite di sostanza ossea attraverso lembi ossei vascolarizzati (lembo preformato di occipitale vascolarizzato) e preservazione dei siti donatori per nuove ricostruzioni alla fine della crescita, di solito nella ricostruzione nasale. La chirurgia delle sequele complesse richiede una buona conoscenza di chirurgia maxillofacciale e di microchirurgia. Se sono utilizzate tecniche chirurgiche inadeguate, ai risultati insufficienti si aggiungono delle mutilazioni, spesso inaccettabili, legate alla cicatrizzazione. Parallelamente a questa attivita chirurgica, si e sviluppato un importante progetto di ricerca eziologica sulla noma, i cui principali risultati sono qui presentati.

Background Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. Objective To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. Material and methods A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. Results Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3–26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively. Conclusion Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.

El noma es una afeccion gangrenosa que provoca destrucciones graves en la cara. Afecta de forma casi exclusiva a ninos de corta edad que viven en paises en vias de desarrollo y tiene una mortalidad elevada. Los ninos que sobreviven suelen sufrir secuelas muy mutilantes que les marginan de la sociedad. Los factores de riesgo son conocidos (malnutricion, enfermedades debilitantes), pero no asi su etiologia. El servicio de cirugia plastica y reconstructiva de los Hospitales Universitarios de Ginebra (Suiza) tiene mas de 30 anos de experiencia en la cirugia de las secuelas del noma. Los pacientes que presentan las lesiones menos graves se operan en misiones quirurgicas, mientras que los que precisan una reconstruccion mas compleja se trasladan. En este articulo, despues de describir las particularidades de las secuelas del noma y las dificultades que se encuentran en el tratamiento de estos pacientes, se revisan las principales tecnicas quirurgicas utilizadas para su reconstruccion. Los problemas que se han descubierto durante el seguimiento a largo plazo de estos pacientes han contribuido a la evolucion de las tecnicas quirurgicas utilizadas: empleo de grandes colgajos libres para la reconstruccion de los tejidos blandos yugales con el fin de disminuir el riesgo elevado de recidiva de constriccion mandibular (colgajo miocutaneo de serrato anterior), reconstruccion de las perdidas de sustancia oseas con colgajos oseos vascularizados (colgajo prefabricado de boveda craneal vascularizado) y conservacion de los sitios donantes potenciales para nuevas reconstrucciones al final del crecimiento (sobre todo en la reconstruccion nasal). La cirugia de las secuelas complejas requiere unos buenos conocimientos de cirugia craneomaxilofacial y de microcirugia. Cuando se utilizan tecnicas quirurgicas inadecuadas, se obtienen resultados insuficientes, a los que se anaden mutilaciones cicatriciales, que a menudo son inaceptables. En paralelo a esta actividad quirurgica, se ha desarrollado un importante proyecto de investigacion etiologica sobre el noma, cuyos resultados principales se expondran aqui.

Aim Primary peritoneal serous carcinoma (PPSC) is a rare condition, histologically identical to ovarian serous carcinoma and often diagnosed at late stage. There is not any standardized treatment for PPSC. A retrospective multicentric study was performed in French speaking centers to evaluate cytoreduction surgery and Hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinomatosis from different origins. The manuscript's aim was to study the particular population with PPSC. Methods Between September 1997 and July 2007, 36 patients with PPSC from 9 institutions underwent 39 procedures. Results Mortality and morbidity rates were 5.6% and 20.6% respectively. The overall survival at 1, 3 and 5 years are respectively 93.6, 71.5 and 57.4%. The median overall survival was not reached. By univariate analysis, the only factor that had prognostic value was PCI (p = 0.03). Conclusions The therapeutic approach combining cytoreductive surgery with HIPEC may achieve long-term survival in patients with PPSC.

Please cite this paper as: Deraco M, Virzi S, Raspagliesi F, Iusco D, Puccio F, Macri A, Famulari C, Solazzo M, Bonomi S, Grassi A, Baratti D, Kusamura S. Secondary cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent epithelial ovarian cancer: a multi-institutional study. BJOG 2012;119:800–809. Objective To assess the efficacy and morbidity and mortality of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent epithelial ovarian cancer (EOC). Design A retrospective study conducted using information extracted from a multi-institutional prospective database on peritoneal surface malignancies (PSMs). Setting Four Italian centres specializing in locoregional treatment of PSM. Population Patients with recurrent EOC. Methods Fifty-six patients underwent 57 combined procedures. CRS was performed using peritonectomy procedures and HIPEC using the closed-abdomen technique with cisplatin and doxorubicin or cisplatin and mitomycin-C. Main outcome measures Overall survival (OS), progression-free survival (PFS), morbidity and mortality rates. Results The median age of the patients was 55.2 years (range 30–75 years). The median peritoneal cancer index was 15.2 (range 4–30). Forty-seven patients had microscopic residual disease (completeness of cytoreduction, CC-0), seven had residual disease ≤2.5 mm (CC-1) and one had residual disease >2.5 mm (CC>2). Major complications occurred in 15 patients (26.3%), and procedure-related mortality occurred in three patients (5.3%). The median follow-up time was 23.1 months. The median OS and PFS were 25.7 (95% CI 20.3–31.0) and 10.8 (95% CI 5.4–16.2) months, respectively. The 5-year OS and PFS were 23% and 7%, respectively. Independent prognostic factors affecting OS according to the multivariate analysis were Eastern Cooperative Oncology Group performance status, preoperative serum albumin, and completeness of cytoreduction. Conclusions Patients with recurrent EOC treated with CRS and HIPEC showed promising results in terms of outcome. The combined treatment strategy could benefit subsets of patients wider than that defined for conventional secondary debulking surgery without HIPEC. These data warrant further evaluation in randomised clinical trials.

Aim This retrospective multi-institutional study addresses the role of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of multicystic peritoneal mesothelioma (MCPM). MCPM is an uncommon tumour with uncertain malignant potential and no current standard therapy. Additionally, poorly defined pathological and biological features of this disease were investigated. Methods Twelve patients with MCPM underwent 14 procedures of cytoreduction and HIPEC in two Italian referral centres. Nine patients had recurrent disease after previous debulking (one operation in six patients, two in two, four in one). Biological markers related to mesothelioma origin and clinical features were assessed by immunohistochemical studies. Results Median follow-up was 64 months (range 5–148). Optimal cytoreduction (residual tumour nodules ≤2.5 mm) was performed in all the procedures. One grade IV postoperative complication (NCI/CTCAE v.3.0) and no operative death occurred. All the patients are presently alive with no evidence of disease, including two patients who underwent the procedure twice, due to locoregional disease recurrence. Five- and ten-year progression-free survival was 90% and 72%, accounting for a. statistically significant difference (P = 0.0001) with progression-free survival following previous debulking surgery (median 11 months; range 2–31). All cases showed low proliferative activity assessed by mitotic rate and Ki-67 expression. Conclusions MCPM is a borderline tumour with a high propensity to local–regional recurrence. Definitive tumour eradication by means of cytoreduction and HIPEC seems more effective than debulking surgery in preventing disease relapse. Low mitotic rate and poor Ki-67 expression might be related to the peculiar behaviour of MCMP.

Aim The aim of the present study was to address the economic cost of the innovative comprehensive approach involving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat peritoneal surface malignancies, and to compare it with the financial support received by our centre. Methods A retrospective economic analysis was carried out on 382 consecutive procedures performed at a tertiary referral centre during the period 1995–2008. The costs of the combined therapy were estimated using the activity-based costing methodology. The financial support was assessed according to the current diagnosis-related group classification and reimbursement rates. Results The mean cost for one hospital stay was €36,015.89 (range 28,435.24–82,189.08); mean length of stay was 24.3 days (range 9–108). In counterpart, our hospital received a total financial support of €804,483.30, resulting in a deficit of €1861,301.99 for the two years. Conclusion The Italian current diagnosis-related groups classification does not include cytoreduction and HIPEC. This results in a relevant economic deficit for the hospitals offering this treatment option to their patients and a slow diffusion of the technique in our country. Two corrective measures are needed: to include this procedure in the official list of medical acts, and to determine its specific cost for reimbursing.

Il noma e un’infezione che provoca distruzioni severe a livello del volto. Colpisce quasi esclusivamente bambini che vivono in paesi in via di sviluppo con elevata mortalita. Per i bambini che sopravvivono gli esiti sono molto mutilanti, causando la loro messa al bando della societa. I fattori di rischio sono conosciuti (malnutrizione, malattie debilitanti), ma non l’eziologia. Il servizio di chirurgia di plastica e ricostruttiva degli ospedali di Ginevra in Svizzera hanno piu di 20 anni di esperienza nella chirurgia degli esiti di noma. I pazienti che presentano lesioni meno severe vengono operati durante le missioni chirurgiche; quando necessitano di una ricostruzione piu complessa vengono trasferiti. Dopo aver descritto le particolarita degli esiti di noma e le difficolta riscontrate durante il trattamento di questi pazienti, gli autori analizzeranno le principali tecniche chirurgiche utilizzate per la ricostruzione. I problemi scoperti in occasione del follow-up a lungo termine di questi pazienti hanno contribuito all’evoluzione delle tecniche chirurgiche utilizzate: utilizzo di ampi lembi liberi per la ricostruzione dei tessuti molli giugali per diminuire il rischio elevato di recidiva di costrizione mandibolare (lembo muscolocutaneo di gran dentato), ricostruzione delle perdite di sostanze ossee con lembi ossei vascolarizzati (lembo prefabbricato di calvarium vascolarizzato), preservazione delle unita donatrici potenziali per nuove ricostruzioni alla fine della crescita, in particolare nella ricostruzione nasale. La chirurgia degli esiti complessi richiede una buona conoscenza di chirurgia cranio-maxillo-facciale e di microchirurgia. Quando le tecniche chirurgiche utilizzate sono insufficienti, ai risultati insufficienti si aggiungono mutilazioni cicatriziali spesso inaccettabili.

La noma es una afeccion gangrenosa que provoca destrucciones graves en la cara. Afecta de forma casi exclusiva a ninos de corta edad que viven en paises en vias de desarrollo y tiene una mortalidad elevada. Los ninos que sobreviven suelen sufrir secuelas muy mutilantes que les marginan de la sociedad. Los factores de riesgo son conocidos (malnutricion, enfermedades debilitantes), pero no asi su etiologia. El servicio de cirugia plastica y reconstructiva de los Hospitales Universitarios de Ginebra (Suiza) tiene mas de 20 anos de experiencia en la cirugia de las secuelas de la noma. Los pacientes que presentan las lesiones menos graves se operan en misiones quirurgicas, mientras que los que precisan una reconstruccion mas compleja se trasladan. Despues de describir las peculiaridades de las secuelas de la noma y las dificultades que se encuentran en el tratamiento de estos pacientes, se revisan las principales tecnicas quirurgicas utilizadas para su reconstruccion. Los problemas que se han descubierto durante el seguimiento a largo plazo de estos pacientes han contribuido a la evolucion de las tecnicas quirurgicas utilizadas: empleo de grandes colgajos libres para la reconstruccion de los tejidos blandos yugales con el fin de disminuir el riesgo elevado de recidiva de constriccion mandibular (colgajo miocutaneo de serrato anterior), reconstruccion de las perdidas de sustancias oseas con colgajos oseos vascularizados (colgajo prefabricado de boveda craneal vascularizado) y conservacion de los sitios donantes potenciales para nuevas reconstrucciones al final del crecimiento (sobre todo en la reconstruccion nasal). La cirugia de las secuelas complejas requiere unos buenos conocimientos de cirugia craneomaxilofacial y de microcirugia. Cuando se utilizan tecnicas quirurgicas inadecuadas, se obtienen resultados insuficientes, a los que se anaden mutilaciones cicatrizales, que a menudo son inaceptables.

Improved survival has been reported for diffuse malignant peritoneal mesothelioma (DMPM) treated by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). The issue of treatment failure has never been extensively addressed. The present study assessed the failure pattern, management, and outcome of progressive DMPM following comprehensive treatment. Clinical data on 70 patients with DMPM undergoing cytoreduction and HIPEC were prospectively collected; after a median follow-up of 43 months, disease progression occurred in 38 patients. Progressive disease distribution in 13 abdominopelvic regions was analyzed. In 28 patients undergoing adequate cytoreduction (residual tumoror =2.5 mm), clinicopathological factors correlating to disease progression in each region were investigated. Median time to progression was 9 months [95% confidence interval (CI) 1.6-35.9]. Median survival from progression was 8 months (95% CI 4-16.2). The failure pattern was categorized as peritoneal progression (n = 31), liver metastases (n = 1), abdominal lymph-node involvement (n = 2), pleural seeding (n = 4). Small bowel was the single site most commonly involved (n = 27). Residual tumoror =2.5 mm (versus no visible) was the only independent risk factor for disease progression in epigastric region (P = 0.047), upper ileum (P = 0.029), upper jejunum (P = 0.034), and lower jejunum (P = 0.002). Progressive disease was treated with second HIPEC in 3 patients, debulking in 4, systemic chemotherapy in 16, and supportive care in 15. At multivariate analysis, time to progression9 months (P = 0.009), poor performance status (P = 0.005), and supportive care (P = 0.003) correlated to reduced survival from progression. We conclude that minimal residual disease, compared with macroscopically complete cytoreduction, correlated to failure in critical anatomical areas, suggesting the need for maximal cytoreductive surgical efforts. In selected patients, aggressive management of progressive disease seems worthwhile.

Multicystic peritoneal mesothelioma (MPM) and well-differentiated papillary peritoneal mesothelioma (WDPPM) are exceedingly uncommon lesions with uncertain malignant potential and no uniform treatment strategy. The aim of the current study was to review our experience with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in these clinical settings. Four women with MPM and eight with WDPPM underwent 13 procedures of cytoreduction and close-abdomen HIPEC with cis-platin and doxorubicin. Seven patients had recurrent disease after previous debulking (one operation in five patients, two in one, four in one). Potential clinicopathological prognostic factors were assessed. Optimal cytoreduction (residual tumor nodules ≤2.5 mm) was performed in 12 of 13 procedures. Median follow-up was 27 months (range 6–94). One grade 4 postoperative complication (NCI/CTCAE v.3.0) and no operative mortalities occurred. One patient underwent the procedure twice due to locoregional MPM recurrence. Transition of typical WDPPM to malignant biphasic mesothelioma was documented in one patient who died of disease progression following incomplete cytoreduction and HIPEC. Following multimodality treatment, 5-year overall and progression-free survival were 90.0% (standard error = 9.0) and 79.7% (11.9), respectively. Progression-free survival following previous debulking surgery (median 24 months; range 2–87) was statistically worse (P = .0156). Incomplete cytoreduction and poor performance status correlated to both reduced overall and progression-free survival after cytoreduction and HIPEC. MPM and WDPPM are borderline tumors capable of transformation into potentially lethal processes. Definitive tumor eradication by means of cytoreduction and HIPEC seems more effective than debulking surgery in preventing disease recurrence or transition to aggressive malignancies.

Aims: CDX-2 is a highly sensitive and specific marker of intestinal epithelial cells and their neoplastic counterparts. CDX-2 status in pseudomyxoma peritonei (PMP) has been barely reported. The aim of this study was to investigate the clinicopathological features of 42 cases of PMP with a special emphasis on CDX-2. Methods and results: All patients were treated by cytoreduction. Immunohistochemistry was performed for CDX-2, MUC-2, MUC-5AC, cytokeratin (CK) 7 and CK20. Statistical correlation was evaluated for age, sex, completeness of cytoreduction and histological subtype with overall and progression-free survival (OS and PFS). PMP consisted of 32 cases of disseminated peritoneal adenomucinosis and 10 cases of peritoneal mucinous carcinomatosis. The appendix evaluated in 25 cases showed two mucinous adenocarcinomas and 21 low-grade appendiceal mucinous neoplasms. CDX-2 was diffusely positive in 40 cases, with the remaining two cases being focally positive. All cases demonstrated diffuse reactions to CK20 and MUC-2, and variable reactions to MUC-5AC, while CK7 was variably positive in 38 cases. Five-year OS was 97%. Histological type was significantly correlated with PFS (P = 0.02). Conclusions: CDX-2 is diffusely and strongly positive in PMP. This is a useful marker to confirm an appendiceal origin of PMP, particularly when used in conjunction with CK7, CK20, MUC-2 and MUC-5AC.

Aims: We report the effects of cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP) in the treatment of advanced/ recurrent epithelial ovarian cancer (EOC) on survival, morbidity and mortality. Patients: Forty EOC patients were studied. Median age was 52.5 years (range: 30e68) and median follow-up 26.1 months (range: 0.3e 117.6). Most patients presented advanced disease (stage III/IV). Previous systemic chemotherapy included cisplatin-based, taxol-based or taxol/platinum containing regimens. Results: After the CRS, 33 patients presented no macroscopic residual disease. Five-year overall survival was 15%; the mean overall and progression-free survivals were 41.4 and 23.9 months, respectively. The morbidity, toxicity and mortality rates were 5%, 15% and 0%, respectively. Conclusion: Our results suggest that CRS þ IPHP merits further evaluation by a formal prospective trial.

Aims Inflammation-based scores such as neutrophil-lymphocyte ratio (NLR) and Onodera nutritional index (ONI) have been identified as new prognosticators in several tumors. We conducted a prognostic analysis of these markers and performed a risk stratification of PMP patients submitted to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods 226 patients from two peritoneal surface malignancies centers participated in this study. Cox proportional modeling was used to select predictors of overall survival (OS) among baseline inflammation-based scores, serum tumor markers, clinical and surgical variables. Risk stratification was done using conditional inference tree model. Results One hundred eighty-two cases had diffuse peritoneal adenomucinosis subtype. Fifty-four cases had received previous systemic chemotherapy. The means of ONI and NLR were 51.4 (SD = 9.8) and 3.2 (SD = 2.3), respectively. Two hundred ten cases were optimally cytoreduced. Cox analysis identified completeness of cytoreduction, histological subtype, previous systemic chemotherapy, NLR, and CA 19-9 as independent prognosticators. Conditional inference tree method identified two poor prognostic subsets: NLR ≤2.7 and CA 19-9 > 336 (5yr-OS = 15%) and NLR >2.7 and ONI ≤42 (5yr-OS = 30%). Conclusions NLR, ONI, and CA 19-9 are new prognosticators that contributed to improve prediction of OS in PMP patients treated by CRS and HIPEC. These markers allowed a risk stratification that could optimize therapeutic management of PMP patients.

Noma is a devastating gangrenous disease that leads to severe tissue destructions in the face. It is seen almost exclusively in children living in less developed countries. The exact prevalence of the disease is unknown and the cause remains unknown too. Risk factors are: malnutrition, a compromised immune system, poor oral hygiene and a lesion of the gingival mucosal barrier, as well as an unidentified bacterial factor. Herpes viruses might also contribute. Studies of the buccal flora in acute phases of noma and comparison with control children do not exist. Our study takes place in Niger. For each child (cases and controls) we take samples of gingival fluid, saliva, blood and mouth mucosal swabs. The samples are analysed in Geneva in different laboratories. We control the serologies for Herpes viruses and measles. We also perform a nutritional assessment and the mucosal swabs are cultivated for the presence of viruses. The gingival flora is investigated by microarrays. These microarrays are instrumental to test for the presence of thousands of different bacteria in each clinical sample. This method allows a qualitative and quantitative description of the oral flora in noma-children and control cases. This is the first large scale study on the etiology of noma which uses new technical approaches for humanitarian purposes.

Cirrhotic patients after liver transplantation show a near-normal glucose homeostasis when in stable condition. In contrast, the basal and insulin-mediated whole-body protein metabolism remain altered several years after the graft. To examine whether the persisting defect of protein metabolism was due to the muscle, 7 non-diabetic liver-transplanted patients in stable condition were studied by means of the catheterization of the brachial artery and the deep forearm vein (to measure the balance across the forearm) and the infusion of labelled leucine and phenylalanine associated with indirect calorimetry. Whole-body proteolysis (as determined by endogenous leucine flux, ELF), protein synthesis (from non-oxidative leucine disposal, NOLD) and leucine oxidation (LO) were reduced in comparison to previously obtained values in a normal population. Insulin infusion (while maintaining euglycemia) induced a not significant variation of forearm phenylalanine Ra (24.4--16.5 micromol/100 ml forearm min(-1); proteolysis) and Rd (18.5--19.7; protein synthesis). In contrast, the whole-body insulin-dependent inhibitions of ELF (31.5--21.8 micromol/m(2) min) and NOLD (27.3--18.4) were impaired with respect to a normal population. On the basis of the present results, we conclude that skeletal muscle is not responsible for the alterations of leucine metabolism persisting after liver transplantation. By exclusion, this points to the liver as the major determinant of the leucine metabolism defect.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is an effective but potentially morbid treatment for colorectal cancer peritoneal metastases. The impact of treatment-related morbidity on long-term survival has been reported in various malignancies, but it has never been assessed in this clinical setting.The aim of this study was to assess the impact of major postoperative complications on oncological outcomes after cytoreduction and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases.Two prospective databases were reviewed. Major complications were defined as grade 3 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The extent of peritoneal involvement was scored by the use of the Peritoneal Cancer Index.This study was conducted in 2 high-volume peritoneal malignancy management centers.One hundred one consecutive patients with peritoneal metastases potentially amenable to macroscopically complete cytoreduction were selected.Peritonectomy procedures and multivisceral resections were used to remove all macroscopic tumor, and mitomycin-C plus cisplatin-based hyperthermic intraperitoneal chemotherapy was used to control microscopic residual disease.The primary outcomes measured were overall and disease-specific survival.Mortality and major morbidity were 3.0%, and 23.8%. Median follow-up was 44.9 months (95% CI, 24.1-65.7). Five-year disease-specific survival was 14.3% for patients who experienced major complications and 52.3% for those who did not (p = 0.001). Five-year overall survival was 11.7% for patients who experienced major complications, and 58.8% for those who did not (p = 0.003). At multivariate analysis, major morbidity correlated to both worse overall and disease-specific survival, along with a Peritoneal Cancer Index19, and suboptimal cytoreduction. Poor performance status correlated only to worse disease-specific survival, and liver metastases correlated to worse overall survival. Longer operative time (OR, 4.1; 95% CI, 1.3-12.6; p = 0.01) and Peritoneal Cancer Index19 (OR, 2.6; 95% CI, 1.1-6.0; p = 0.02) were independent risk factors for major morbidity.This study is limited by its observational design.The prevention of major complications, by refining surgical technique and patient selection, is crucial because it affects oncologic outcome.

Background The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. Methods Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. Results Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84·4, 25·7 and 29·0 per cent respectively. The median annual centre volume was 17 (range 6–66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78–284) and 96 (86–284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. Conclusion The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10–15 million inhabitants would be ideal.

Diabetes mellitus frequently complicates cirrhosis but the pathogenic mechanisms are unknown. To assess the contribution of reduced insulin action and secretion, 24 cirrhotic-diabetic patients waiting for liver transplant because of an unresectable hepatocarcinoma underwent an oral glucose tolerance test (OGTT) to assess the beta-cell function and an insulin clamp combined with [3-(3)H]glucose infusion to measure whole body glucose metabolism before and 2 years after the transplant. Seven cirrhotic nondiabetic patients, 11 patients with chronic uveitis on similar immunosuppressive therapy, and 7 healthy subjects served as control groups. Cirrhotic patients showed a profound insulin resistance, and diabetics in addition also showed increased endogenous glucose production (P

Favorable oncological outcomes have been reported in several trials with the introduction of Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the treatment of Advanced Epithelial Ovarian Cancer (EOC). However most of the studies testing the combined approach are observational and have been conducted in inhomogeneous series so that the evidence supporting the performance of this combined treatment is still poor. Median Overall and Disease Free Survivals of up to 64 months and 57 months, respectively have been reported. Although a rate of morbidity of up to 40% has been observed in some series the CRS + HIPEC continues to gain an increased popularity. Several prospective randomized trials are ongoing using the procedure in various time points of the disease. In this review several issues such as the impact of cytoreduction and residual disease (RD) on outcomes as well as the role of HIPEC will be updated from the literature evidence. Some controversial points HIPEC related will also be discussed. Recent experiences regarding the introduction of a more aggressive surgical approach to upper abdomen to resect peritoneal carcinomatosis (PC) allowed increased rates of optimal cytoreduction and has demonstrated an apparent better outcome. This evidence associated with the positive results phase III trial testing normothermic intraperitoneal as first-line chemotherapy is guiding some investigators to propose the CRS + HIPEC in the primary setting. Several prospective phase II and III trials have recently been launched to validate the role of the combined treatment in various time points of disease natural evolution.

Noma is a devastating ancient illness that causes severe facial disfigurement in >140,000 children every year mainly in Africa, South America and India. The cause of noma remains unknown but infection, oral hygiene and immune status likely all contribute

Inferior vena cava thrombosis after liver transplantation is uncommon. We describe a case of this unusual complication occurring after piggy-back (end-to-side) graft implantation. Renal failure, lower limb edema, and hemodynamic instability were the presenting symptoms requiring immediate surgical correction with a left renal-to-splenic vein shunt over a ringed 2.5-cm prosthesis. The decision to go ahead with the shunt was preceded by an intraoperative confirmation of a 10-cm H2O pressure gradient between the caval and portal circulations. This gradient, unlike that observed in liver cirrhosis, ultimately turned a splenorenal shunt into a renal-splenic one. Six months after the procedure, the patient is alive and well with normal liver and renal function. The technique described may be useful in the management of other clinical conditions of acute infrahepatic caval hypertension.

To assess the efficacy and morbidity and mortality of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent epithelial ovarian cancer (EOC).A retrospective study conducted using information extracted from a multi-institutional prospective database on peritoneal surface malignancies (PSMs). Setting Four Italian centres specializing in locoregional treatment of PSM.Patients with recurrent EOC.Fifty-six patients underwent 57 combined procedures. CRS was performed using peritonectomy procedures and HIPEC using the closed-abdomen technique with cisplatin and doxorubicin or cisplatin and mitomycin-C.Overall survival (OS), progression-free survival (PFS), morbidity and mortality rates.The median age of the patients was 55.2 years (range 30-75 years). The median peritoneal cancer index was 15.2 (range 4-30). Forty-seven patients had microscopic residual disease (completeness of cytoreduction, CC-0), seven had residual disease ≤2.5 mm (CC-1) and one had residual disease2.5 mm (CC2). Major complications occurred in 15 patients (26.3%), and procedure-related mortality occurred in three patients (5.3%). The median follow-up time was 23.1 months. The median OS and PFS were 25.7 (95% CI 20.3-31.0) and 10.8 (95% CI 5.4-16.2) months, respectively. The 5-year OS and PFS were 23% and 7%, respectively. Independent prognostic factors affecting OS according to the multivariate analysis were Eastern Cooperative Oncology Group performance status, preoperative serum albumin, and completeness of cytoreduction.Patients with recurrent EOC treated with CRS and HIPEC showed promising results in terms of outcome. The combined treatment strategy could benefit subsets of patients wider than that defined for conventional secondary debulking surgery without HIPEC. These data warrant further evaluation in randomised clinical trials.

Noma is a devastating gangrenous disease that leads to severe tissue destructions in the face. It is seen almost exclusively in children living in less developed countries. The exact prevalence of the disease is unknown and the cause remains unknown too. Risk factors are: malnutrition, a compromised immune system, poor oral hygiene and a lesion of the gingival mucosal barrier, as well as an unidentified bacterial factor. Herpes viruses might also contribute. Studies of the buccal flora in acute phases of noma and comparison with control children do not exist. Our study takes place in Niger. For each child (cases and controls) we take samples of gingival fluid, saliva, blood and mouth mucosal swabs. The samples are analysed in Geneva in different laboratories. We control the serologies for Herpes viruses and measles. We also perform a nutritional assessment and the mucosal swabs are cultivated for the presence of viruses. The gingival flora is investigated by microarrays. These microarrays are instrumental to test for the presence of thousands of different bacteria in each clinical sample. This method allows a qualitative and quantitative description of the oral flora in noma-children and control cases. This is the first large scale study on the etiology of noma which uses new technical approaches for humanitarian purposes.

Background: The natural history of chordoma is characterized by a high failure rate and a poor functional outcome. The purpose of this study was to review the long-term outcome of our institutional experience. Methods: The clinical features, type of treatment, pathologic assessment, and follow-up of 56 consecutive patients with chordoma were reviewed. Results: Fifty sacral and six mobile spine chordomas (median size, 13 cm; range, 2–30 cm) were treated at our center between January 1933 and December 2000. Twenty-eight patients affected by sacrococcygeal chordoma and operated on after 1977 form the basis of our study. Surgical margins were rated as wide in 11 cases, marginal in 13 cases, and intralesional in 4 cases. The median follow-up was 71 months (range, 15–200 months). Seventeen patients’ disease recurred. Ten patients died as a result of disease. Nine patients remained continuously free of disease. The estimated 5- and 10-year overall survival was, respectively, 87.8% and 48.9%; disease-free survival was 60.6% and 24.2%. Radiotherapy was considered for marginal and intralesional resections. Conclusions: High sacral amputation can achieve a good rate of wide-margin resections for sacrococcygeal chordomas. Adjuvant radiotherapy may offset the negative effect in the prognosis of marginal resections.

To date the basic guidelines in surgical oncology of the stomach may be summarized in the correct definition of "R0" exeresis (curative operation), but there is still much debate on which should practically be the extension of the gastric resection and which the kind of lymphatic dissection in order to fulfill all the criteria for a correct definition of "curative surgery". As regards the T factor, almost all Authors agree on the fact the a correct R0 gastric resection must include a tumor-free distal margin at least 6 cm from the superior edge of the neoplasm; a safe distal margin should be at least at 1 cm. below the pylorus. Provided that these principles are thoroughly observed, there is no oncologic advantage in performing a total gastrectomy instead of a sub-total gastric resection. Differently, as regards the N factor, there is no agreement on which kind of lymph nodal dissection shoul be routinely adopted: published reports on this subject are somewhat controversial and also whereas a systematic extended lymphadenectomy showed a possible statistical benefit in long term-survival, unacceptable morbidity rates discourage a diffuse application of extended lymphatic dissection out of dedicated; institutions. Anyhow, at the moment it is almost universally accepted that a minimum of 25 removed nodes are necessary for a correct and comparable staging of gastric cancer. At last, literature data do not support the routine use of splenectomy, with the only exception of those cases with documented lymph nodal enlargement at the splenic hilum.

BACKGROUND The aim of this study was to determine the effects of preoperative radiation therapy (RT) on the objective responses of patients with rectal carcinoma to their treatment. These effects were assessed with endorectal ultrasound (EUS) evaluation, histopathologic grading of postirradiation tumor mass reduction in the surgical specimen, and analysis of local and distant recurrences. METHODS Fifty-nine consecutive patients with palpable adenocarcinoma of the rectum, classified by EUS examination as uT2–uT3 (which meant involvement of the muscular layer and the perirectal adipose tissue, respectively), received 45 grays (Gy) over 3 weeks (2 fractions per day of 1.5 Gy each) given as photons supplied through a high-energy linear accelerator (18 MeV) through 3 fields: 1 posterior and 2 opposed lateral. Surgery was scheduled 2–3 weeks after the end of RT and included a sphincter-saving resection (39 patients) and an abdominoperineal resection (20 patients). RESULTS Greatest tumor dimension, which was evaluated with rectal endoscopy before RT and measurement of the lesion in the fresh specimen, showed a decrease among two-thirds of the patients; the decrease amounted to approximately one-third of the initial measurement. An echoendoscopic downstaging of the T component was observed among 24.5% of the patients. Complete tumor regression occurred in 8.5% of patients, whereas in 69% only the presence of rare residual cancer cells and prominent fibrosis were found at the pathologic examination of the specimen. Finally, the tumor regressed to pT0 and pT1 in 13.6% of the patients. The overall and disease free 2-year survival rates were 94.0% and 73.7%, respectively, for pT2 and pT3 patients, and 100% for those whose tumors regressed to pT0–pT1 after a median follow-up of 2 years. CONCLUSIONS Hyperfractionated preoperative RT appears to be efficient in achieving tumor shrinkage and destroying the tumor. In this study, the subset of patients with a good response to RT therapy had an excellent clinical outcome at the time of a 2-year follow-up. Cancer 1999;86:398–404. © 1999 American Cancer Society.

PURPOSE: This study was performed to analyze the outcomes of patients with local (pelvic) recurrence (following radical surgery for rectal cancer) who subsequently underwent a new operation. METHODS: Forty-five patients (19 percent of 213 local recurrences) were explored surgically because the disease was deemed to be confined to the pelvis with a limited extension and, therefore, amenable to surgical cure. RESULTS: Only 21 of the 45 patients who underwent surgical exploration had an oncologically radical operation (RO). In the remaining 24 patients, either a simple exploration or palliation or a nonradical procedure (R1-R2) was performed. In the RO group, there was a 19 percent five-year survival ratevs.a 0 percent rate in the R1-R2 group (median survival, 4 months). Site of recurrence (anastomosisvs.other sites) was statistically associated with a higher chance of long-term survival for those who underwent an RO operation. CONCLUSIONS: The prognosis of locally recurrent rectal cancer is dismal; less than 10 percent of all patients who underwent surgical treatment benefit from reoperation with an overall survival for five years. On the basis of these results, we no longer consider the surgical approach as the primary option for treating locally recurrent rectal cancer.

C IRRHOSIS caused by hepatitis C virus (HCV) accounts for at least 30% of all liver transplants (OLT) currently performed in adults.’ Good survival of patients with such an indication has been described, even though the reappearance of viral genome (HCV-RNA) occurs in more than 90% of patients during the first year after transplantation.‘.’ The course of recurrent HCV graft infection is generally benign. Nevertheless, some concerns about the long-term outcome of the disease have arisen since at least 50% of HCV-RNA positive patients develop chronic hepatitis within two years’,2 and 35% of livers are seriuosly injured (chronic active hepatitis and cirrhosis) 5 years after transplantation.4 In the present study, a therapeutic attempt to prevent recurrent HCV infection was undertaken in a group of HCV-RNA positive transplant recipients, using a combination of interferon and ribavirin early after OLT. The preliminary results of this pilot experience, the first of its kind, are reported herein.

PURPOSE: Radiolabeled monoclonal antibodies (MAbs) have been reported to allow tumor intraoperative detection by means of a gamma-detecting probe. The technology is called the Radioimmunoguided Surgery (RIGS ® ) system. The main inconveniences of the method are 1) the long interval needed for clearance of unattached MAbs from the patient's body, between the injection of the MAb and surgery, and 2) the low sensitivity of current MAbs used in detecting small tumors. We describe a new method to overcome these inconveniences using biotinylated MAbs and avidin in order to obtain a rapid blood clearance of the radiolabeled MAbs both anticarcinoembryonic antigen and antitumor-associated glycoprotein-72 MAbs. METHODS: Twenty patients with primary and recurrent colorectal cancer have been enrolled in the study; 125 I-biotinylated MAbs FO23C5 (anticarcinoembryonic antigen) and B72.3 (antitumor-associated glycoprotein-72) followed by cold avidin were injected in 13 patients and 7 patients, respectively. RESULTS: A decrease of 94±3 perceNt of circulating radioactivity was Achieved in 3 to 5 days. PatientS underwent surgery approximAtely seven days after MAb injections rather than afder four weeks. Tumors were localized in 14/20 (70 pErcent) Patients (true positive), 2 (10 percent) were false Negative, and 4 (20 percent) were true negative. The overall sensitivity level in early-stage primary cancers was 37 percent when related to the presencE of disease and 75 percent when related to antigenic exprescion. The sensitivity for moRe advanced cancer and for recurRences was 10 percent. MoreOver, the in vivo tumor dargeting of biotinylated MAb was demonstrated in frozen tumor section by direct streptoavidin-peroxidasE staining. CONCLUSIONS: The avidin-biotin system may enhance applicability and effectiveness of radioimMunoguided surgery (RIGS ® ).

Radioactive antibodies that react with tumour-associated antigens to "tag" antigen-positive tumour cell deposits were given to 20 patients with primary or recurrent colorectal cancer. The tumour associated antigen TAG 72-specific monoclonal antibody B72.3 labelled with 125-Iodine was used, and the radioactivity in the tumour was sought during operation with a hand-held gamma detecting probe. Tumour was detected by the probe in 7 of 15 patients with primary cancer, with a mean tumour: normal tissue ratio of 3.9, and in 4 of 5 patients with recurrent disease, with a mean tumour: normal tissue ratio of 2.0. Immunohistochemical analysis of surgical specimens confirmed the results of the intraoperative detection. The incidence of TAG 72-positive tumours (11/20, 55%), detected by immunohistochemistry, was lower than the 80% in the other series, possibly because of sampling errors or because the cases studied were uncomplicated with small primary tumours. Results obtained with the probe were instrumental in modifying the operation in two of the four "positive" patients with recurrences, allowing the removal of tumour masses that would otherwise have been overlooked.