Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases.

BACKGROUND: This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin- and irinotecan-based systemic chemotherapy regimens. METHODS: Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9-2.2). RESULTS: Of 50 eligible patients, 38 (76%) had received > or =4 lines of chemotherapy. Most presented with synchronous disease (72%), >4 hepatic metastases (58%), 25-50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (>48 h) WHO G1-2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0-18.3); 2-year survival was 19.6%. CONCLUSION: Radioembolisation produced meaningful response and disease stabilisation in patients with advanced, unresectable and chemorefractory mCRC.

A multicentric phase II clinical trial on intra-arterial hepatic radiotherapy with 90yttrium SIR-spheres in unresectable, colorectal liver metastases refractory to i.v. chemotherapy: preliminary results on toxicity and response rates.

BACKGROUND: In patients locally progressing after two lines of chemotherapy, some locoregional approaches showed encouraging results in terms of local control of disease. The aim of our study was to evaluate toxicity, clinical response and quality of life in 48 patients with unresectable colorectal liver metastases submitted to selective internal radiotherapy (SIRT). MATERIALS AND METHODS: Up to now 35 patients with unresectable colorectal liver metastases, refractory to two lines of chemotherapy, underwent intra-arterial infusion of resin microspheres with yttrium-90 (SIR-spheres). Pre-treatment evaluation included a CT scan, blood tests, a PET scan and arteriography of celiac trunk, hepatic and superior mesenteric artery; extrahepatic uptakes and pulmonary shunts more than 10% were excluded by a Scinti-scan. The gastroduodenal artery was embolized before the SIR-spheres injection. Other exclusion criteria were liver dysfunction and anatomical vascular anomalies. The clinical response was evaluated by CT-scan following the RECIST criteria. Median follow-up was 4 months. RESULTS: Median number of metastases was 4 (range, 1-15), 38% of cases presenting hepatic involvement < 25%. The median SIRT dose delivered was 1.7 GBq. Median pulmonary shunt was 6%. No operative mortality occurred; early toxicity (within 48 hours) was 20.6%, shown as fever, acute pain and leucocytosis. The late toxicity was 24.1% with chronic pain, jaundice and nausea being the most frequent. All the toxic events were graded 2 or 3 according to the WHO scale. Preliminary results were available in terms of clinical response after 6 weeks: 12.5% had a partial response, 75% a stable disease, while progression of disease, was observed in 12.5% of the patients. CONCLUSION: SIRT is a safe treatment in terms of acute and late toxicity. Intra-arterial microspheres could represent a good therapeutic option for patients with progressing liver metastases only, after two lines of systemic chemotherapy.

Natural history of the neoplastic locoregional disease: clinical and pathological patterns.

A great number of locoregional treatments are currently carried out to treat a variety of locoregional neoplastic diseases. Indications are the treatment of primary and metastatic liver tumors, peritoneal mesotheliomas, peritoneal spread of ovarian carcinomas, peritoneal recurrences of gastrointestinal cancers, peritoneal spread of retroperitoneal sarcomas, melanomas and sarcomas of the limbs, some primary tumors of the brain, breast, kidney, lung, bladder. But to deal with locoregional therapy demands to clarify some features of these malignancies. At this regard, the knowing of their natural history can be crucial to guide the choice of the correct locoregional treatment. For instance peritoneal carcinomatosis is considered as a main step of disease progression for ovarian cancer and often for gastrointestinal tumors as well. However when the tumors are confined on the surface of the peritoneum, basing on their own natural history, they can be considered as localized diseases. Selected patients with peritoneal neoplastic seeding, previously considered in a preterminal condition, can be considered as candidates for curative treatment, using cytoreductive surgical tecniques (16) and hyperthermic intraperitoneal chemotherapy (19). The same can be thought about others primary or metastatatic tumors when the neoplastic deposits are confined within a definite site or region of the body. In this paper the main aspects of liver metastases and peritoneal carcinomatosis natural history, two of the most frequently recognized indications for locoregional therapy, are presented.

Doxorubicin in isolation limb perfusion in the treatment of advanced limb soft tissue sarcoma.

Hyperthermic antiblastic perfusion/HAP) has been proven to be an effective neoadjuvant treatment in the treatment of advanced soft tissue limb sarcoma. As a matter of fact high percentage of limb sparing surgery, local control and functional results have been obtained wide this technique. Many antineoplastic drugs have been associated to hyperthermia by isolation limb perfusion, the aim of this paper was to describe the results obtained with doxorubicin in association to hyperthermia with or without Tumor Necrosis Factor (TNF) alpha in order to identify the most effective regimen in the multidisciplinary treatment of soft tissue limb sarcoma. A total of 106 patients have been evaluated. Three different study were performed: the first was a phase I study carried out in order to assess the maximum tolerable dose (MTD) of doxorubicin during HAP; the second was a phase II study with doxorubicin, and the third was a phase I - II study aimed at evaluating the MTD and tumor response of TNF alpha in association to doxorubicin and hyperthermia. Grade IV limb toxicity was recorded in 11 patients ( 4 in trial A, 3 in trial B, and 4 in trial C). The grade of limb reaction was strictly related to TNF dosage (> 1 mg) and temperature level (> 41.5 degrees C), therefore the best regimen is represented by temperature level not exceeding 41.5 degrees C and 1 mg of TNFalpha. The trimodality association (TNF, doxorubicin and hyperthermia) was proven to be the best regimen able to obtain a 77% of objective response (complete response, 22%) and a 77% of limb sparing in patients candidate to amputation. The results above mentioned showed the HAP with doxorubicin and TNFalpha (1 mg) is a very effective neoadjuvant treatment in the multidisciplinary treatment of advanced soft tissue limb sarcoma.

Epirubicin and its metabolites levels in experimental liver metastases after different administration routes.

Locoregional chemotherapy in the 80's was considered an effective palliative treatment for unresectable hepatic metastases. With the advent of new drugs supporting effective systemic chemotherapy it was disregarded for many years. Recently, following the advent of new drugs and the developing of new association scheme, it has regained interests also for its adjuvant and neoadjuvant role to hepatic resections. Current schemes of locoregional and systemic chemotherapy for liver metastases are based on continuous infusions using implantable pumps but confirmation, in term of tissue drug concentration, that continuous infusions do better than bolus infusions is still lacking. To address this specific aspect we have experimentally compared these two different administration modalities using an anthracyclin, Epiadryamicin (EPI), with high plasmatic clearance and main biliary escretion (8,16) and infused through arterial, portal and systemic routes. The most high EPI concentration within the tumour was obtained after bolus-arterial infusion but also for continuous infusions the artery resulted better than other routes. Differently the most high EPI liver concentration resulted after portal infusion both if infused with a bolus or in 5 minutes time. This experiment may therefore legitimate the clinical use of this drug with bolus repeated infusions through the hepatic artery.

Epiadryamicin concentration in experimental hepatic metastases after bolus or continous infusion through systemic or locoregional routes.

Locoregional chemotherapy in the 80's was considered an effective palliative treatment for unresectable hepatic metastases: it significantly improved the response rates if compared with systemic chemotherapy but didn't modify the survival (7,19). With the advent of new drugs supporting effective systemic chemotherapy it was disregarded for many years. Recently, following the advent of new drugs and the developing of new association scheme, it has regained interests also for its adjuvant and neoadjuvant role to hepatic resections (1,2,3,9,13,14,15,18). Loco-regional drug administration is feasible through two different administration routes, portal system and hepatic artery; the hepatic arterial infusion, in terms of tumor tissue antiblastic concentration, seems to be the most effective (6) Current schemes of chemotherapy for liver metastases are based on continuous infusions using implantable pumps (11, 12) but confirmation, in term of tissue drug concentration, that continuous infusions do better than bolus infusions is still lacking. To address this specific aspect we have experimentally compared these two different administration modalities using an anthracyclin, Epiadryamicin (EPI), with high plasmatic clearance and main biliary escretion (8,16).

Targeted laparoscopic abdominal adhesiolysis.

Postoperative abdominal pathogenic bands may produce intermittent subocclusive intestinal crises or chronic abdominal pain. Laparotomy has been widely used to define the diagnosis and perform adhesiolysis, but recurrences of the bands are frequent. Laparoscopy may reduce their incidence; nevertheless, 10-25% of cases recur with this procedure as well. Instead of using widespread adhesiolysis to treat this condition, a successful outcome may be achieved by removing only the pathogenic bands. It is thus essential to identify them. In order to do so, we performed a combined laparoscopic-endoscopic procedure. Following an abdominal focused radiological and endoscopic workup, two patients with intermittent abdominal pain from colonic subocclusion underwent laparoscopic adhesiolysis. This procedure was guided by intraoperative colonoscopy. During laparoscopic exploration of the abdominal cavity, intraoperative colonoscopy revealed the site of the obstacle whichcorresponded precisely to the position of the colonoscopic intraluminal. Thus, we identified the location of the transit obstacle and selected the bands to be removed. We then performed a targeted adhesiolysis. There were no postoperative complications. Symptom-free abdominal function was achieved in both cases 3 days after the operation. Both patients are symptom-free 1 year after treatment. Our preliminary experience indicates that this combined procedure, if properly performed (i.e., with a minimal amount of air inflation), is helpful in performing correct laparoscopic adhesiolysis.

Differential device performances for hepatic arterial chemotherapy: a technical report on totally implantable pumps and ports for both continuous and bolus infusion.

Performances of totally implantable infusion systems were analyzed in patients with colorectal liver metastases undergoing intra-arterial treatment. It consisted of 14-day continuous infusion of 5-fluor-2'deoxyuridine with pumps (pump14, 44 patients) or ports fed by external pumps (port14, 34 patients), or bolus infusion of cisplatin (port21, 57 patients) or epirubicin (port7, 22 patients) every 3rd week and weekly, respectively. Toxicity and disease progression were the most common causes of treatment interruption. System failure occurred in 2 pump14, 9 port14, 6 port21 and 2 port7 cases. Pocket problems were most frequent in the pump14 group (30%), whereas catheter- and infusion-related problems were mostly observed in the port14 group (109%). The devices were still functional after 12 months in 92% of pump14, 24% of port14, 65% of port21 and in 78% of port7 patients. Although implantable ports allow adequate infusion periods, in most cases they appear especially suitable for bolus infusions.

[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.

Distribution of human recombinant interferon-alpha 2 in rat plasma, liver, and experimental liver metastases.

It has been ascertained that one of several possible reasons for negligible interferon activity in solid tumors, namely, hepatic metastases induced in rats after intraportal injection of Walker carcinoma 256 cells, is the significantly lower levels of interferon in the interstitial fluid of metastases in comparison to normal liver and plasma.

Effect of gastric cold irrigation on stress ulceration.

Gastric cold irrigation is widely used in the treatment of gastric bleeding. The purpose of this study was that of studying the effect of cooling on gastric mucosal lesions induced by hemorrhagic shock. The gastric transmucosal potential difference (GTPD) and the severity of ulceration were assessed in rats subjected to continuous gastric irrigation with 0.1 N HCl at a temperature of 37 or 5 degrees C. The effect of gastric cooling was evaluated in basal conditions and in rats subjected to hemorrhagic shock. Although gastric cooling has been able to cause ulcers in basal conditions, it showed a protective effect during hemorrhagic shock, reducing the degree of ulceration and improving the GTPD recovery. It is likely that the decrease in cellular metabolic requirements induced by cooling plays an important role in mucosal protection during hemorrhagic shock.

[Hemobilia caused by an intrahepatic aneurysm]. / Emobilia da aneurisma intraepatico.

The authors describe one case of hemobilia for intrahepatic aneurysm treated successfully with the placement of Gianturco's stainless steel coil during hepatic arteriography.

Variations in transmucosal gastric potential difference during hemorrhagic shock in the rat.

Transmucosal gastric potential difference (TGPD) was measured in the antrum and fundus of the stomach in two groups of rats submitted to hemorrhagic shock. In the first group the stomach contained 2 cm3 of 0.1 N HCl and in the second 2 cm3 of physiological saline. After the hemorrhage both antral and fundal TGPD diminished significantly in both groups. Antral TGPD dropped from -20 to -6 mV (p less than 0.001) in the first group and from -22 to -12 mV (p less than 0.01) in the second group; fundal TGPD dropped from -41 to -16 mV (p less than 0.001) in the first group and from -40 to -17 mV (p less than 0.05) in the second group. 20 min after reinfusion of blood extracted during the hemorrhage, both antral and fundal TGPD returned to normal values in the rats instilled with physiological saline, while in those treated with HCl TGPD values remained at levels significantly lower than the baseline values (in the antrum -10 mV, p less than 0.001; in the fundus -25 mV, p less than 0.02). Only those rats whose stomachs contained HCl developed ulcers, mainly located in the fundus of the stomach. These results suggest that the energy metabolism of the cells of the gastric mucosa undergoes constant alteration from the earliest stages of hemorrhagic shock. These alterations are greater in the fundus than in the antrum, a fact compatible with the greater incidence of ulcers in the fundus.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood flow of experimental liver metastases in rat as evaluated by the locally injected 133-Xenon washout.

The investigations on blood flow in liver metastases are interesting from both a pathophysiological and a therapeutic point of view. Available data, however, are few and not definitive, as these studies are complex and difficult to perform. In a group of 25 Sprague-Dawley rats, in which liver metastases of Walker-256 carcinoma had been implanted, the blood flows in a metastasis and in the normal liver surrounding it were determined by means of the locally injected 133-Xenon washout. Thirteen sham-operated rats were a control group. Blood flow in the metastases was decreased as a group compared to that in the normal liver surrounding metastases and to that in liver of sham-operated rats. Small metastases showed normal or increased blood flow, large ones decreased or stagnant blood flow. Moreover, a significant inverse correlation was found between blood flow and diameter of metastasis. It is concluded that liver metastases of Walker-256 carcinoma show a decrease in blood flow which is related to the size of metastasis.

[Peptic ulcer: proposal of a data collection chart for electronic processing]. / Ulcera peptica: proposta di una cartella raccolta dati da sottoporre ad elaborazione elettronica.

Given the high incidence of peptic-ulcer disease and the need to develop an adequate means of assessment of medical-surgical treatments, the Authors propose a clinical record card for computer processing.

[Non-hypertensive pheochromocytoma. Description of 2 clinical cases]. / Il feocromocitoma non ipertensivo. Descrizione di due casi clinic.

The Authors describe two cases on non hypertensive ppheochromocytoma, one malignant and one benign. These types of heochromocytoma are generally considered to be nonsecreting tumours, tumours characterised by long periods of inactivity. More recent studies have evidenced, however, that at least in a certain percentage of cases this type of tumour can secrete catecholamicen precursors or metabolites having low activity and hence incapable of causing appreciable pressure alterations. Diagnosis of these forms is always difficult and cannot be done purely on the basis of assay of the urinary catecholamines, but also requires assay of VMA, HVA, metadrenaline and Normetadrenaline. Treatment of this pheochromocytoma is surgical and resolves the hypertensive symptoms in 80% of the benign forms. On the other hand, it rarely leads to cure in the malignant types.

[Vascular access for hemodialysis]. / Gli accessi vascolari in emodialisi.

Reference is made to a personal series of vascular accesses for haemodialysis on 273 patients aged 6 months to 70 yr. During the course of 12 years, 533 operations were performed: 109 cannulations of the saphena, 152 by-pass, 251 arteriovenous fistulae (including 22 on patients under 10 yr of age), and 21 "difficult accesses". An assessment of the advantages and disadvantages of the techniques employed showed that the Cimino-Brescia fistula, combined, if necessary, with transient cannulation, is the soundest access owing to its longer life, lower incidence of complications, and better utilisation of the vascular material available.

Temporary occlusion of the hepatic artery plus infusion and systemic chemotherapy for inoperable cancer of the liver.

Fourteen patients with diffuse tumors of the liver were treated with temporary occlusion of the hepatic artery (HA) by an external tourniquet followed by infusion and systemic chemotherapy. Three patients had primary neoplasms (one hepatocarcinoma and two cholangiocarcinomas) and eleven had metastatic disease (nine from carcinoma of the colon and rectum, one from retroperitoneal liposarcoma, and one from pulmonary small cell cancer). Infusion chemotherapy in all patients was based on 5-FU, Mitomycin and Vincristine. Systemic chemotherapy was FIVB in metastatic carcinoma and Adriamycin in primary liver tumors. All patients showed improvement of the performance status according to the Karnofsky Index. Objective response (OR) was present in 54% of cases. At present, median survival time in 12.5 months. Aggressive treatment combining hepatic ischemia with infusion and systemic polychemotherapy seems to provide an effective method of palliation in diffuse tumors of the liver. Delayed occlusion by an external tourniquet appears safer than intraoperative ligation of the HA.