Mordechai Gutman

Are malignant melanoma patients at higher risk for a second cancer

This study tests whether malignant melanoma (MM) patients are at higher risk of having an unrelated second cancer by comparing the observed incidence of a second cancer in a given population of MM patients with the expected number in an age‐matched and sex‐matched group of healthy people followed for a similar period. The analysis was based on the person‐years method in which the main consideration is the follow‐up period after the diagnosis of MM. Of 370 patients with histologically confirmed MM, 27 (7.3%) had a second noncutaneous invasive cancer, diagnosed either simultaneously (within 6 months, five patients) or after the diagnosis of MM (22 patients). The follow‐up period for the entire MM group was 1253 person‐years, a period during which the expected number of cancer cases in the normal population, according to the Israel Cancer Registry, was 6.6. The observed–expected ratio or the relative risk (RR) was 4.1 (P less than 0.01). After excluding the five patients with simultaneous diagnosis of MM and a second cancer, analysis of the remaining 22 patients in whom MM definitely preceded the second cancer showed an RR of 3.3 (P less than 0.01). For the entire group, there were nine patients with breast cancer, five with head and neck cancer (two with thyroid and three with oral cavity cancer), five with gynecologic cancer (one with uterine and four with ovarian cancer), five myeloproliferative malignancies (one with lymphoma, three with chronic lymphocytic leukemia, and one with myeloma), three gastrointestinal carcinomas (two with colon and one with stomach cancer), and two soft tissue sarcomas. When the differential analysis according to gender and age was done, it was found that the RR was higher for women (5.5, P less than 0.01) than for men where the RR was 2.2 (P less than 0.05). Differential analysis for various age groups showed that the trend for second cancer was consistent in all age groups, with a slight increase in the younger ones. None of the variables of MM, such as location of the primary tumor, level of invasion, or stage, were predictive for a second cancer. Furthermore, the RR for a second cancer did not relate significantly with the treatment given to the MM patient. Concerning the type of second cancer, it was found that the RR was especially high for breast cancer–‐6.6. These data indicate that MM patients may be at higher risk for having a noncutaneous invasive cancer compared with the general population.

Is forequarter amputation justified for palliation of intractable cancer symptoms

Background: Limb-sparing surgery has replaced the radical surgical approach for treating limb sarcomas in most cases. Amputation has been advocated as a palliative procedure for symptomatic locally advanced disease that has already failed to respond to radiation therapy, chemotherapy and limited surgery. Methods: Twelve patients with advanced malignant tumors involving the shoulder girdle or the proximal humerus underwent forequarter amputation (FQA) for palliative purposes. The tumor-related local problems were severe pain, limb dysfunction, tumor fungation, bleeding (requiring emergency FQA in one case) and infection. The preoperative Karnofsky performance status (KPS) in our series ranged from 30 to 70%. Results: No perioperative mortality was observed. The morbidity was well tolerated by the patients. The KPS improved in most of the patients, and was assessed as 90–100% in 9 of the 12 patients. Overall, quality of life was reported to be at least moderately improved by 2 out of 3 patients. Survival was measured in months (3–24 months), but ultimately had no meaning since the procedure was palliative. Lung metastases were the dominant cause of death in our patients. Conclusions: The results of FQA in our series point to its feasibility and the gain in quality of life and performance status in severely ill patients with advanced malignancies. Local symptoms and signs were controlled, and quality of life was restored.

Transureteroureterostomy: an adjunct to the management of advanced primary and recurrent pelvic malignancy.

Abstract Background and aims. The surgical management of advanced primary or recurrent rectal cancer may involve the lower ureter or ureterovesical junction. With unilateral involvement, reconstruction of the ureters with salvage of the ipsilateral renal function should be considered. Patients and methods. With optimal exposure both ureters are visualized. The crossed ureter is incised perpendicularly and then longitudinally on its medial aspect. An anterolateral ureterotomy is made on the recipient ureter. A mucosa-to-mucosa anastomosis is completed. Stents are used selectively. Results. Eleven patients with advanced pelvic malignancy underwent this procedure. There was one major complication requiring ureteronephrectomy of the crossed system. Conclusion. Transureteroureterostomy should be considered as a treatment option in patients with unilateral ureteral obstruction.

Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan in advanced soft-tissue sarcomas: Histopathological considerations

Background: Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan was used as induction treatment in locally advanced extremity soft-tissue sarcomas for limb sparing surgery. The typical histopathological changes that occur in these tumoral masses are described in a series of 30 patients.Methods: Fresh tumor specimens of 27 high grade extensive soft-tissue sarcomas and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks after hyperthermic isolated limb perfusion with tumor necrosis factor-α plus melphalan. The specimens were studied for surgical margins, extent and type of tumor necrosis, lymph node involvement, perineural and vascular invasion, and the effects on adjacent normal tissues such as nerves, muscles, and blood vessels.Results: The typical histological changes were central cystic hemorrhagic necrosis with pericystic extensive fibrosis. Some nonspecific changes were noted in the soft tissues around the mass. In eight cases, more than 90% necrosis was found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%–90% in 4 of 17 cases). In five cases, less than 60% necrosis was noted. The best responses (.90% necrosis) were observed in distally located tumors. The responsive types were malignant fibrous histiocytoma, followed by myxoid liposarcoma and synovial sarcoma. Desmoid tumors showed less necrosis than high grade sarcomas. Vascular invasion was observed in two cases and intralesional venous thrombosis in one case. No perineural invasion or lymph nodes involvement were observed. The soft tissues adjacent to the tumor bed did not show major morphological changes. No correlation was found between the histological changes and each of the following: the anatomical (upper vs. lower limb) or compartmental location of the tumor; whether the tumor was primary or recurrent; and the types of previous treatment (systemic chemotherapy or radiotherapy) and tumor size.Conclusions: This is the first serial histological description of the effects of tumor necrosis factor-α and melphalan administered via hyperthermic isolated limb perfusion on the tumoral masses of limb soft-tissue sarcomas. The small number of specimens and, especially, the variability of tumors preclude definite conclusions. Larger numbers and more homogeneity are needed in future studies.

THE EFFECT OF PNEUMOPERITONEUM ON DISSEMINATION AND SCAR IMPLANTATION OF INTRA-ABDOMINAL TUMOR CELLS

PURPOSE The role of laparoscopy for the treatment of cancer remains controversial, and a particular concern is port site metastases after laparoscopic surgery. Since laparoscopy is being performed with increasing frequency, the question arises as to whether it is a safe oncological procedure. After intraperitoneal inoculation of renal cell carcinoma cells in a mouse model, we compare abdominal wall scar implantation following laparoscopic trocar insertion and pneumoperitoneum with standard laparotomy, and examine the effects on tumor dissemination in the peritoneal cavity. MATERIALS AND METHODS Following intra-abdominal RENCA cell inoculation, Balb/c mice were randomized into group 1-20 mice that underwent carbon dioxide pneumoperitoneum and telescope trocar insertion, group 2-20 subjected to laparotomy and group 3-10 anesthetized only. All animals were sacrificed 2 weeks after inoculation, and abdominal wall metastases and intraperitoneal tumor distribution were evaluated. RESULTS Overall, intra-abdominal implantation of inoculated RENCA tumor cells was detected in 15 of 20 animals (75%) in group 1, 14 of 20 (70%) in group 2 and 10 of 10 (100%) in group 3. Wound metastases developed in 46.7% of the mice in group 1 and 50% in group 2. CONCLUSIONS There was no difference among the groups in the pattern of intraperitoneal tumor implants and scar seeding incidence. Pneumoperitoneum does not facilitate port site metastases.

Increased microvascular permeability induced by prolonged interleukin-2 administration is attenuated by the oxygen-free-radical scavenger dimethylthiourea

Abstract Effective use of interleukin (IL)-2 as an antineoplastic agent may be hindered by severe side-effects, in particular vascular leak syndrome, which leads to generalized, especially pulmonary, edema. The oxygen-free-radical scavenger dimethylthiourea (DMTU) was shown to attenuate IL-2-induced vascular leak syndrome in sheep receiving a single IL-2 injection. However, in the clinical setting multiple injections are necessary to gain a therapeutic effect. The present study tests whether DMTU attenuates IL-2-induced vascular leak syndrome following multiple IL-2 injections without affecting IL-2-induced cytotoxicity in peritoneal mononuclear cells. Mice were treated intraperitoneally with 1×105 units IL-2 three times daily for four consecutive days. DMTU (10 mg/0.5 ml) was administered to the study group once daily, prior to the first IL-2 injection. Comparing the wet/dry weight ratio of lungs, liver, and spleen showed that IL-2 caused a significant (P<0.05) wet/dry increase in all three organs. DMTU attenuated the wet/dry increase in the lungs (P<0.05), in the spleen (P<0.05), and not at all in the liver. IL-2 induced a marked increase in peritoneal mononuclear cell counts, which was not attenuated by DMTU. The cytotoxic effect of IL-2-activated peritoneal mononuclear cells on target B16 cells was also unchanged in animals pretreated with DMTU. In conclusion, we have shown that DMTU ameliorates pulmonary permeability and vascular leak syndrome associated with multiple-dose IL-2 therapy, without eliciting an inhibitory effect on IL-2 induced-cytotoxicity.

Malignant melanoma in different ethnic groups in Israel. Incidence and biologic behavior

Background. The Jewish population of Israel is divided into two ethnic groups: Ashkenazic Jews (AJ) who immigrated from Europe and are fair‐skinned, and Sephardic Jews (SJ) who immigrated from the Orient and Africa and who are dark‐skinned. The biologic behavior of malignant melanoma (MM) in these two groups has not been investigated.

Effect of (+)-cyanidanol-3 on chronic active hepatitis: a double blind controlled trial.

Forty patients with biopsy proven chronic active hepatitis were studied, 22 received (+)-cyanidanol-3 in a dose of 3 g daily and 18 placebo. Side effects related to cyanidanol were fever (four patients), haemolysis (one patient) and urticaria (one patient). All side effects subsided on discontinuation of the medication. Cyanidanol had an effect no better than placebo on symptoms, laboratory tests, and histological findings on liver biopsy.

Intra-arterial chemotherapy with concomitant hemofiltration (chemofiltration) for treatment of loco-regional or pelvic metastases from malignant melanoma

Loco-regional or pelvic metastases from malignant melanoma (MM) of the lower limbs or pelvis are usually refractory to systemic chemotherapy, the limiting factor being systemic toxicity. An attempt to improve this low response rate using a novel loco-regional approach involving intra-arterial high dose chemotherapy with concomitant hemofiltration of the venous effluent of the pelvis, hence chemofiltration, was studied. Chemofiltration was performed in seven MM patients. The arterial catheter and the venous cannula were placed in the aorta and the inferior vena cava just distal to the renal vessels. High-dose melphalan (1 mg/kg) or cis-platinum (200 mg/m2) was injected into the arterial catheter. Blood was pumped out into the hemofiltration unit at a rate of 500–700 ml/min. The filtered blood was returned via a catheter placed in the superior vena cava. Despite the extensive fluid exchange (9,700–15,000 ml), the procedure was well tolerated. Out of six patients who remained with measurable disease, three had a partial response lasting 5–12 months, two had stabilization of their disease for 3 months, and one developed a rapid progression. Chemo-filtration is feasible in MM patients and is a viable option in locally advanced or metastatic malignant melanoma confined to the limb or pelvis.