Preoperative chemotherapy, radiotherapy, and surgical resection of locally advanced pancreatic cancer.

HYPOTHESIS: Neoadjuvant therapy has the potential to induce regression of high-risk, locally advanced cancers and render them resectable. Preoperative chemoradiotherapy is proposed as a testable treatment concept for locally advanced pancreatic cancer. DESIGN: Fourteen patients (8 men, 6 women) with locally advanced pancreatic cancer were surgically explored to exclude distant spread of disease, to perform bypass of biliary and/or gastric obstruction, and to provide a jejunostomy feeding tube for long-term nutritional support. A course of chemotherapy with fluorouracil and cisplatin plus radiotherapy was then initiated. Reexploration and resection were planned subsequent to neoadjuvant therapy. MAIN OUTCOME MEASURES: Tumor regression and survival. INTERVENTIONS: Surgically staged patients with locally advanced pancreatic cancer were treated by preoperative chemotherapy with bolus fluorouracil, 400 mg/m2, on days 1 through 3 and 28 through 30 accompanied by a 3-day infusion of cisplatin, 25 mg m2, on days 1 through 3 and 28 through 30 and concurrent radiotherapy, 45 Gy. Enteral nutritional support was maintained via jejunostomy tube. RESULTS: Of 14 patients who enrolled in the protocol and were initially surgically explored, 3 refused the second operation and 11 were reexplored; 2 showed progressive disease and were unresectable and 9 (81%) had definitive resection. Surgical pathologic stages of the resected patients were: Ib (2 patients), II (2 patients), and III (5 patients). Pancreatic resection included standard Whipple resection in 1 patient, resection of body and neck in 1 patient, and extended resection in 6 patients (portal vein resection in 6, arterial resection in 4). One patient who was considered too frail for resection had core biopsies of the pancreatic head, node dissection, and an interstitial implant of the tumorous head. Pathologic response: 2 patients had apparent complete pathologic response; 1 patient had no residual cancer in the pancreatectomy specimen, the other patient who had an iridium 192 interstitial implant had normal core biopsies of the pancreatic head. Five patients had minimal residual cancer in the resected pancreas or microscopic foci only with extensive fibrosis, and 2 patients had fully viable residual cancer. Lymph node downstaging occurred in 2 of 4 patients who had positive peripancreatic nodes at the initial surgical staging. There was 1 postoperative death at 10 days. Sepsis, prolonged ileus, and failure to thrive were major complications. In the definitive surgery group the median survival was 19 months after beginning chemoradiotherapy and 16 months after definitive surgery. The absolute 5-year survival was 11% of 9 patients, 1 is surviving 96 months (with no evidence of disease) after chemoradiotherapy and extended pancreatic resection including resection of the superior mesenteric artery and the portal vein for stage III cancer. In the nonresected group the mean survival was 9 months (survival range, 7-12 months) after initiation of chemoradiotherapy. CONCLUSION: A pilot study of preoperative chemoradiotherapy with infusional cisplatin and radiation induced a high rate of clinical pathologic response in patients with locally advanced pancreatic cancer and merits further study in these high-risk patients.

Periodontal microsurgery.

Practitioners of periodontics must have familiarity with the various methods of optical magnification and, ultimately, the surgical microscope, if they are going to refine their basic surgical techniques with improved visual acuity, as other areas of medicine and dentistry are doing. Macroscopic versus microscopic vision determines the degree to which surgeons can handle soft and hard tissue for primary wound closure and rapid, non-traumatic healing. Subtle basic microsuturing techniques offer vast improvement in wound closure through magnification and good visual feedback, as opposed to the tactile information traditionally taught in conventional suturing. Periodontal microsurgery began with mucogingival surgery, but has application in every area of periodontal therapy for those who become proficient in this challenging new area of technology.

Alveolar bone anatomic profiles as measured from dry skulls. Clinical ramifications.

The purpose of this study was to evaluate the relationship of alveolar bone morphology to tooth shape and form. 111 dry skulls were evaluated at Baylor College of Dentistry (Dallas, Texas). The skulls were arbitrarily divided into flat, scalloped and pronounced scalloped anatomic profiles according to alveolar bone anatomy. The number of buccal dehiscences and fenestrations was determined for each skull according to their anatomic morphotype. 10 skulls from each group were selected for bone height measurements. The measurements were made with a periodontal probe and ruler from the height of the interproximal bone to the buccal alveolar crest. Kodachrome slides were used to measure mesial-distal tooth width and length from ten skulls from each anatomic category. The average number of fenestrations for each group was 3.5. The mean number of dehiscences for flat and scalloped skulls was 0.5. The average number of dehiscences for pronounced scalloped was 1.2. There were no significant differences when the groups were compared. The mean distance from the height of the interdental bone to the alveolar crest was statistically significant when the groups were compared (flat 2.1 mm, scalloped 2.8 mm, pronounced 4.1 mm) (Tukey, p = 0.05). There were no significant differences when tooth shapes were compared with bone anatomy. Pronounced scalloped anatomic profiles were slightly narrower when compared with the other groups. The observations reported have treatment ramifications when patients with scalloped or pronounced scalloped morphotypes are being considered for dental implant placement.

Current status of periodontal microsurgery.

Periodontal microsurgery has proven to be an effective means of improving the predictability of gingival transplantation procedures used in treating recession. It also promises to make papillary reconstruction a realistic possibility in the hands of most periodontists. The use of microsurgical principles and techniques has been extended to flap reflection and suturing as an ideal means of having precise control of the gingiva without traumatizing the tissue by stretching, distorting, or tearing it. Microsurgical use requires training and practice using visual feedback rather than tactile feedback as is common in macrosurgery. It is an area of great interest and practical application for the growth and future of periodontics.

An overview of periodontal microsurgery.

Optical magnification has broadened the horizons of dentistry in general and periodontics in particular. Improvement in visual acuity, made possible through optical magnification, is becoming an integral part of modern dental practices. Through the quiet trend toward microdentistry, the authors have used microsurgical principles to improve visual acuity and the precision of existing surgical techniques to broaden the scope and character of periodontics, with knowledge and technology borrowed from medicine. The effect of periodontal microsurgery may include more predictable therapeutic results, less invasive procedures with reduced patient discomfort, more rapid healing, improved cosmetic results, and greater patient acceptance. This article provides a brief overview of magnification in dentistry and how it is used in periodontal microsurgery as applied to reconstructive gingival surgery in the treatment of gingival recession.

Liver metastases with 10 human colon carcinoma cell lines in nude mice and association with carcinoembryonic antigen production.

BACKGROUND: The secretion of carcinoembryonic antigen (CEA) by many colorectal tumors is associated with a worse prognosis and a greater likelihood of metastases. The exact biologic function of CEA is not known. In the literature, it has been postulated CEA may be a tumorigenicity-enhancing factor. METHODS: Ten different human colonic adenocarcinoma cell lines (RW-7213, RW-2982, LS174T, SW1116, RW-5928, DLD-2, SW-48, DLD-1, SW-480, and HCT-8) with a wide range of CEA production (from undetectable to 5200 ng/ml in culture medium) were injected into the spleens of groups of nude mice as a model for experimental hepatic metastasis. RESULTS: There was a wide range in local tumorigenicity in the spleen (from 0-90%) and in liver metastases (from 0-70%). The capacity to grow in both liver and spleen was associated with CEA production. The four cell lines that secreted the highest amounts of CEA produced the highest tumorigenicity in the spleen (67-90%) with frequent liver colonization (25-70%). The two cell lines that secreted no detectable CEA produced neither splenic tumors nor hepatic colonies. Low-level CEA production was associated with intermediate and more variable tumorigenicity. CONCLUSIONS: There was an association between CEA secretion and the ability of 10 different colorectal cell lines to grow in nude mouse spleen and liver models.

In vivo selection of a highly metastatic cell line from a human pancreatic carcinoma in the nude mouse.

A cell line with high metastatic capacity to the liver was established by sequential passages of a human pancreatic cancer cell line through the nude mouse liver. A subline, L3.5, established after five passages of the fast-growing variant (FG) of the human pancreatic cancer COLO 357 through the nude mouse liver produced extensive hepatic metastases in 100% of experimental animals when injected into the spleen. The incidence of pulmonary metastases decreased from 43% for FG to 9% for L3.5. The L3.5 cell line showed aggressive growth with almost complete replacement of the hepatic parenchyma in one third of the mean time required for the development of macroscopic metastases of FG in the liver after splenic injections of tumor cells. This study indicates that the nude mouse provides a good model for in vivo selection of metastatic cells from human pancreatic cancer. The L3.5 cell line will be valuable in the study of human pancreatic cancer metastasis, particularly in the area of survival and growth of metastatic cells in the microenvironment of the liver.

An IgG human monoclonal antibody reactive with a surface membrane antigen expressed on malignant breast cancer cells.

A human IgG3 monoclonal antibody (HMab), F86, that reacts with breast cancer cells was obtained by fusion of antibody-secreting Epstein-Barr virus (EBV)-transformed cells from a draining lymph node with the human fusion partner HMMA2.11TG/O. F86 reacts with an antigen expressed on the surface of five malignant human breast cancer cell lines and several human malignant myelomonocytic cell lines but is not detected on normal peripheral blood mononuclear cells. Studies with tissue sections of a human breast cancer line xenografted in nude mice have demonstrated that the F86 antigen is expressed both on the cell surface and in the cytoplasm of tumor cells. The F86 antigen is also expressed by the tumor cells in the original tumor specimen of a patient from whom one of the test cell lines and the xenografts were derived. Functionally, the F86 antibody does not mediate complement lysis or antibody-dependent cellular cytotoxicity in vitro. The F86 antigen could not be labeled by [35S] methionine or 125I and immunoprecipitated. The nature and expression of antigens such as that detected by the HMab F86 and how they became immunogenic and/or suppress an active immune response can be addressed through the use of HMab.

Heterogeneity of potential for hematogenous metastasis in a human pancreatic carcinoma.

Human pancreatic carcinoma, a disease with grave prognosis, frequently metastasizes to the liver, with detrimental consequences for the host. Good models of experimental metastasis for this disease are lacking. We describe a model of hepatic metastasis from the fast-growing variant (FG) of the human pancreatic carcinoma COLO 357. We also show that the slow-growing variant (SG) of COLO 357 lacks the potential for forming hepatic and pulmonary metastases following injection into the spleen of the nude mouse. This expression of heterogeneity of potential for hematogenous metastases can be exploited by pursuing studies aiming at identifying differences between the cells with and without metastatic potential.

Invasion and metastasis following orthotopic transplantation of human pancreatic cancer in the nude mouse.

A good experimental model for metastasis of human pancreatic cancer would be a valuable tool for the study of this process, which contributes significantly to morbidity and mortality. Models of experimental metastasis using injection of tumor cells into the portal or systemic circulation bypass some important steps of the metastatic process. We describe invasion and metastasis following orthotopic transplantation of human pancreatic carcinoma into nude mice. Tumor pieces were used as xenografts in this study, and metastases were observed in the regional lymph nodes, liver, lungs, and distant lymph nodes of the animals. Peritoneal implants and ascites were not observed in this study. Orthotopic transplantation of human pancreatic cancer in the nude mouse appears to be a promising model of spontaneous metastasis relevant to clinical reality.

A human breast stromal sarcoma cell line with features of malignant cystosarcoma phyllodes.

A cell line was established from a portion of a 25-cm stromal sarcoma of the left breast of a 65-year-old woman. The clinical course was rapid with tumor recurrence on the chest wall less than 1 month after mastectomy. Other cutaneous and abdominal metastases occurred shortly thereafter, and death followed within 3 months despite chemotherapy. The cultured cells, designated RW-972, produced large amounts of acid mucopolysaccharides (hyaluronic acid) and mimicked the aggressive growth characteristics seen in the patient. After injection into nude mice, the tumor grew rapidly and occasionally produced metastases. This unique cell line, RW-972, presumably derived from the stromal component of a human malignant cystosarcoma phyllodes, might be useful in studies of experimental therapy of this rare tumor type and of lobular stromal cells of breast. It may also be used to investigate hyaluronic acid production by tumor cells.

Cell culture of the mucinous variant of human colorectal carcinoma.

Two cell lines, RW-2982 and RW-7213, have been established for the first time from the mucinous variant of human colorectal carcinoma, which is a distinctive and important subtype that has a worse prognosis than the more common nonmucogenic large bowel carcinoma. Methods of establishment and observations made during 7 and 3 years, respectively, of continuous culture are described. These cell lines required 4-9 months of adaptation to tissue culture conditions before noticeable growth occurred. Both cell lines have the following unique properties: (a) growth in vitro as delicate branching three-dimensional tumor particles within a wide gel of insoluble, often translucent mucus (proteoglycan); (b) production of large quantities of carcinoembryonic antigen; (c) ability to survive or adapt to growth in media free of serum, hormones, growth factors, and all protein; and (d) tumorigenicity in multiple sites in nude mice, including liver, with especially rapid growth in the peritoneal cavity as gelatinous material that is nonadherent and noninvasive and thus resembles pseudomyxoma peritonei. Unlike other reported colorectal cell lines, these mucus-coated particulate cell lines will not readily grow as monolayers and grow much more slowly with a doubling time of 2 weeks or more. A serially transplantable tumor from the RW-7213 surgical specimen has also been maintained in nude mice since August 8, 1984. This tumor retains properties of the original specimen. Observations made on the tumor biology of mucogenic colorectal carcinoma using these cell lines are discussed.

The in vitro response of fibroblasts to the fluid that accumulates under a vapor-permeable membrane.

We decided to examine whether the mechanism for production of granulation tissue during moist wound healing under a vapor-permeable membrane (VPM) is related to a fibroblast growth-promoting substance in the wound fluid beneath the VPM. The experimental design utilized growth curves performed on synchronized fibroblast cultures derived from 2 normal infants. Cell counts were performed at days 1, 4, 7, and 11 (saturation density). VPM fluid (MWF, moist wound-healing fluid) from 7 different patients was used to supplement growth medium (GM) in the test growth curves. Both 2% MWF alone and 2% MWF plus 2% human serum (2 + 2) were evaluated for each patient. Control curves were conducted using GM supplemented with 2%, 4%, and 10% human serum (HS). When 2% MWF alone was added to culture medium, all cells lifted off the surface of the flask within 4-7 days. If (2 + 2) was used to supplement the medium, detachment did not occur. At days 4, 7, and 11, (2 + 2) flasks had significantly greater cell densities than did flasks supplemented with either 2% or 4% HS alone (p less than 0.001). At days 4 and 7, (2 + 2) cell counts were the same as 10% HS cell counts (p = 0.99). By day 11, (2 + 2) cell counts exceeded those of 10% HS (p less than 0.01). We conclude that the fluid that collects under the specific VPM used in this study when added to HS causes synergistic stimulation of fibroblast cell division and an altered pattern of fibroblast growth.

Differential characteristics of two newly established human breast carcinoma cell lines.

Two human breast carcinoma cell lines, EP and MW, were established in culture from malignant pleural effusions. In addition to producing tumors in antithymocyte serum-immunosuppressed mice, both cell lines showed epithelial characteristics and anchorage-independent growth in soft agar. EP and MW differed in morphology (spindle-shaped versus round), chromosomal mode (hyperdiploid versus near triploid), estrogen receptor content (43.8 versus 5.1 fmol/mg protein), cloning efficiency (0.24 versus 15%), and activities (milliunits/10(6) cells) of creatine phosphokinase (25.7 versus 62.6) and lactate dehydrogenase (346.7 versus 778.5). Electron microscopy revealed that MW cells had more perinuclear filamentous material and more frequent intracytoplasmic vacuole formation than did EP cells. While having no effect on MW cells at the concentrations studied (10(-5) to 10(-11) M), beta-estradiol (10(-7) M) stimulated the growth of EP cells by 106% over the hormone-depleted control. In a variety of systems, EP was consistently the more drug sensitive of the two lines. In vitro, EP was significantly (p less than 0.001) more sensitive to methotrexate, vincristine, and 5-fluorouracil, respectively. In antithymocyte serum-mouse xenografts, EP displayed a greater response to three different dosages of a combination of cyclophosphamide, methotrexate, and 5-fluorouracil. One such dosage (cyclophosphamide, 32.0 mg/kg/day; methotrexate, 13.0 mg/kg/day; 5-fluorouracil, 190.0 mg/kg/day; for 1 day) reduced EP and MW tumor weights to 5.9 and 41% of controls, respectively. These results correlated well with the clinical responses.

Cytotoxic liponucleotide analogs. II. Antitumor activity of CDP-diacylglycerol analogs containing the cytosine arabinoside moiety.

Among events limiting the effectiveness of cancer chemotherapy are the general lack of preferential uptake of anticancer drugs by tumor cells and the occurrence of drug resistance. An approach has been undertaken to explore whether or not such events can be favorably altered or circumvented therapeutically by development of a new class of anticancer molecules, cytotoxic liponucleotide analogs. The design of cytotoxic liponucleotide analogs encompasses both biochemical and biophysical aspects of liponucleotide and glycerophospholipid structure and metabolism. Several cytotoxic liponucleotide analogs of cytidine diphosphate diacylglycerol (CDPdiacylglycerol/dCDPdiacylglycerol), containing the 1-beta-D-arabinofuranosyl moiety, were tested for antitumor activity. Multispecies ara-CDPdiacylglycerol (1-beta-D-arabinofuranosylcytosine 5'-diphosphate diacylglycerol), which contains egg lecithin-derived mixed fatty acyl chains, was more active than 1-beta-D-arabinofuranosylcytosine (ara-C), a clinically used anticancer drug, against leukemia L5178Y and P388 ascites cells in mice. At identical single doses (50 mg/kg per day times 4) administered intraperitoneally, ara-CDPdiacylglycerol prolonged the life spans of L5178Y tumor-bearing mice 93%, while ara-C prolonged life by 18%. Ara-CDPdiacylglycerol increased life spans of P388 tumor-bearing mice by 357% at doses of 50 mg/kg per day times 4; the maximum increase with ara-C was 159% (85 mg/kg per day times 4). Against a P388 ara-C-resistant cell line (P/Ara-C, kinase deficient) in mice, ara-CDPdiacylglycerol prolonged survival times by 34% at a dose of 50 mg/kg per day times 4 and by 55% at 75 mg/kg per day times 4; the drug was not active against two other ara-C-resistant murine leukemia mutants (CA 55, CA5b). With cell line-derived human colon carcinoma HCT-15 grown in mice immunosuppressed with anti-thymocyte serum, ara-CDPdiacylglycerol at a single daily dose of 50 mg/kg per day times 4 significantly reduced tumor weights to 21% of the controls; the same dose schedule of ara-C caused no observable reduction of tumor weights. Results of these preliminary antitumor evaluations indicate that cytotoxic liponucleotide analogs should be investigated further to determine their potential as antineoplastic molecules.