Laparoscopic hyperthermic isolated limb perfusion a new minimally invasive approach for HILP.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) represents a limb-sparing treatment for unresectable soft tissue sarcoma (STS) of the extremities with substantial complete response rates. HILP often provides good functional limb preservation, hence a significant improvement also in terms of quality of life of the patient. Notwithstanding these clear advantages, the traditional technique is still hindered by relatively high post-operative morbidity. METHOD: We treated a 78-year-old female with unresectable angiosarcoma of the left leg using a new surgical approach: an entirely laparoscopic HILP. RESULTS: No conversion from laparoscopic to "open" surgery was necessary. Since no abdominal muscle section was performed, post-operative pain was low and easily manageable; early mobilisation and early discharge were achieved. Patient developed moderate toxicity, which resolved spontaneously within 3-4 weeks, with complete return to normal daily activities after 30 d. Complete clinical response with preservation of leg function was obtained. CONCLUSIONS: We describe for the first time an entirely laparoscopic HILP. Demonstration of this technique's efficacy and safety on a large series of patients is clearly necessary but its therapeutic efficacy appears to be comparable to the standard technique. Furthermore, laparoscopic HILP has shown low post-operative morbidity: no wound complications, mild and easily manageable post-operative pain and early discharge from the hospital and early resuming of daily activities.

Anti-tumoral effects of somatostatin analogs: a lesson from the CLARINET study.

Octreotide and lanreotide, the first-generation somatostatin analogs, successfully control hormone hyperproduction, and related syndromes, in patients with acromegaly and neuroendocrine tumors. However, their anti-tumor effect, rather evident in large number of pituitary adenomas in acromegalic patients, has been hypothesized for a long time in patients with neuroendocrine tumors as well, although a significant tumor shrinkage has rarely been observed. However, the recent publication of the CLARINET study has strengthened the evidence, already emerged with the PROMID trial, that the long-term treatment with the first-generation long-acting somatostatin analogs may exert an anti-tumor activity on G1 and G2 enteropancreatic neuroendocrine tumors, as well. After the publication, majority of international guidelines have updated their algorithms in line with these results and this class of drugs obtained the indication as anti-tumor agents in the majority of patients with neuroendocrine tumors.

Surgical prevention and treatment of lymphedema after lymph node dissection in patients with cutaneous melanoma.

Despite the development of minimal access dissection techniques, use of superficial groin dissection alone, and other recommendations to reduce morbidity in melanoma treatment, the incidence of lymphedema is still significant. The purpose of the current study was to assess the efficacy of microsurgical methods to limit the morbidity of inguinal lymphadenectomy. We conducted a retrospective review of patients who underwent groin dissection for melanoma treatment from February 2006 to April 2009. A total of 59 melanoma patients with positive groin lymph nodes comprised 18 patients (T-group) with melanoma in the trunk and 41 patients (E-group) who had melanoma in an extremity and currently have lymphedema. The T-group patients underwent primary prevention of lymphedema with microsurgical lymphatic-venous anastomoses (LVA) performed simultaneously with groin dissection. The E-group patients underwent LVA to treat the secondary lymphedema after an accurate oncological and lymphological assessment. Limb volume measurements and lymphoscintigraphy were performed pre- and postoperatively to assess short and long term outcome. No lymphedema occurred after microsurgical primary preventive approach in the T- group. Significant (average 80% reduction of pre-op excess volume) reduction of lymphedema resulted after microsurgical treatment for secondary leg lymphedema. Post-operative lymphoscintigraphy in 35 patients demonstrated patency of microsurgical anastomoses in all cases with an average follow-up of 42 months. Study results demonstrate that microsurgical LVA primary prevention prevented lymphedema after inguinal lymphadenectomy in the T-group patients. In addition, lymphatic-venous multiple anastomoses proved to be a successful treatment for clinical lymphedema with particular success if treated at the early stages.

Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study.

INTRODUCTION: Malignant pleural mesothelioma is an ideal model for testing new locoregional multimodality approaches because of its aggressive local behavior. METHODS: This study was planned to investigate the feasibility, safety, and pharmacokinetics of a multimodality therapy including an operation, pleural space perfusion (60 minutes) with cisplatin (100 mg/m2), hyperthermia (41. 5 degrees C), and postoperative radiotherapy (55 Gy to chest wall incisions). The effects of the extent of resection and perfusion temperature on cisplatin pharmacokinetics were evaluated. Ten patients with epithelial or mixed, stage I or II, malignant pleural mesothelioma underwent the following procedures: group A (3 patients), pleurectomy/decortication and normothermic pleural space antineoplastic perfusion; group B (3 patients), pleurectomy/decortication and hyperthermic perfusion; and group C (4 patients), pleuropneumonectomy and hyperthermic perfusion. Operations were selectively applied depending on tumor extent. Platinum levels were serially measured by atomic absorption in systemic blood, perfusate, lung, and endothoracic fascia. RESULTS: The overall procedure was completed in every case, without any death or toxicity. No lung damage was demonstrated after treatment. Major complications included 1 wound infection and 1 diaphragmatic prosthesis displacement. The mean peak platinum plasma levels were reached within 45 to 60 minutes after perfusion was started. Systemic drug concentrations were greater after pleurectomy/decortication than after pleuropneumonectomy (P =.006). The local tissue/perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion rather than normothermic perfusion. CONCLUSION: This multimodality approach is feasible, pharmacokinetically advantageous, and safe enough to undergo further clinical investigations.

Isolated lung perfusion with platinum in the treatment of pulmonary metastases from soft tissue sarcomas.

A multimodality approach including operation and isolated lung perfusion with platinum was used in six patients with lung metastases from soft tissue sarcomas. Staged thoracotomies were used in two patients with bilateral lesions. The inclusion criteria generally applied for surgical excision were adopted in this study. The pulmonary artery and a portion of the left atrium were isolated from systemic circulation and cannulated. The cannulas were then connected to a perfusion circuit and normothermic isolated lung perfusion was done for 60 minutes. The lung was then flushed and metastasectomy was done. Serial blood (systemic and pulmonary), tissue (normal lung and tumor), and urine samples were obtained for platinum content measurement by flameless atomic absorption spectroscopy. Lung damage was assessed by light and electron microscopy examination and by serial respiratory tests. Isolated lung perfusion was accomplished in all patients without any death, operative complication, or systemic toxicity. After operation, interstitial and alveolar edema developed in two patients (48 hours after treatment), necessitating respiratory support in one case. Total platinum concentrations in pulmonary plasma were about 43 times greater than those in systemic plasma. No differences in platinum concentrations between normal lung and metastatic tissue were found. Thus the proposed isolated lung perfusion technique is feasible and safe enough to be offered as a valid model to study combined chemosurgical approaches in the treatment of lung metastases.

Intraperitoneal mitoxantrone: a feasibility and pharmacokinetic study.

Fractionated doses have been advocated to prevent chemoperitonitis after intraperitoneal infusion of mitoxantrone. Patients with peritoneal carcinomatosis of various origin underwent surgery, including intestinal resections, with minimal residual disease. Peritoneal mitoxantrone in 1000 ml/m(2) saline was planned on the first post-operative day in groups of four patients (5 mg/m(2) for 3 and 5 days, 7.5 mg/m(2) for 3 and 4 days, 10 mg/m(2) for 2-4 days, if possible). Due to dose-limiting myelosuppression, only one and three patients received the 7.5-mg 4-day and 10-mg 3-day regimens, respectively. A total of 20 patients were consequently treated. Neither major complications nor severe pain were observed. Pharmacokinetics were completed on the 1st day in five 5-mg and five 10-mg patients, on the 5th day in three 5-mg patients, and on the 3rd day in one 10-mg patient. On the 1st day, mean peritoneal peak concentrations of mitoxantrone resulted 1.45 +/-0.56 (range 0.48-1.9) and 1.9+/-0.85 (range 1.27-3.13) microg/ml in the 5-mg and 10-mg patients, respectively. Mean dialysate/plasma exposure (AUC) ratio was 115. Even in patients with sutures, early post-operative fractionated intraperitoneal mitoxantrone appears feasible and safe, with a high local advantage, for up to 5 days of treatment and a maximum tolerated total dose of 20-25 mg/m(2).

Cryosurgery as a means to improve surgical treatment of patients with multiple unresectable liver metastases.

BACKGROUND: The aim of the study was to evaluate the results of cryosurgery in patients with multiple (five or more), heavily pretreated, unresectable liver metastases. MATERIALS AND METHODS: Nineteen patients with multiple unresectable liver metastases were entered into a prospective nonrandomized trial. The liver tumours were treated during surgery under ultrasound guidance. All the patients were followed-up to assess complications, treatment response and sites of recurrence. RESULTS: 140 metastases were identified in 19 patients (mean, 7; range, 5-25) and 13 patients had a synchronous liver resection. Cryosurgery was used to treat 90 metastases (mean diameter, 30 mm; range, 10-135). There were no treatment-related deaths and the overall rate of complications was 21%. During a mean follow-up of 28 months (range, 5-60), tumours recurred at the site of cryosurgery in two patients (10%), in the remaining liver in nine patients (47%) and elsewhere in five patients (26%). Three patients had no evidence of disease 48, 50 and 60 months after liver cryosurgery, respectively. CONCLUSION: Cryosurgery may be effective in the treatment of patients with multiple unresectable liver metastases and should be investigated in multimodality treatment programmes.

Intrahepatic arterial flow distribution after ligation of a right replaced hepatic artery. A case report.

A basic requirement for arterial chemotherapy of liver tumors is complete catheter perfusion of the liver. In cases with atypical anatomy of the hepatic artery, it is frequently impossible to obtain this goal by means of a single catheter. In a patient with a right replaced hepatic artery, the aberrant vessel was ligated and the left hepatic artery was perfused through a catheter inserted into the gastroduodenal artery. Perfusion scans performed through the catheter 14 and 135 days after arterial ligation showed a fall in the arterial flow to the right liver (right/left ratio 0.43 and 0.60). In contrast, a nearly complete perfusion of the liver (0.91 right/left ratio) was obtained 28 days after ligation, when the perfusion scan was performed immediately after catheter infusion of 90,000,000 degradable starch microspheres (DSM: diameter = 40 m). DSM administration is supposed to increase back pressure in the lobe receiving native circulation, thus activating intrahepatic collateral flow to the ischemic lobe. As regards regional treatment of liver tumors, obvious conclusions are to be drawn.

[Hyperthermia in adjuvant therapy of locally advanced carcinoma of the rectum. Study protocol and initial clinical experience]. / L'ipertermia nella terapia adiuvante del carcinoma del retto localmente avanzato. Protocollo di studio ed esperienza clinica iniziale.

Since January 1992 a feasibility study was set up to establish the possible role of pelvic hyperthermochemotherapy for the local control of rectal cancer. Patients with resectable rectal cancer (clinical stage III-IV) are eligible for the study. Only patients submitted to abdominoperineal resection with or without extended pelvic linfoadenectomy (PLND) and/or resection of contiguous organs are included in the initial pilot phase of the study. Until now, two patients with stage III rectal cancer submitted to abdominoperineal resection and PLND have been treated. A single (40 mg) push of MMC was injected in the circuit with median local temperature of 46.0 +/- 0.3 and 45.9 +/- 0.5 degrees C and the pelvis was perfused for 60 min. There were no local or systemic complications. The ratio between the pelvis and plasma AUCs showed a high local pharmacokinetic advantage. The treatment can contribute to complete the standard protocols of adjuvant therapy. Since the simple decrease of local recurrence could represent an important clinical aim, this experience, even initial, supports us to continue the study.

[Isolated hyperthermic antiblastic perfusion in recurrent melanoma of the extremities]. / La perfusione isolata ipertermico-antiblastica nel melanoma recidivo degli arti.

Twenty-two patients with recurrent melanoma of the limbs, underwent Hyperthermic Antiblastic Perfusion (HAP). HAP lasted 60 min, with maximal local temperature of 40.5-42 degrees C and melphalan 10 mg/L limb volume as antiblastic agent. Fourteen patients had in-transit metastases and 8 local recurrences. Regional nodes were involved in 6 patients. Systemic leakage monitored with 125I or 99Tc ranged between 5 and 30% (mean 19%). No operative mortality nor major complications occurred. Local toxicity scored Wieberdink grade I in 6 patients, grade II in 11 and III in 5. Response rate (UICC) in the 9 patients treated with unexcised lesions was 88% (55% complete responses). After a median follow-up of 27 months (1-92) 9 patients relapsed after a median time of 17 months, and 15 patients are currently disease free, 4 of them being re-excised and one reperfused. Actuarial 5 year survival is 67%, with 45% disease free to the first relapse. Our results are consistent with the literature indicating HAP as a safe procedure with a high evidence of clinical responses.

[Performance and complications of totally implantable port device in bolus hepatic intra-arterial chemotherapy]. / Funzionalità e complicanze dei "port" totalmente impiantabili per la chemioterapia intraarteriosa epatica in bolo.

The performances of totally implantable ports were analyzed in patients with colorectal metastases undergoing intraarterial treatment. Seventy-nine patients received bolus infusion of Cisplatin (DDP, 57 cases) or Epirubicin (EPI, 22 cases) every 21 and 7 days, respectively. Disease progression or toxicity were the most common causes of interruption of treatment, whereas failure of ports occurred in six and two patients out of DDP and EPI groups, respectively. The incidence of single problems for each port was 65% in DDP group and 64% in EPI group, whereas rate of complications for each patient was 30% and 32%, respectively. The 12-months device duration rate in the two groups was 65% (median 17 months) in DDP group and 78% (median 18 months) in EPI group. The implantable ports employed for bolus arterial infusion, allowed adequate treatment periods in most cases, without any difference as far as intervals between cycles is concerned.

[Lacking effect of timing of surgery in relation to the menstrual cycle on prognosis of breast cancer in premenopausal women]. / Mancato effetto della temporizzazione della chirurgia in relazione con il ciclo mestruale sulla prognosi del cancro della mammella nelle donne in premenopausa.

The influence of timing of surgery in relation to menstrual period on survival of breast cancer patients has been both advanced advocated and disputed. A meta-analysis on published series showed a statistically significant overall odds reduction when surgery is performed in the luteal phase. The records of 165 premenopausal M- breast cancer women, not on hormonal therapies, consecutively operated on from 1977 to 1991 were reviewed. All patients underwent modified radical mastectomies or quadrantectomies plus operative radiotherapy, Node-positive patients received standard adjuvant chemotherapy. Cox regression analysis was used to estimate the relative risk (RR) of death in three models including timing of surgery, age, histology, pathological T and N. In each model, patients were divided into two groups according to the criteria proposed by Badwe, Hrushesky, and Senie. Multivariate analysis showed a significant association between pT and pN and survival, whereas no association with survival was observed for timing of surgery according to Badwe or Hrushesky or Senie criteria (RR = 1.26, RR = 0.91, and RR = 0.88 respectively). Up-to-date agreement on the menstrual phase and relative expected better prognosis is still lacking.

[Effects of adjuvant hyaluronidase in tumors refractory to chemotherapy. Review of the literature and pharmacokinetics of cisplatin after regional administration in animals and humans]. / Effetto della ialuronidasi adiuvante in tumori refrattari alla chemioterapla. Revisione della letteratura e farmacocinetica del cisplatino dopo somministrazione regionale nell'animale e nell'uomo.

Several clinical studies have recently suggested that topical or systemic adjuvant hyaluronidase may increase the therapeutic index of anticancer drugs. In cases of disease progression, further objective responses have been observed after the association of hyaluronidase to the previously employed drugs. Some evidences suggest that hyaluronidase improves local diffusion as well as tissue and tumor uptake of the associated drugs. Hence, plasma and tissue concentrations of platinum following administration of cisplatin alone and associated with hyaluronidase have been investigated in 20 rats after intraperitoneal injection and in 10 patients with colorectal liver metastases and local progression of the disease after regional and systemic chemotherapy with intraarterial cisplatin and intravenous 5-fluorouracil. Three out of six refractory patients treated with hepatic intraarterial cisplatin + hyaluronidase showed one minor response and two stable diseases, respectively, without any apparent increase of treatment related toxicity. In turn, adjuvant hyaluronidase increased both the extent distribution and lasting time of cisplatin in the body and reduced plasma levels of total and free platinum originating from cisplatin, without any modification of either unbound fraction of platinum or total body clearance. Hence, adjuvant hyaluronidase seems to increase tissue extraction of cisplatin and, particularly, liver extraction after intraarterial administration in man. These results encourage further studies aimed to determine the clinical role of adjuvant hyaluronidase in patients refractory to regional chemotherapy.

[Lipiodol with and without Gelfoam in primary liver tumors. Plasma levels of Mitoxantrone and clinical results]. / Lipiodolizzazione associata o meno a Gelfoam in pazienti con tumore epatico primitivo. Livelli plasmatici di Mitoxantrone e risultati clinici.

Transcatheter chemoembolization with various drugs is employed for palliative treatment of hepatocellular carcinoma. Thirty-seven patients (33 with Child A or B cirrhosis) were treated with 14 mg/m2 of Mitoxantrone and up to 20 ml of Lipiodol, followed by Gelfoam embolization as indicated. Sixty-nine cycles were given, with mean (+/-SD) Lipiodol and emulsified Mitoxantrone doses of 11.3 +/- 3.8 ml and 11.8 +/- 5.2 mg, respectively. Thirteen, 16, and 8 patients received one, two, and three cycles, respectively, with time intervals of 123 +/- 60 days. Thirty patients had Gelfoam embolization at the first cycle, 9 at the second and 4 at the third. At the first cycle, 10 patients underwent serial measurements of serum Mitoxantrone up to two hours after a full dose of emulsified drug. Drug levels resulted much lower than those reported after plain arterial infusion, with AUC levels (+/-SE) of 5924 +/- 1015 and 4381 +/- 429 ng/ml x 120 min in 6 and 4 cases treated with and without Gelfoam, respectively. No treatment related deaths occurred. Complications were mild and transient, including nausea vomiting in most cases, fever > 38 degrees C 67%, pain 74%, ascites 8% jaundice 3%, bleeding 3%, pancreatitis 3%, myelosuppression 44%, diarrhea 5%. Treatment response rate was 49% (including 16% minor response) with 16% early progressions. With a median follow-up of 12 months, the 12-month response duration and survival rates were 56% and 79% respectively. Transcatheter chemoembolization with Mitoxantrone deserves further evaluation in randomized studies.

[Pancreatic cancer. Analysis of 149 cases in our 17-year experience]. / Il carcinoma del pancreas. Analisi di 149 casi in 17 anni di esperienza.

The Authors analyse a series of 149 consecutive patients with carcinoma of the pancreas or the periampullary region. Curative surgical treatment was achievable in 55 patients, palliative procedures included surgery in 68 patients; biliary decompression with endoscopic or percutaneous procedure in 25 patients and chemotherapy in one patient with lymphoma. Perioperative complications consisted in gastroplegia (33%), pancreatic fistula (22%), biliary fistula (7.3%), abdominal abscess (5.5%) and hemoperitoneum (1.8%). Five patients died within 30 days after surgery (9%). The overall median postoperative survival was 37, 29 and 21 months in papillary, choledochal and pancreatic cancer, respectively.

[Function and complications of diverse totally implantable systems for continuous intra-arterial infusion of FUdR in colorectal hepatic metastases]. / Funzionalità e complicanze di diversi sistemi totalmente impiantabili per l'infusione intraarteriosa continua di FUdR nelle metastasi epatiche colo-rettali.

Different totally implantable arterial infusion systems were compared in patients with liver metastases from colorectal cancer undergoing continuous intra-arterial infusion. Seventy-eight patients received continuous FUdR infusion using either totally implantable pumps (group a = 44 pts.) or ports fed by external portable pumps (group b = 34 pts.), and 57 patients received bolus infusion of Cisplatin (group c). Devices were cared for patency even after interruption of treatment, commonly caused by disease progression. Pocket problems most frequently occurred in group a (30%) compared to groups b (9%) and c (7%), whereas a higher incidence of catheter and infusion related problems was observed in group b (109%). System failure was recorded as a cause of interruption of treatment in two, 9, and 6 cases in groups a to c, respectively. The 12-months patency rate was 92% in group a, 24% in group b (median 9 months), and 65% in group c (median 17 months). Though implantable ports allow adequate infusion periods in most cases they seem more adequate for bolus infusions.

Peripheral tissue release of interleukin-6 in patients with chronic kidney diseases: effects of end-stage renal disease and microinflammatory state.

To examine if uremia influences muscle interleukin-6 (IL-6) metabolism we studied the exchange of IL-6 across the forearm in 16 patients with chronic kidney disease (CKD) (stages 3 and 4), in 15 hemodialysis (HD)-treated end-stage renal disease (ESRD) patients (n=15), and in six healthy controls. In addition, we performed an analysis of both IL-6 protein and IL-6 mRNA expression in muscle of CKD (stage 4) patients showing evidence of inflammation and in controls. A release of IL-6 from the forearm was observed in patients with elevated IL-6 plasma levels. Arterial IL-6 was directly related to released IL-6 (r=0.69; P<0.004) in HD patients. Both IL-6 protein and IL-6 mRNA expression were increased in muscle of inflamed CKD patients vs controls (P<0.05). Although muscle net protein balance was similar in all patients, it was significantly more negative in HD patients with high than in those with low IL-6 plasma levels (P<0.05). In addition, net protein balance was related to the forearm release of IL-6 in HD patients only (r=0.47; P<0.038). These data demonstrate that IL-6 expression is upregulated in muscle, and that muscle tissue, by releasing this cytokine, may contribute to the inflammatory response in HD patients. The release of IL-6 from peripheral tissues is associated with an increase in muscle protein loss in HD patients, suggesting that muscle release of IL-6 is linked to protein catabolism in these patients. The release of IL-6 from peripheral tissues may act as a signal for the inflammatory response and contribute to functional dysregulation in uremia.