Deficiency in maturation process of macrophages in human cancer.

Peripheral blood mononuclear cells were cultured from normal individuals and patients with cancer. The analysis of these results indicated a lower number of macrophage precursors (monocytes) in patients with cancer as compared to the number in normal individuals. The macrophage yield was 1.9 +/- 1.1 X 10(4)/ml of blood in patients with cancer versus 7.2 +/- 2.0 X 10(4)/ml of blood in normal individuals. This low yield of macrophages in patients with cancer was not associated with serum factors. Furthermore, a study of the adherent cell population suggests in intrinsic defect in the maturation process in vitro in patients with cancer.

Dose-dependent radiation effect on microvasculature and repair.

It has been postulated that the damage to microvasculature may be a major factor in the manifestation of late radiation damage to organized tissue. In this study, the radiation damage to microvasculature was investigated in a rabbit model during the early phases of irradiation with the use of vascular permeability as a marker. By means of a triple isotopic technique, the vascular, extravascular, and intracellular spaces could be defined. A forelimb and hindlimb of New Zealand White rabbits were irradiated with single doses of 2-30 Gy. 125I- and 131I-labeled bioscreened albumin were used to determine the changes in vascular permeability due to irradiation. The rabbits were sacrificed at various intervals post irradiation. Vascular and extravascular spaces and the respective albumin concentrations in tissue samples from irradiated limbs were compared with control values from the unirradiated contralateral limbs in each animal. The results indicated a definite increase in the vascular permeability of albumin secondary to irradiation. The increase in vascular permeability was apparent instantaneously with irradiation, even at 2 Gy. The microvascular compromise appear to be dose related. When examined at 16-24 hours post irradiation, the excess extravasation of albumin was significant at and beyond 8 Gy. At 10-30 days post irradiation, injury was not apparent up to 15 Gy. Thus there appeared to be an instantaneous injury at the capillary level due to irradiation, which appeared to be dose related. A repair process became evident as early as 16-24 hours and appeared to be dose related as well as related to elapsed time post irradiation.

In vitro peripheral monocyte culture: possible use as a prognostic indicator for renal cell carcinoma patients.

An in vitro assay was applied to follow 39 patients with renal cell carcinoma. A mononuclear cell-rich fraction was cultured from peripheral blood of patients over a period of 7 days. The number of adherent matured monocytes (macrophages) was analyzed and quantitated at the end of the culture period. Functional activities were analyzed by antibody-coated sheep red blood cells and nonspecific esterase staining techniques. Macrophage yield in patients with detectable tumor burden was 2.06 +/- 2.81 X 10(4) cells/ml blood, and mean values at 3, 6, and 9 months post nephrectomy were 3.67 (n = 21), 6.73 (n = 12), and 9.41 (n = 10) X 10(4) cells/ml blood, respectively. Some of the patients were followed over 30 months. The improvement was significant, and macrophage yield was close to normal values (8.24 +/- 3.14 X 10(4) cells/ml). In the absence of other reliable in vitro assays for these patients, this assay appears to be highly useful in following these patients during the postsurgical period.

Apparent cellular ingress of albumin in Walker 256 tumor and rat muscle.

Tissue albumin distribution was measured in Walker 256 tumor and skeletal muscle in vivo in 36 rats. Vascular, extravascular-extracellular, and total tissue water spaces were determined for each tissue sample by isotopic techniques. Tissue interstitial and lymph albumin values were calculated from thoracic duct albumin concentrations, and vascular albumin was determined from serum albumin levels. Total tissue albumin was measured by dilution. These data demonstrate a third tissue albumin pool that equilibrates in 3 days compared to the rapid equilibration (2 hr) of vascular and extracellular-extravascular spaces. The pool is present in both muscle and tumor but appears to equilibrate more rapidly in tumor tissue. This finding suggests that cellular ingress of albumin occurs in vivo, which may explain increased albumin catabolism in tumor-bearing hosts.

Recruitment with high physiological doses of estradiol preceding chemotherapy: flow cytometric and therapeutic results in women with locally advanced breast cancers--a Southwest Oncology Group study.

One theoretical method of increasing chemotherapeutic efficacy in breast cancer is to temporarily increase the number of tumor cells in cycle through hormonal recruitment prior to initiation of chemotherapy. In an effort to determine when and if this could be reliably accomplished, 50 women with locally advanced and/or metastatic breast cancer with known estrogen receptor (ER) status were entered into a serial breast biopsy study designed to measure increases in S-phase fraction (SPF) and proliferative index (PI; S + G2 + M) following administration of a high physiological dose of estrogen via estradiol vaginal suppositories prior to chemotherapy. Blood levels of estradiol were maintained in a range (0.5-5 nM) known to increase SPF in vitro. Compliance with suppository administration was monitored by serial blood sampling. Tumors were sampled at 0, 24, 48, 72, and/or 96 h. Thirty-one ER-positive and 9 ER-negative women had evaluable baseline biopsies and at least 1 subsequent biopsy. An increase was seen for SPF in 20 (69%) and for PI in 23 (79%) of 29 ER-positive patients at 48 h after estrogen initiation (95% confidence intervals, 49-85% for SPF and 60-92% for PI); similar increases were seen at 72 h. Median baseline SPF and PI values in ER-positive patients for whom increases were noted at 48 h were 6.2 and 8.5%, respectively. The median relative increases in these patients were 170 and 100%, respectively, at 48 h. The increases observed at 24 h in 4 (SPF) and 6 (PI) of the 9 ER-negative patients could have occurred by chance alone. Twenty-five of the 28 locally advanced (T4 and/or N2-3) patients achieved a complete response during combined modality treatment (estradiol-chemotherapy, mastectomy, and radiation). At a minimum follow-up time of 42 months, estimated 5-year progression-free and overall survivals are 30 and 49%, respectively, with a median time to progression of 35 months. Twenty-two women had metastatic disease (19 also had locally advanced disease). Thirteen had a complete or partial response, with a median duration of 12 months. Median progression-free and over-all survival times for all metastatic patients are 4 and 17 months, respectively. Estimated 5-year survival for metastatic disease patients is 27%. A high physiological dose of estrogen administered to patients with locally advanced ER-positive tumors can reliably increase the tumor SPF and PI within 48 h.(ABSTRACT TRUNCATED AT 400 WORDS)

One versus 2 years of CMFVP adjuvant chemotherapy in axillary node-positive and estrogen receptor-negative patients: a Southwest Oncology Group study.

PURPOSE: To determine if prolonged adjuvant treatment (2 years v 1 year) with combination chemotherapy (cyclophosphamide, methotrexate, fluorouracil [5-FU], vincristine, and prednisone [CMFVP]) in poor-prognosis breast cancer patients (estrogen receptor [ER]-negative, stage II to IIIA) would result in improved disease-free and overall survival rates. PATIENTS AND METHODS: Four hundred forty-five women with ER-negative node-positive breast cancer were enrolled by the Southwest Oncology Group (SWOG) over a period of 5 years (1979 to 1984). Randomized assignments were made to either 1 or 2 years of adjuvant CMFVP. Doses were daily oral cyclophosphamide 60 mg/m2, intravenous (i.v.) weekly methotrexate 15 mg/m2, i.v. weekly 5-FU 400 mg/m2, i.v. weekly vincristine .625 mg/m2 for the first 10 weeks, and prednisone weeks 1 through 6 with doses decreasing from 30 mg/m2 to 10 mg/m2. RESULTS: The median follow-up duration is 8.6 years, with a maximum of 11.3 years. Treatment arms were not significantly different as regards either survival or disease-free survival rates (P = .33 and P = .24, respectively). The five-year survival rate is 57% on the 1-year arm and 62% on the 2-year arm. Patients with three or fewer nodes and premenopausal status were associated with improved survival. Compliance on the 2-year arm was poor, with only 37% completing the full 2 years of treatment. SWOG grade 3 to 4 toxicity was experienced by 47% of patients on the 1-year arm and by 52% on the 2-year arm. There were no treatment-related deaths. CONCLUSION: We conclude that 2-year adjuvant treatment with CMFVP is not an improvement over 1-year treatment. Moreover, 2 years of CMFVP is difficult to complete. However, the results are not definitely negative. A moderate improvement attributed to prolonged chemotherapy, especially among patients with four or more positive nodes, cannot be ruled out.

Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.

PURPOSE: To determine whether the addition of surgical ovariectomy to standard chemotherapy prolongs disease-free survival (DFS) and overall survival in premenopausal patients with estrogen receptor (ER)-positive operable breast cancer with positive axillary nodes. PATIENTS AND METHODS: Three hundred fourteen premenopausal patients with ER-positive, node-positive breast cancer were enrolled between July 1979 and July 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive either of the following: (1) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (i.v.) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 i.v. weekly for 1 year, vincristine .625 mg/m2 i.v. weekly for the first 10 weeks, and prednisone weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (2) bilateral ovariectomy followed by CMFVP. RESULTS: The median follow-up time is 7.7 years and the maximum 13.2 years. Treatment arms are not significantly different with respect to either survival or DFS (one-sided log-rank, P = .55 and .70, respectively). The 7-year survival rate is 71% on the CMFVP arm and 73% on CMFVP plus ovariectomy. No significant differences were observed in node or receptor level subsets. CONCLUSION: We conclude that, in this study, the addition of ovariectomy did not improve results over chemotherapy alone in the treatment of premenopausal women with node-positive, ER-positive, operable breast cancer. Our sample size was too small to detect a small improvement. The death hazards ratio of CMFVP/CMFVP plus ovariectomy was 1.22 (95% confidence interval [CI], .79 to 1.89).

Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study.

PURPOSE: A national cooperative group trial was conducted in patients with early-stage cutaneous malignant melanoma to determine if oral vitamin A can increase disease-free survival or survival. PATIENTS AND METHODS: Two hundred forty-eight patients with completely resected melanoma of Breslow's thickness greater than 0.75 mm and clinically negative lymph nodes were randomized to oral vitamin A (100,000 IU/d) for 18 months or to observation. Patients were stratified by Breslow's thickness of primary lesion (0.76 to 1.50 mm, 1.51 to 3.00 mm, or > 3.00 mm), sex, and type of therapy (excision, excision plus node dissection, excision plus perfusion, or excision plus both). The median duration of follow-up observation of living patients is greater than 8 years. The relative risk (RR) in disease-free survival and overall survival in the treatment compared with the observation group was calculated using Cox proportional hazards models. RESULTS: Overall, there was no difference in disease-free survival or overall survival between the two groups. Examination of treatment by stratification interactions and subset analysis did not show any treatment-effect differences based on sex or type of therapy. There was also no difference between groups in disease-free survival based on Breslow's thickness of the primary lesion. Overall, 12% of patients who received vitamin A experienced grade 3 or 4 toxicities. CONCLUSION: Based on the lack of overall survival benefit, further evaluation of vitamin A as adjuvant therapy for melanoma does not appear warranted.

Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.

PURPOSE: To compare chemohormonal therapy, chemotherapy alone, and hormonal therapy alone in postmenopausal patients with estrogen receptor (ER)-positive operable breast cancer and positive axillary nodes with respect to survival and disease-free survival (DFS). PATIENTS AND METHODS: Eight hundred ninety-two postmenopausal women with ER-positive, node-positive breast cancer were enrolled by the Southwest Oncology Group (SWOG) from July 1979 to March 1989 and 74 by the Eastern Cooperative Oncology Group (ECOG) between June 1987 and March 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive the following: (1) tamoxifen 10 mg twice daily by mouth for 1 year; (2) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (IV) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 IV weekly for 1 year, vincristine .625 mg/m2 IV weekly for the first 10 weeks, and prednisone during weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (3) the combination of tamoxifen and CMFVP. RESULTS: The median follow-up duration is 6.5 years, with a maximum of 12.8 years. Treatment arms are not significantly different with respect to either survival or DFS (log-rank, 2 df, P = .82 and .23, respectively). The 5-year survival rate is 77% for the tamoxifen arm, 78% for CMFVP, and 75% for the combination. No significant differences were observed in node or receptor level subsets. Severe or worse toxicity was experienced by 56% of patients on CMFVP and 61% on CMFVP plus tamoxifen, compared with 5% on tamoxifen alone. CONCLUSION: CMFVP chemotherapy, either alone or in combination with tamoxifen, has not been shown to be superior to tamoxifen alone in the treatment of postmenopausal women with node-positive, ER-positive, operable breast cancer.

Immediate effect of irradiation on microvasculature.

The immediate effects of irradiation on microvasculature in muscle in an animal model are described in this paper. By using triple isotopes of 125I, 131I, and 22Na, the transcapillary transfer of albumin from the vascular bed to the extravascular space is determined in terms of mg/g of tissue, after single doses of 2 to 14 Gy. These results reveal an increase in the extravascular albumin immediately after irradiation and suggest an instantaneous compromise in vascular permeability even after 2 Gy. This effect was apparently dose related.

Perioperative interstitial irradiation in the conservative management of early breast cancer.

Conservation of the breast in early breast cancer with limited resection and radiation is proving to be as effective as modified radical mastectomy in survival and in loco-regional control. Management at the University of Kansas Medical Center consists of an interstitial implant at the time of lumpectomy to facilitate perioperative irradiation with Iridium-192 to the tumor bed. An axillary node dissection is also performed at that time. Two to 3 weeks later external beam irradiation is delivered to the entire breast. One hundred and twenty-three breasts in 120 patients have been treated between June 1982 and June 1986. There were 49 pathological Stage I, 63 Stage II, 8 Stage III carcinomas, and 3 carcinomas in situ, consisting of 72 T1, 43 T2, 5 T3, and 3 TIS lesions. Patients have been followed for a median of 30 months. One patient had a "true" recurrence in the breast. Another patient developed recurrence in a different quadrant. Ninety percent of the patients had good to excellent cosmetic results, 7% were considered fair, and 3% had poor results. Seven patients developed mild arm edema, 4 were found to have moderate edema, and 1 had severe arm edema. Our preliminary results indicate that interstitial irradiation immediately after excision results in excellent local control, with very satisfactory cosmesis and no morbidity due to the simultaneous excision and irradiation.

Radiobiological advantages of an immediate interstitial boost dose in conservative treatment of breast cancer.

Minimum surgery with irradiation is emerging as one of the main modalities of therapy for operable early breast cancer. Between June 1982 and June 1986, 110 breasts with Tis, T1 to T3 lesions have been treated at our institution with lumpectomy and interstitial irradiation to the tumor bed with Iridium-192 perioperatively followed by external beam irradiation. There have been two local recurrences at or near the vicinity of the primary, at a median follow-up of 60 months. To analyze the parameters that might have contributed to the local control, we have examined the treatment volumes, prescribed dose to the tumor bed, dose at the core of the tumor bed, and dose to the surrounding normal tissue. Immediate interstitial implant has the radiobiological advantage of delivering continuous low dose irradiation, immediately upon removal of gross tumor to residual foci. Implantation of the afterloading catheters intraoperatively facilitates accurate dose delivery and avoidance of geographical misses. By precise treatment of any residual foci, immediately upon removal of the gross mass, perioperative interstitial irradiation improves local control and by facilitating less radical surgical excision, leads to better cosmetic results.

Cosmetic results in early breast cancer treated with lumpectomy, peri-operative interstitial irradiation, and external beam radiation.

Patients with operable breast cancer were treated at the University of Kansas Medical Center with lumpectomy, peri-operative interstitial Iridium, and external beam radiotherapy, and concomitant adjuvant chemotherapy in a majority of node positive cases. Examination of the cosmetic results in 85 breasts followed for at least 2 years, at a median of 41 months revealed 20% to be excellent, 44% to be very good, 24% good, 9% fair, and 4% to have poor results. In this paper cosmesis is analyzed with reference to the size of the primary, its location, age of the patient, whether the patient received adjuvant chemotherapy, and whether the regional nodes were treated. In this group of patients, the size and the site of the primary, patient's age, and whether adjuvant chemotherapy was administered or not, did not adversely affect the aesthetic outcome. Treatment of the regional nodes gave a worse mean cosmetic score compared to the group in whom only the breast was treated (37.51 vs. 58.98 respectively, p less than 0.001). Among the 11 patients with fair/poor cosmesis, all had regional nodal treatment, 7/11 had inner quadrant lesions, and 7/11 had lesions greater than T1. Further follow-up and accrual would be needed to confirm our results and affirm if other factors would change.

The use of teaching examinations in surgical instruction.

A mode of teaching is described which introduces a new concept to clinical instruction in addition to the seminars, lectures, conferences, and audiovisual tools ordinarily used. It has the following advantages: (1) It allows the student to evaluate himself. (2) It allows him to detect and repair defects in his knowledge without damage to his class standing or to his ego. (3) It evaluates the areas of strength and weakness in the teaching programs. (4) It is a dynamic teaching process in which the student participates and which appears to stimulate a greater interest in and a greater retention of the material administered.

Gastric bypass for morbid obesity: results and complications.

Seventy-five patients underwent a 90 percent distal gastric bypass for morbid obesity. The average weight was 121.4 kilogram, height 164 centimeters, and age 31.4 years in these 70 women and five men. There was a total of 20 surgical complications in the 75 patients, with wound infection being the most common. Sixteen chronic complications were noted and consisted of vomiting, diarrhea, reflux esophagitis, dysphagia, and vitamin deficiencies. None of the above complications were life-threatening or required dismantling of the bypass. Of 54 patients followed for 12 months or more after gastric bypass, there was a 24.5 percent average weight decrease at 6 months, and this progressed to 35.8 percent by 12 months. Fifty-two patients undergoing small bowel bypass previously at the same institution had a 25.4 percent weight reduction at 12 months. Of 54 patients, 83 percent followed for one or more years after gastric bypass have had an excellent or good clinical result, whereas only 42 percent of the 52 patients undergoing small bowel bypass have had an excellent or good clinical result with the same criteria. It is concluded that the Mason 90 percent distal gastric bypass is a suitable form of surgical treatment for the morbidity obese patient who cannot lose weight by dietary measures.

Management of the morbidly obese patient after small bowel bypass failure.

Fourteen patients underwent small bowel bypass (SBB) takedown for complications such as chronic nausea and vomiting, excessive flatus, intractable diarrhea, liver dysfunction, electrolyte imbalance, hyperoxaluria with renal stones, and arthritis. The average weight loss in these 14 patients after SBB was 93 pounds (34% of initial weight), with a mean follow-up of 23 months. Four of the 14 patients had SBB takedown only and gained an average of 36 pounds over the ensuing 14 months. Similarly, three patients had SBB takedown with delayed (asynchronous) gastric bypass (GB) and gained an average of 55 pounds during the 14 months prior to GB. Following GB these three patients lost only an additional 8 pounds over a 12 month period, leaving them 47 pounds heavier than at the time of SBB takedown. In contrast, seven patients treated with SBB takedown and synchronous GB not only maintained the weight reduction obtained with SBB, but, in addition, had further modest weight reductions (average, 18 pounds), for a mean follow-up of 8 months. There were no serious operative or late complications with any of the above operations. In addition, the complications leading to SBB takedown resolved in each case. It is concluded that synchronous GB is an effective means of maintaining the weight reduction in the morbidly obese patient after SBB takedown.

Complications of jejunoileal bypass for morbid obesity.

Fifty-two patients had jejunoileal bypass surgery. End-to-end (Scott) or end-to-side (Payne) shunts were randomly selected for each patient; 31 standard length shunts and 21 shortened bypasses were performed. Only 22 patients had an acceptable result, whereas 30 patients had inadequate weight loss (less than 2.3 kg [5 lb] per month per year) or had gastrointestinal tract, metabolic, or surgical complications judged severe enough to render the outcome less than adequate. There was one death, and four patients required reanastomosis of the bypass. The primary deteriminant of success was age, ie, younger patients had clearly better results than older patients. In general, shorter shunts produced more weight loss than standard bypass procedures, but were associated with an increased complication rate. Three new complications of jejunolieal bypass are reported: acute comonic dilation with necrosis, beriberi, and lupus erythematosus.

Computed tomographic mammography. Diagnosis of mammographically and clinically occult carcinoma of the breast.

If breast cancer can be detected early, while it is still localized and before it can be palpated, the prognosis for cure is excellent. Heretofore, conventional mammography has been the only means available to detect cancer at such an early stage. Two cases of minimal breast carcinoma measuring less than 5 mm in diameter have been detected and correctly diagnosed using computed tomographic mammography (CT/M). Both cases occurred in fatty breasts and were clinically and mammographically occult. These cases demonstrate the value of CT/M in the diagnosis of minimal breast carcinoma that would have been missed otherwise.

Intraoperative implantation radiation therapy plus lumpectomy for carcinoma of the breast.

The preponderance of evidence indicates that lumpectomy plus radiation therapy produces the same survival as modified radical mastectomy in patients with early breast cancer and further suggests that the local failure rate may be lower in the patients who undergo irradiation. In this series, patients were treated with immediate implantation of the tumor bed with iridium Ir 192. There have been two recurrences in the breast from 110 breast cancers (44% had a clinical stage greater than T1, and 41% had axillary-node involvement) in 107 patients followed up for four to 52 months (25.8 +/- 13.3 months [mean +/- SD]). These preliminary data suggest that local treatment failure can be minimized by aggressive, immediate intraoperative implantation of the tumor bed with iridium Ir 192.

Treatment of renal cell carcinoma with renal infarction, delayed nephrectomy, medroxyprogesterone, and xenogeneic immune RNA.

The authors have used xenogeneic immune ribonucleic acid (RNA) in the treatment of patients with renal cell carcinoma. This has been used in conjunction with renal artery embolization, delayed nephrectomy, and progestational therapy, using immune RNA derived from sheep cell lymphocytes immunized with patient's tumor. Four of 5 patients with Stage I disease had extremely large primary tumors. This group is alive with no evidence of disease at twelve to twenty-four months. There are no Stage II tumors in this group. One patient with Stage III tumor is alive at twenty-two months without evidence of disease. Three patients with metastases are stable at five to twenty-two months. Two patients have progressive disease at three and six months. This treatment has not been effective in patients with massive tumor burden. The results in the other groups are encouraging.