Alan G. Wile

Hormones and breast cancer

Patients with successfully managed breast cancer have generally been denied subsequent exposure to increased levels of estrogen (endogenous or exogenous) based on the belief that exacerbation of the cancer would occur. The advent of oral contraceptives, the trend toward childbearing later in life, and the demonstration of the protective value of menopausal estrogen replacement therapy against osteoporosis and cardiovascular disease requires that this issue be reexamined. New information bearing on this subject includes the recognition of estrogen receptors, the isolation of youth rather than pregnancy as the factor resulting in poor prognosis, epidemiologic studies showing no increased risk of breast cancer in women using oral contraceptives or taking hormonal replacement therapy, the beneficial effect of pregnancy subsequent to successfully managed breast cancer, and the absence of an adverse effect of oral contraceptives upon established breast cancer. In view of the lack of evidence relating estrogen to exacerbation of existing breast cancer, it may be in the best interest of our patients to liberalize our attitude to renewed hormonal exposure in patients with successfully managed breast cancer.

Hematoporphyrin phototherapy of cancer

Hematoporphyrin phototherapy of cancer is a new modality for cancer diagnosis and treatment that is currently undergoing clinical trials worldwide. A variety of tumors have been studied, e.g., breast (mostly recurrent skin), lung, bladder, eye, head and neck, gynecological and brain. The most success to date has been with lung and the gynecological tract. Cell and animal studies are being conducted to elucidate the basic photobiological mechanisms involved, as well as the histopathological events associated with tumor destruction. Although major questions remain to be resolved, hematoporphyrin phototherapy is an exciting new therapeutic modality for the treatment of cancer, especially in sites where the unique features of lasers and fiber optics are advantageous.

The Pharmacokinetics of Cisplatin in Experimental Regional Chemotherapy

Cisplatin (DDP) is attractive for use in regional chemotherapy because of its tendency for protein binding. A study of regional chemotherapy was conducted in rabbits bearing the VX‐2 carcinoma. Modes of therapy examined were intravenous (IV), intra‐arterial (IA), IA with stopflow, IA with outflow occlusion, and isolation‐perfusion (I‐P). Each mode was evaluated by examining the pharmacokinetics of DDP in systemic and regional administration and measuring tissue concentrations of DDP. It was observed that the systemic exposure to DDP was significantly less for IA with outflow occlusion and I‐P when compared to IV, IA, or IA with stopflow occlusion (P = 0.003). Tumor concentrations were highest with IA infusion with outflow occlusion (P = 0.002) and IA stopflow occlusion (P = 0.03). Tumor tissue concentrations were always higher than adjacent muscle DDP concentrations. The authors conclude that significant pharmacologic advantage can be demonstrated for certain modes of DDP administration in this rabbit model, and that these promising results should be followed by clinical trials. Cancer 59:695‐700, 1987.

Giant adrenal myelolipomas: CT and MRI findings

The computed tomographic (CT) and magnetic resonance imaging (MRI) features of three giant myelolipomas of the adrenal gland are presented in two patients. CT demonstrates large, fatty retroperitoneal tumors that may be confused with retroperitoneal liposarcoma or very large renal angiomyolipoma. MRI with coronal and sagittal imaging is more sensitive than CT in defining the most likely origin of these tumors as the adrenal gland.

Increased cisplatin tissue levels with prolonged arterial infusion in the rat

Prolonged arterial infusions of cisplatin (DDP) have been effective in the treatment of regionally confined malignancies. It is unclear whether the route or schedule of DDP administration was responsible for the observed therapeutic benefit. To resolve this issue, tumor and normal tissue platinum (Pt) levels were determined in rats bearing hind‐limb rat mammary tumors after intravenous (IV) and intra‐arterial (IA) DDP infusions of constant dose and varying lengths. Infusions of DDP at 6 mg/kg were conducted IA over 30 minutes, and 3, 6, 24, and 48 hours and IV over 30 minutes and 48 hours. After infusion, Pt concentrations in solubilized tissue homogenates were measured by flameless atomic absorption spectroscopy. Maximum tumor Pt levels were seen after 48‐hour IA infusion (29.3 μg Pt/mg tissue). IA infusions of 24 hours or less resulted in significantly lower Pt levels. Maximum tumor Pt concentration after IV administration was only 0.98 μg/mg tissue (48‐hour infusion). Muscle Pt levels adjacent to the tumor were highest in the IA infused extremities, but at the 48‐hour interval, were 53‐fold less than tumor levels. Tumor and adjacent muscle Pt levels were not significantly different from each other after IV administration. This study provides pharmacologic evidence that lengthening the duration of IA DDP infusion increases tumor levels of Pt over that of IV or rapid IA administrations. The benefit of prolonged IA DDP infusions is dependent upon both route and schedule of drug administration.

Control of pelvic cancer with hyperthermic isolation-perfusion

Eight patients with refractory pelvic cancer were treated with a technique of hyperthermic pelvic isolation-perfusion (rectosigmoid colon 7, bladder 1). The procedure was successful in achieving regional hyperthermia in all patients. All five patients experiencing severe pelvic pain prior to surgery had resolution of pain, although in one patient this relief was transient. Five patients had additional intraabdominal procedures at the time of laparotomy to control unsuspected foci of recurrent cancer. There were no operative deaths. Five complications occurred in four patients although only one was considered life threatening (fracture of aorta at the time of cross-clamping). Sloughing of necrotic tumor occurred between 1 and 2 weeks postperfusion and at times was dramatic. The efficacy of this technique is impressive and it is suggested that it be utilized earlier in the course of disease in patients with uncontrolled pelvic cancer.

Soluble suppressor factors elaborated in experimental malignant ascites

Soluble suppressor factors in the sera of cancer patients inhibit lectin-stimulated lymphocyte proliferation. These factors, derived from human material, preclude easy corroboration by other investigators. To gain a general understanding of soluble suppressor factors and to avoid the necessary restrictions of human experimentation, an animal model was devised. Sprague-Dawley rats were injected ip with the Walker 256 carcinoma. The resultant ascites proved to be a stable, reproducible source of soluble suppressor factors. Ascites inhibited phytohemagglutinin (PHA)-induced blastogenesis of normal splenocytes by 98%. The possibility of a toxic effect was eliminated by vital staining of splenocytes and by examination in a specific lymphotoxin assay. Suppressor activity persisted after heating at 100 degrees C for 40 min. Extraction by lipid solvents revealed that the bulk of suppressor activity resides in the lipid phase. The active fraction of heat-treated ascites passed through an Amicon PM-10 filter. Thin-layer chromatography revealed the presence of prostaglandins E2 and F2 alpha. Tissue culture supernatants from short-term cultures derived from tumor-bearing animals revealed suppressor activity from thymus, spleen, and liver cultures (97, 91, and 71%, respectively). No suppressor activity was detected in cultures of cancer cells. This study has demonstrated in this animal model that prostaglandins play a major role in suppression of lectin-induced blastogenesis. All suppressor factors appear to be host derived. An understanding of the mechanism of release of these suppressor substances may open new avenues in the immunotherapy of cancer.

Hepatic artery-biliary fistula. An unusual complication of infusion therapy

This report describes a patient with carcinoid metastatic to the liver in whom a hepatic artery catheter was placed for infusion therapy. This resulted in a previously unreported complication of a hepatic artery-biliary fistula. The clinical presentation of this complication and mode of management are described. The etiologic factors responsible for this complication are discussed. It is speculated that as more aggressive therapy for hepatic metastases is undertaken, this potential complication will be seen more frequently.

Murine monoclonal antibodies to human pancreatic cancer: specificity and sensitivity.

Pancreatic carcinoma (n = 7), pancreatitis tissue (n = 4), normal pancreas tissue (n = 5), colonic adenocarcinoma (n = 4) and in vitro human pancreatic cancer cell lines (n = 6) were studied with the murine monoclonal antibodies (MAbs) 3DS2A, AR1-28, AR2-20, Ca19-9 and CA17-1A to determine their immunohistologic specificity and sensitivity for use as radiolabeled diagnostic imaging agents. Using the avidinbiotin-immunoperoxidase staining technique, MAbs 3DS2A and AR1-28 stained 86 and 100% of pancreatic cancer specimens, respectively. MAbs 3DS2A and AR1-28 are suitable agents for use as radiolabeled diagnostic imaging agents in patients with pancreatic cancer.