Eitan Shiloni

Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer

We describe here the preliminary results of the systemic administration of autologous lymphokine-activated killer (LAK) cells and the recombinant-derived lymphokine interleukin-2 to patients with advanced cancer. This regimen was based on animal models in which the systemic administration of LAK cells plus interleukin-2 mediated the regression of established pulmonary and hepatic metastases from a variety of murine tumors in several strains of mice. We treated 25 patients with metastatic cancer in whom standard therapy had failed. Patients received both 1.8 to 18.4 X 10(10) autologous LAK cells, generated from lymphocytes obtained through multiple leukaphereses, and up to 90 doses of interleukin-2. Objective regression of cancer (more than 50 per cent of volume) was observed in 11 of the 25 patients: complete tumor regression occurred in one patient with metastatic melanoma and has been sustained for up to 10 months after therapy, and partial responses occurred in nine patients with pulmonary or hepatic metastases from melanoma, colon cancer, or renal-cell cancer and in one patient with a primary unresectable lung adenocarcinoma. Severe fluid retention was the major side effect of therapy, although all side effects resolved after interleukin-2 administration was stopped. Further development of this approach and additional patient follow-up are required before conclusions about its therapeutic value can be drawn.

Laparoscopic cholecystectomy in octogenarians

Background: This study aimed to assess the outcome of laparoscopic cholecystectomy (LC) in patients 80 years old or older. Methods: All consecutive patients 80 years old or older who underwent LC for symptomatic gallstone disease were evaluated. Data analysis included patients’ age, gender, indication for surgery, comorbid condition, American Society of Anesthesiology (ASA) score, preoperative endoscopic retrograde cholangio pancreatography (ERCP), intraoperative cholangiogram, operative time, conversion to open surgery, morbidity, mortality, and length of stay. Results: In this study, 67 patients (31 men and 36 women) with a mean age of 84 years (range, 80–90 years) were evaluated. Of these 67 patients, 38 (57%) underwent surgery for complicated diseases including acute cholecystitis in 15 patients (22%), gallstone pancreatitis in 17 patients (25%), cholangitis in 3 patients (4.5%), and obstructive jaundice in 3 patients (4.5%). A total of 38 patients (57%) had a preoperative ASA of 3 or 4; 23 (34%) had a preoperative ERCP; and 6 (9%) had intraoperative cholangiogram. The mean operative time was 94 ± 20 min. Five patients (7.4%) underwent conversion to open surgery because of unclear anatomy. Complications occurred in 12 patients (18%) including pulmonary edema in 3 patients, myocardial infarction in 1 patient, atelectasis in 2 patients, common bile duct injury in 1 patient, urinary tract infection in 2 patients, wound infection in 2 patients, and intraabdominal infected hematoma in 1 patient. The mean length of stay was 5.3 days. There was no mortality. Conclusions: In octogenarians LC is safe and associated with acceptable morbidity and mortality. Therefore, it should be considered for this age group. The relatively high incidence of complicated gallstone disease in this age group may be decreased if surgery is offered to them at earlier stage of the disease, leading to further decrease in perioperative morbidity.

Pancreaticojejunostomy versus controlled pancreaticocutaneous fistula in pancreaticoduodenectomy for perianipullary carcinoma

BACKGROUND Anastomotic leak of the pancreaticojejunostomy is a major cause of morbidity and mortality following pancreaticoduodenectomy. Reports have described a large variety of techniques for performing this anastomosis and managing the pancreatic stump. In an attempt to obviate the pancreaticojejunostomy, we prospectively studied the technique of ligating the pancreatic duct and using external drains to create a temporary controlled pancreaticocutaneous fistula. PATIENTS AND METHODS Thirty-five consecutive patients who were to undergo pancreaticoduodenectomy for periampullary carcinoma were prospectively randomized to one of two groups: pancreaticojejunostomy (PJ) (n = 18) or controlled pancreaticocutaneous fistula (CPF) (n = 17). The groups were well matched for age, sex, coexisting medical illnesses, type of tumor, and preoperative condition. Except for the management of the pancreatic remnant, all patients in both groups underwent an identical procedure. Major morbidity, length of hospitalization, duration of the controlled pancreatic fistula, and mortality were analyzed over a mean follow-up interval of 26 months (range 5 months to 7.5 years). RESULTS The CPF group experienced lower overall operative morbidity rates than the PJ group (24% versus 56%, P < 0.01). Two patients (11%) in the PJ group and none in the CPF group died (P = NS). Half the morbidity in the PJ group and both mortalities were related to anastomotic leak. The CPF and PJ groups left the hospital after mean stays of 26.4 and 42.2 days respectively (< 0.01). CONCLUSIONS Compared to pancreaticojejunal anastomosis, creation of a temporary controlled pancreaticocutaneous fistula in patients who undergo pancreaticoduodenectomy for periampullary malignancy has no appreciable risk. It is associated with reduced morbidity and shorter length of hospitalization.

Autologous cell vaccine as a post operative adjuvant treatment for high-risk melanoma patients (AJCC stages III and IV)

This study evaluates the overall survival and disease free survival of melanoma patients that were treated with an autologous melanoma cell vaccine, administered as a post-operative adjuvant. Included are 43 patients with totally resected metastatic melanoma (28-AJCC stage III, 15-AJCC stage IV), with a median follow up of 34 months (6–62). The treatment consisted of eight doses of a vaccine made of 10–25×106 autologous melanoma cells either released from the surgical specimen or grown in cell cultures. Tumour cells were conjugated with hapten dinitrophenyl, mixed with Bacille Calmette Guérin and irradiated to 110 Gy. Both disease free survival and overall survival were found to be correlated with intensity of evolving delayed type hypersensitivity to subcutaneous injection of unmodified melanoma cells. Patients with a delayed type hypersensitivity reaction of ⩾10 mm had a median disease free survival of 17 months (mean 35 months) and a mean overall survival of 63 months (median not reached). In contrast, patients with a negative or weak delayed type hypersensitivity had a median disease free survival of 9 months (relative risk of recurrence=4.5, P=0.001), and a median overall survival of 16 months (relative risk of death=15, P=0.001). Stage III patients with a positive delayed type hypersensitivity reaction had an improved disease free survival of 16 months and a mean overall survival of 38 months, whereas patients with a negative delayed type hypersensitivity had a median disease free survival of 7 months (relative risk=4.5, P=0.02) and a median overall survival of 16 months (relative risk=9.5, P=0.005). The adjuvant administration of autologous melanoma vaccine was associated with improved disease-free and overall survival to selected patients who successfully attained anti-melanoma reactivity as detected by positive delayed type hypersensitivity reactions to unmodified melanoma cells.

Antitumor effect of recombinant tumor necrosis factor-α against murine sarcomas at visceral sites: tumor size influences the response to therapy

SummaryWe examined the antitumor efficacy of rTNF-α administration on established tumor at two visceral sites, lungs and liver. Treatment of B6 mice harboring multiple (>100 foci of ≤0.5 mm diameter) 10-day pulmonary macrometastases from the MCA-106 sarcoma, with dosages of rTNF-α (5–10 μg, single dose i. v.) that caused hemorrhagic necrosis and regression of a 6 mm MCA-106 s. c. tumor, had no impact on the number (or size) of lung nodules. Similarly, rTNF-α failed to show an antitumor effect in B6 mice with advanced day 8 or 10 multiple (>100 foci of ≤0.5 mm diameter) hepatic metastases at single i. v. doses up to 20 μg, as measured by either enumeration of residual liver nodules or survival. B6 mice injected s. c. with MCA-106 sarcoma and treated with rTNF-α as a single i. v. dose on day 0, 3, 5, or 7 experienced marked tumor regression only after the day 7 rTNF-α injection, when the tumor had achieved a size of 5–6 mm in diameter. Since tumor size appeared important for rTNF-α susceptibility in vivo, we next induced a single hepatic tumor of the MCA-106 sarcoma by the direct injection of cells into the left lobe of the liver and treated these mice at day 10 when the nodule had achieved a size of 5–6 mm in diameter. Increasing doses of rTNF-α (up to 8 μg) given as a single i. v. injection resulted in increasingly greater reductions in hepatic tumor as well as significant survival benefit of the treated mice. Sites of regressing hepatic tumor exhibited central necrosis accompanied by polymorphonuclear leukocytes and lymphocytes. Collectively, these results show that rTNF-α administration can mediate a significant antitumor effect on visceral tumor and suggest that tumor size is an important factor in rTNF-α susceptibility not only for tumors growing at s. c. sites but also for those established at visceral sites.

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma.

This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients started the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3–50 months). Of the 12 responding patients, 11 attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival – 54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies.

Paracecal hernia: A cause of intestinal obstruction

During a two-year period, five patients were treated by us for acute intestinal obstruction caused by an incarcerated paracecal hernia. All patients underwent surgery early, so none required bowel resection. The possibility of an internal hernia as a cause of intestinal obstruction and a profound knowledge of the pericecal anatomy, however, are necessary for successful diagnosis and treatment of paracecal hernias.

Placement of a Peritoneal Dialysis Catheter With Routine Omentectomy–Does it Prevent Obstruction of the Catheter?

OBJECTIVE To find out if routine omentectomy reduced the incidence of obstruction and other complications of catheters inserted for continuous ambulatory peritoneal dialysis (CAPD). DESIGN Retrospective study. SETTING Teaching hospital, Israel. SUBJECTS 60 patients with end stage renal failure who needed catheters for CAPD. INTERVENTION Routine omentectomy during insertion of the catheter, usually under local anaesthesia. MAIN OUTCOME MEASURES Short and long term morbidity, and mortality. RESULTS No patient died as a result of the procedure. The catheter obstructed in only one patient (2%) during a mean follow-up period of 28 months (range 2-108), and 90% of the catheters survived one year. CONCLUSIONS Routine omentectomy during insertion of a catheter for CAPD under local anaesthesia is safe and the incidence of obstruction is low. Prospective randomised studies are needed before it can be recommended as the procedure of choice.

Conservative Treatment of a Traumatic Tear of the Left Hepatic Duct: Case Report

Injury to the extra-hepatic biliary system in blunt abdominal trauma is rare and difficult to diagnose. In adults, all reported cases were treated surgically. We report a case of a traumatic tear of the left hepatic duct that was treated successfully by endoscopic retrograde cholangiopancreatography and stenting.

Retroviral transduction of interferon-γ cDNA into a nonimmunogenic murinefibrosarcoma: generation of T cells in draining lymph nodes capable of treating established parental metastatic tumor

Gene modification of tumor cells with the cDNA for interferon γ (IFNγ) has been shown to increase the immunogenicity of some tumor cells. In order to explore further the possible therapeutic relevance of these previous findings, two clones of the nonimmunogenic MCA-102 fibrosarcoma of C57BL/6 origin were retrovirally transduced with the cDNA encoding murine IFNγ: 102.4JK (4JK), a clone with relatively high major histocompatibility complex (MHC) class I expression, and 102.24JK (24JK), a clone with low expression of surface MHC class I molecules. Retroviral transduction of tumor cells with the cDNA encoding for IFNγ resulted in a substantial up-regulation of MHC class I surface expression in the 24JK clone but little change of class I in the 4JK clone. In an attempt to generate antitumor lymphocytes, these gene-modified cells were inoculated into mouse footpads and draining lymph nodes (DLN) were removed, dispersed, and cultured in vitro for 10 days with irradiated tumor cells and interleukin-2. DLN from mice bearing either unmodified tumor or tumor transduced with cDNA encoding neomycin resistance (NeoR) or IFNγ, were used to treat recipients harboring 3-day pulmonary metastases induced by the parental, unmodified tumor. Treatment with DLN cells obtained following the injection of 24JK tumor cells modified with the gene for IFNγ significantly reduced the number of pulmonary metastases in four separate experiments, compared to groups treated by DLN cells generated from inoculation of either the unmodified, parental 24JK clone or the same clone transduced with theNeoR gene only. In contrast, DLN cells induced either by IFNγ-transduced 4JK (high expression of MHC class I) or an unmodified 4JK tumor (moderate expression of MHC class I) had significant but equal therapeutic efficacy. Although the in vitro growth rate of tumor cell lines was unaffected by the insertion of the mouse IFNγ cDNA, their in vivo (s.c.) growth rates were significantly slower than those of the nontransduced tumors. Thus, after retroviral transduction of the murine IFNγ cDNA into a nonimmunogenic tumor with a very low level of surface expression of MHC class I, modified tumor cells could elicit therapeutic T cells from DLN capable of successfully treating established pulmonary metastases upon adoptive transfer. This strategy significantly confirms previous observations on the potential therapeutic effects of gene modification of tumor cells with IFNγ and extends the realm of therapeutic possibilities to include the use of DLN cells for the development of T-cell based immunotherapies against nonimmunogenic human tumors.