A phase I and clinical pharmacology study of intravenously administered carminomycin in cancer patients in the United States.

Carminomycin (CMN) was administered i.v. to 44 patients with a variety of nonhematological cancers every 4 weeks at doses of 15, 20, 22.5, and 25 mg/sq m. Granulocytopenia was the dose-limiting toxicity. The median granulocyte count for previously untreated patients receiving 22.5 mg/sq m was 0.962 cells/microliters, and for previously treated patients receiving 20 mg/sq m it was 0.420 cell/microliters. Moderate to severe phlebitis was associated with drug administration in 50% of cases. Nausea, vomiting, and alopecia were mild. Three of nine patients who received a total CMN dose of greater than or equal to 100 mg/sq m (mean, 132 mg/sq m) developed unexplained decreases in radionuclide cardiac ejection fraction, with one patient developing decreased QRS amplitude and congestive heart failure at a total dose of 160 mg/sq m. CMN is rapidly metabolized to carminomycinol. The elimination half-lives of CMN and carminomycinol are 6 to 10 and 50 hr, respectively. CMN was found to be a more potent inhibitor of human granulocyte-macrophage colony-forming units than was carminomycinol. Objective partial responses were seen in two of seven previously untreated patients with non-small cell lung cancer and one of three patients with squamous cell carcinoma of the head and neck previously untreated with chemotherapy.

Postsurgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen: a Cancer and Leukemia Group B study.

PURPOSE: To compare two cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP) regimens with a doxorubicin-based regimen--vinblastine, doxorubicin, thiotepa, and Halotestin (Upjohn, Kalamazoo, MI) (VATH)--in patients with stage II node-positive breast carcinoma. METHODS: Nine hundred forty-five women were treated with a 6-week induction course of CMFVP. They were then randomized to receive one of two consolidation CMFVP regimens: 6-week courses or 2-week courses. Following completion of CMFVP consolidation, patients were again randomized to either continue the CMFVP regimen or to receive six escalating doses of VATH. RESULTS: Among all patients, with a median follow-up time of 11.5 years, there is no statistically significant difference in disease-free survival (DFS) between the two consolidation CMFVP regimens. VATH intensification treatment is statistically significantly superior to CMFVP in terms of DFS (P = .0040). For patients with one to three involved nodes, there is currently no significant difference between VATH and CMFVP; however, among those with four or more positive lymph nodes, there is a significant difference in favor of VATH (P = .0037). There is also improved overall survival with VATH (P = .043; median, > 14 years v 10 years). This difference is also statistically significant in patients with four or more involved lymph nodes, among postmenopausal patients, and among postmenopausal estrogen receptor-positive patients. CONCLUSION: Chemotherapy with crossover to escalating doses of VATH following CMFVP was well tolerated and effective. Inauguration of VATH as a treatment intensification at the eighth month produced a major increase in relapse-free and overall survival. The observation that sensitivity to VATH is retained so long after mastectomy raises questions about the proper duration of adjuvant chemotherapy and lends support to further investigation of cross-over designs in future trials to postoperative adjuvant chemotherapy regimens.

Hemodynamic and functional changes in xenogenic, perfused, isolated lungs.

Hyperacute pulmonary rejection was reproduced by perfusion of the isolated lung with heparinized heterologous blood. The cat lung was perfused with dog venous blood at a pressure of 30 mm. Hg. Pulmonary hemodynamic and functional studies showed that blood flow decreased to 14 per cent of the control and pulmonary vascular resistance increased sevenfold. Dynamic pulmonary compliance decreased only slightly to 83 per cent at 15 minutes, but normal pH, PO2, and PCO2 were maintained in the pulmonary venous blood even 15 minutes after the start of perfusion, because perfusion was decreased to a greater extent than ventilation.

Saphenous vein graft as a conduit for hepatic artery catheters in anomalies of the hepatic arterial system.

Access to the hepatic arterial system for perfusion chemotherapy is complicated by a high rate (45%) of anomalies including replaced and/or accessory arteries, as well as atrophic, absent, or thrombosed vessels. The use of a short segment of saphenous vein graft provides access for hepatic arterial perfusion in each of these situations and is safe, easily performed, and enduring.

Mechanisms of arterial injuries associated with total hip replacement.

Five cases of arterial complications of total hip replacement, all of which can be explained on the basis of intraoperative injury, are reported, with diagrammatic analysis of the intraoperative mechanisms of injury involved. The injuries were manifested as hemorrhage, ischemia, or development of a pulsatile mass. Vascular structures affected include the external iliac, common femoral, medial femoral circumflex, and lateral femoral circumflex arteries. Arterial damage may result from retractor injury, thermal injury from methylmethacrylate, or direct penetration from polymer or gouging during acetabular preparation. An understanding of the mechanisms and location of arterial injury following hip replacement will aid the vascular surgeon in diagnosis, exposure, and repair of these injuries.

Multiple malignancies of the lung and head and neck. Second primary tumor or metastasis?

Independent primary cancers of the head and neck and of the lung may be confused with lung metastases from a head and neck tumor. We retrospectively reviewed the cases of 55 patients who had head and neck malignancies and pulmonary lesions. To distinguish between independent primary tumors and lung metastases we applied an algorithm using the following criteria: sequence of appearance of the lesions; tumor histology; radiologic appearance of the lesions; and presence of malignant anterior cervical adenopathy. In this group of 55 patients, 40 were categorized as having independent primary malignancies and 15 were categorized as having pulmonary metastases from the head and neck tumor. In cases in which the origin of the pulmonary lesion is unclear, the patient should be treated as though independent primary malignancies were present since this offers the best chance for cure.

Cinemicroscopy of hyperacute pulmonary rejection.

Rejection processes were studied in xenografts and allotransplants of cat or dog lungs to dogs. Cinemicroscopy of the microcirculation in untreated animals showed almost immediate sludging, cellular aggregation, reduced vascular caliber, diminished blood flow, and rapid development of perivascular edema. The principal mechanisms of the extremely rapid xenograft rejection include capillary and arteriolar obstruction due to cellular aggregation. Pretreatment with heparin was virtually valueless, while methylprednisolone offered temporary protection.

Pulmonary complications in primary acquired hypogammaglobulinemia: surgical considerations.

With the discovery and routine use of antibiotics, a virtually new disease--primary acquired hypogammaglobulinemia--was recognized. More precise clinical, genetic, and laboratory endeavor has proved, in fact, that it is really one of a whole host of individual disease entities, all with the common feature of inadequate production and marshalling of gamma globulin to combat infection. Although the condition has been recognized in children's medicine for two decades, the survival of these early victims into adolescence and adulthood is now bringing them to the attention of surgeons as candidates for drainage or resection of suppurative disease of the lung, air tubes, and pleura. In fact a triad has emerged, with some of these patients having infectious disease in the lungs and sinuses associated with enlargement of the spleen when first seen. Often it is the radiologist who first suspects the diagnosis when he recognizes one or more features of this diagnostic triad. Three personal cases are presented together with a technique of management that appears successful. As with the recognition of any new disease, occult and subclinical presentations become more common as suspicion progresses, and ease of confirmation is afforded.

Details of technique and results of staging laparotomy in the diagnosis of Hodgkin's disease.

The operative procedure for staging laparotomy in Hodgkin's disease is described in detail. Of 18 patients undergoing this procedure, staging laparotomy changed the stage of disease and subsequent therapy in 38%. Complications of the operation were minor, occurring in only two patients. Abnormal lymphangiography and splenomegaly proved unreliable clinical diagnostic findings. Most disturbing was the 100% incidence of amenorrhea in the women receiving pelvic irradiation following oophoropexy.

Limb loss despite functioning distal bypass.

Five patients are reported who failed to heal ischemic foot wounds despite patient, functioning in situ saphenous vein grafts to infrapopliteal arteries. All were diabetic and two died before amputation could be performed. Contributing to this paradoxical failure of attempted limb salvage were: (a) extensive preexistent gangrene, (b) infection and failure of wound management, and (c) occlusive disease in runoff beds despite the distal site of anastomosis. Distal occlusive disease included one or more of the following: (a) stenosis in a named artery of the foot, (b) stenosis of collaterals from the peroneal artery, and (c) incomplete pedal arches. Distal in situ saphenous vein bypass should continue to be broadly applied for limb salvage, but careful judgement in patient selection and attention to the management of the ischemic wound itself remain critical to success.

Tissue-cultured head and neck tumors: their use in in vitro assays of immune response.

Samples of 35 tumors from the head and neck region (25 squamous cell, 2 basal cell, 5 parotid, 3 melanoma, and 1 lymphosarcoma) were cultured after dispersement with either trypsin or collagenase treatment. Growth was established in 14 (40%). Cultured tumor cells were then used as target cells in in vitro assays of patients' cellular and humoral immunity to their own or similar tumors. Preliminary data suggest this may be a reliable method of monitoring responses in patients receiving immunotherapy for head and neck malignancies.

In vitro detection of cytotoxic cellular immunity against tumor-specific antigens by a radioisotopic technique.

[(3)H]Thymidine-labeled tumor cells are used to evaluate the cytotoxic cellular immune response against tumor-specific antigens; the loss of label due to destruction and detachment of target cells from the surface of the culture vessel is measured. Spleen cells from mice immunized against Moloney virus-induced rhabdomyosarcoma specifically destroyed the sarcoma cells, while cells from normal syngeneic mice did not. Peripheral blood lymphocytes from patients with malignant tumors were specifically cytotoxic to autologous tumor cells and to allogeneic tumor cells histopathologically identical to the autologous tumor, but not to autologous nonmalignant fibroblasts, or to allogeneic tumor cells from a histologically dissimilar tumor. Serum from the same patients specifically protected autologous tumor cells from lymphocyte cytotoxicity. This serum-mediated protection of tumor cells against autologous cellular immunocytotoxicity also extended to histologically identical allogeneic tumor cells. Cross-reactivity of anti-tumor cellular immunocytotoxicity in vitro, and its "blocking" by autologous serum, strongly suggest the presence of common tumor antigens. The antagonism demonstrated in vitro between serum and cellular immunity may explain the continued growth of malignant tumors in the face of demonstrable cellular immunity.

Posterolateral exposure for renal artery reconstruction.

Anterior approaches to the renal arteries are complicated by the intervening renal veins, inferior vena cava, and abdominal viscera. We describe techniques of direct posterolateral access to both right and left renal arteries by use of an extended retroperitoneal exposure. This approach allows for grafting from the aorta or iliac artery on either side and is particularly suitable on the left side for direct retropancreatic splenorenal artery anastomosis, which is described in detail. It is also useful for distal reconstruction of branch renal arteries, renal artery embolectomy, and autotransplantation "bench surgery." We have used this approach in 28 patients with no operative deaths and two reconstructive occlusions.

Atraumatic control in calcified arteries.

We have attempted distal saphenous vein bypasses for limb salvage in increasingly difficult situations. Severe calcification in the recipient artery makes vascular control and anastomosis troublesome. An atraumatic method of intraluminal control, which has been of aid in this situation, is described.

Problems in differentiating between pancreatic lymphoma and anaplastic carcinoma and their management.

A group of 6 patients with malignancies involving the pancreas is presented, with a range of diagnosis from primary reticulum cell sarcoma to probable anaplastic carcinoma. Even with adequate biopsy and autopsy material, it may be difficult to provide a definitive tissue diagnosis in these patients. Although this entire spectrum of tumors is uncommon, it is important to try to establish a diagnosis whenever possible. Biopsy of the tumor should be performed, even from the pancreas itself, if necessary, particularly when the initial presentation of the disease is unusual or if the pattern of metastasis is different from that usually seen with carcinoma of the pancreas. It is suggested that a therapeutic trial of appropriate radiotherapy and chemotherapy be instituted in patients of this type even if a diagnosis of lymphoma is not firmly established. The possibility exists of survival of some of these patients for periods of one year or more as a result of successive therapy.

Operative angiography by intraarterial digital subtraction angiography: a new technique for quality control of carotid endarterectomy.

Fifty patients who had carotid bifurcation endarterectomy as their sole surgical procedure underwent intraoperative completion angiography by means of portable intraarterial digital subtraction angiography. All had subsequent intravenous digital subtraction angiography or duplex scanning during early follow-up. After the endarterectomy site was closed and before the wound was closed, 6 to 8 ml of contrast was injected through a 21-gauge needle while fluoroscopy was performed with a conventional C-arm. The C-arm was coupled to a Quantel IDIS Mobile Digital Subtraction Angiogram Unit (Quantel Medical Products Group, Clemmons, N.C.) for image enhancement and immediate playback. There were no postoperative deaths or neurologic complications. Abnormal radiographic results led to reopening of endarterectomy sites in eight patients, which resulted in successful correction of the defects. There was a single asymptomatic occlusion of the internal carotid artery at 3 weeks in the patient with the only false-negative result on the completion study. Intraarterial digital subtraction angiography is a safe and useful technique for intraoperative quality control of carotid endarterectomy. It provides visual images that can be easily repeated in several projections, uses small volumes of contrast, and has no timing requirements for filming and injecting.