Russell J. Nauta

Vitamin D receptors in breast cancer cells.

Summary1,25-(OH)2-Vitamin D3, the active metabolite of vitamin D, is a secosteroid hormone with known differentiating activity in leukemic cells. Studies have demonstrated the presence of vitamin D receptors (VDR) in a wide range of tissues and cell types. Antiproliferative activity of 1,25-(OH)2-vitamin D3 has been documented in osteosarcoma, melanoma, colon carcinoma, and breast carcinoma cells. This study was designed to analyze vitamin D receptor level in breast cancer cells as a marker of differentiation and as a predictor of growth inhibition by 1,25-(OH)2-vitamin D3.VDR messenger RNA was found to be present in relatively high levels in well-differentiated cells and in low levels in poorly differentiated cells. All cell lines had detectable VDR mRNA. Radiolabeled ligand binding assay showed a similar pattern. MCF-7 and T47D cells, which express VDR at moderate levels, showed significant growth inhibition by 10−9 M 1,25-(OH)2-vitamin D3 (p < 0.05). MDA-MB-231 cells, which have very low levels of VDR, demonstrated no growth inhibition by 1,25-(OH)2-vitamin D3 at concentrations up to 10−6 M. Based on these results it can be stated that VDR expression is lost with de-differentiation and that receptor is essential for the antiproliferative response to 1,25-(OH)2-vitamin D3.

The role of calcium ions and calcium channel entry blockers in experimental ischemia-reperfusion-induced liver injury

Verapamil administered before treatment, but not after treatment, had a beneficial effect on a 90-minute warm ischemia-reperfusion rat liver injury model. The possible activation of proteases converting the xanthine dehydrogenase to xanthine oxidase, the significant mitochondrial calcium loading during the ischemic period, and the potentiation of calcium and oxygen-derived free radicals to promote injury to mitochondria are mechanisms supported by this study, based on both histologic observations and on the pattern of enzyme leak after the acute ischemic event.

Extended surgical resection in T4 gastric cancer.

BACKGROUND Some physicians still consider invasion of adjacent organs by the carcinoma of stomach as a sign of incurable disease. METHODS This retrospective study has been done with particular reference to 353 T4 gastric cancer patients who underwent combined gastrectomies with adjacent organs. RESULTS Subtotal gastrectomy was performed in 237 (67.1%) patients and total gastrectomy was performed in 116 (32.9%) patients. Organs most commonly resected with the stomach were the transverse colon in 159 (45%) cases, the tail of pancreas and spleen in 150 (42.5%), the left lobe of liver in 101 (28.5%), and the head of pancreas in 37 (10.5%) patients. A total of 110 postoperative complications occurred in this subset of patients corresponding to a complication rate of 31.2%. A total of 48 postoperative deaths occurred in this subset of patients corresponding to a mortality rate of 13.6%. The 5-year survival rate for all patients who underwent combined gastrectomy with adjacent organs was 25%. Of the node-negative T4 gastric cancer resections, 37% survived 5 years whereas the T4 node-positive resections have only a 15% 5-year survival. CONCLUSIONS Patients who present with T4 gastric cancer (about 20% of the patient population) will benefit from aggressive en bloc surgical resection and should not be considered unresectable.

Intensive preoperative radiotherapy with local hyperthermia for the treatment of gastric carcinoma

In order to devitalize maximally tumour tissue and improve the prognosis of gastric cancer patients, a method employing preoperative intensive radiotherapy with local hyperthermia as adjuvant treatment was evaluated. In order to estimate the effectiveness of preoperative intensive radiation and radiation with local microwave hyperthermia in radical gastric cancer treatment, 293 patients were randomized into three respective treatment groups: surgery alone, surgery preceded by preoperative radiation; and surgery followed by preoperative radiation and hyperthermia. Preoperative radiation therapy to a total dose of 20 Gy in four 5 Gy fractions did not improve 3- or 5-year survival in gastric cancer patients in comparison with surgery alone. Local hyperthermia in combination with radiation therapy followed by surgery produced a significant improvement in 3-year survival of 22.1% (from 35.5 +/- 4.9% to 57.6 +/- 6.3%, P < 0.05) and 5-year survival of 21.3% (from 30.1 +/- 4.7 to 51.4 +/- 6.6%, P < 0.05). In unresectable gastric cancer patients, radiation therapy and radiation therapy with hyperthermia both increase mean survival. In conclusion; intensive preoperative radiation therapy in total dose 20 Gy plus local microwave hyperthermia significantly improved 3- and 5-year survival in comparison with surgery alone. Further development and evaluation of equipment to produce reliable and safe delivery systems for hyperthermia is needed.

The effect of extracellular calcium on colonocytes: evidence for differential responsiveness based upon degree of cell differentiation

Calcium supplementation decreases the incidence of colon cancer in animal models and may prevent colon cancer in man. Potential mechanisms include binding of mitogens and direct effects of calcium on colonic epithelial cells. In this study, the effects of extracellular calcium on epithelial cell growth and differentiation were studied in three colon carcinoma and two colonic adenoma cell lines. The characteristics studied included morphology, cell cycle kinetics, [Ca2+]IC (intracellular calcium concentration), proliferation, and expression of differentiation markers such as carcinoembryonic antigen (CEA) and alkaline phosphatase (AP). Sodium butyrate (NaB) and 1,25‐dihydroxyvitamin D3 were used as controls in the latter three assays as these two agents are known differentiating agents. Alteration of [Ca+2]EC (extracellular calcium concentration) did not affect carcinoembryonic antigen (CEA) or alkaline phosphatase (AP) expression. NaB enhanced the expression of AP three‐fold and CEA five‐fold. This effect was augmented by increasing [Ca2+]EC. The exposure of cells to 1,25‐(OH)2‐Vitamin D3 increased CEA but not AP. [Ca2+]IC increased in response to 1,25‐(OH)2‐vitamin D3 and NaB but not with variation in [Ca2+]EC. Increased [Ca2+]EC inhibited proliferation of well‐differentiated cells, but had no effect on poorly‐differentiated cells. Morphological studies showed that extracellular calcium was necessary for normal cell—cell interactions.

Modulation of vitamin D receptor and estrogen receptor by 1,25(OH)2-vitamin D3 in T-47D human breast cancer cells

1,25(OH)2-Vitamin D3 inhibits breast cancer cell proliferation through interaction with the vitamin D receptor (VDR). Regulation of VDR is under the influence of several factors which include the functional ligand for this receptor (1,25(OH)2-vitamin D3) as well as heterologous steroid hormones. We evaluated the nature of homologous regulation in T-47D human breast cancer cells with a radiolabelled ligand binding assay and a ribonuclease protection assay for VDR. Significant VDR up-regulation, as measured by hormone binding assays, occurred with pre-incubations with 10(-9)M through 10(-6)M 1,25(OH)2-vitamin D3 (P < 0.05). A 7-fold VDR up-regulation with 10(-8)M 1,25(OH)2-vitamin D3 occurred at 4 h treatment and was not associated with an increase in VDR mRNA expression on ribonuclease protection assay. This supports the hypothesis that up-regulation of VDR is probably the result of ligand-induced stabilization of pre-existing receptor. All-trans-retinoic acid, the progesterone analog R-5020, and prednisone were found to induce heterologous up-regulation of the VDR. We then determined with ligand binding assays whether 1,25(OH)2-vitamin D3 could influence receptor levels for another hormone in a manner analogous to the heterologous regulation of VDR. Regulation of estrogen receptor (ER) by 1,25(OH)2-vitamin D3 was studied in T-47D and MDA-MB-231 breast cancer cells. Incubation of T-47D cells, which are ER (+), with 10(-8)M 1,25(OH)2-vitamin D3 did not result in up-regulation of ER. Yet estrogen binding was significantly up-regulated in a cell line that is ER(-), MDA-MB-231. The increased estrogen binding was associated with a shift in binding affinity and ribonuclease protection assay showed absence of ER mRNA in these cells, suggesting an up-regulation of estrogen binding proteins and not of the ER itself.

Observation versus operation for abdominal pain in the right lower quadrant: Roles of the clinical examination and the leukocyte count

In-hospital observation of patients with abdominal pain in the right lower quadrant has been suggested as a means of improving diagnostic accuracy and of decreasing the incidence of negative laparotomy. An analysis of 97 patients brought to the operating room over a 12 month period in a university hospital suggests that patients with the classic pattern of migratory pain, rebound tenderness, and an increased number of metamyelocytes in the peripheral blood smear most likely require operation. Leukocytosis alone was not predictive of a surgically remediable disease, which suggests that a period of observation in patients with atypical patterns of pain and no peritoneal signs is a sound treatment plan.

Postoperative complications requiring relaparotomies after 700 gastrectomies performed for gastric cancer

BACKGROUND Prevention of fatal postoperative complications and improved management of patients with complications are important means of increased survival in gastric cancer patients. PATIENTS AND METHODS A study of 700 patients undergoing gastrectomy was performed to examine factors that contributed to a high rate of postoperative complications. RESULTS Of 700 patients undergoing gastrectomy for adenocarcinoma, 40 (5.7%) underwent reexploration because of serious complications. The frequency of the relaparotomies varied from 2.1% and 4.4% after regular subtotal and total gastrectomies, respectively, to 20% and 30.4% after palliative and conventional total gastrectomies, respectively. The complications that required reexploration most frequently were anastomotic leakage and incompetence of sutures (11, 27.5%), intra-abdominal abscesses (8, 20%), and pancreatic necrosis (7, 17.5%). A combination of preventive measures allowed the attainment of low rates of esophagojejunal anastomotic leakage (0.8%). CONCLUSION We believe that the decision to perform an urgent reexploration, based on clinical findings, should generally be made by a group of experienced surgeons (not only the primary surgeon). Timely relaparotomy prevented death in 37.5% of the patients with serious acute postoperative complications.

Intraoperative radiation therapy of hepatic metastases: technical aspects and report of a pilot study.

Surgical resection of hepatic metastases offers long-term survival, and possible cure, for selected patients with colorectal carcinoma. Fifty percent of patients considered candidates for resection are found to have disease confined to the liver. The resections necessary are often more extensive than predicted preoperatively, which provides an opportunity for innovative approaches using radiation therapy. The intraoperative radiation therapy technique presented here offers the ability to control multiple metastatic deposits in patients not deemed resectable. This is achieved using remote afterloading interstitial (Ir-192) radiation therapy to deliver tumoricidal radiation doses to limited volumes within the liver. The technique was used to treat 11 patients in a pilot study, delivering radiation doses of 20 Gy to the periphery of predetermined target volumes in a single treatment. The number of metastatic deposits treated ranged from 2 to 11 separate tumors with maximum diameters from 3 to 9 cm (median 6 cm). Hospitalizations were from 6 to 23 days (median 8) with only one patient experiencing a surgically related complication (wound dehiscence and pneumonia). There were no radiation related complications on follow-up to 18 months. Biopsies of two treated sites in a patient undergoing reoperation confirmed control of tumors by this procedure. This technique is offered as a standby procedure to patients undergoing exploration for hepatic resection at our institution.

Metastatic cancer. A relative contraindication to vena cava filter placement.

From October 1979 to November 1984, 41 patients underwent placement of vena cava filters for prevention of pulmonary emboli. After filter placement, no pulmonary emboli were documented. No patient died due to filter placement. However, 20 of these 41 patients are dead. Eighteen deaths were caused by cancer. Ten (24%) patients died within 2 months of filter placement. Five (12%) patients died prior to hospital discharge. All ten of these patients had known, widely metastatic cancer. Among the ten patients who died more than 2 months after filter placement, six had well‐differentiated, slow growing tumors. Only three of these patients had brain metastases. Among the 21 survivors only two suffered from cancer. Strict adherence to accepted indications for vena cava filter placement required operative procedures on a small but significant number of patients who demonstrated no significant improvement in quality of life or time out of hospital. Filter placement in patients with aggressive cancers and proven metastases should be performed only after analysis of predicted survival and after detailed discussions with patients and referring physicians. Filter placement in patients with aggressive metastatic cancer may cause discomfort, risk, and expense with little hope for improvement of hospital course, longevity, or quality of life. Cancer 59:161–163, 1987.