Chemoradiotherapy with 5-fluorouracil/leucovorin, surgery and adjuvant chemotherapy for locally advanced rectal cancer.

The aim of this study was to demonstrate a pathologic complete response (pCR) rate of at least 10% with an acceptable toxicity achieved by preoperative chemoradiotherapy with 5-fluorouracil (5-FU)/leucovorin in patients with locally advanced rectal cancer. Patients were treated by radiotherapy targeting 50 Gy and 5-FU/leucovorin intravenously during the 1st, 4th and 7th week after start of radiotherapy followed by surgery and adjuvant chemotherapy. In 71 evaluable patients, the pCR rate was 14.1% (95% CI, 6.0-22.2); the local relapse rate, 6.1%; the 5-year disease-free survival, 54% and the overall 5-year survival, 68%. The most severe adverse events were neutropenia (17%), diarrhoea (17%), infection (8%) and fatal cardiovascular function (1%). This therapy yielded a high rate of pCR, a low rate of local relapse and a long disease-free and overall survival. To increase its feasibility, radiation dose reduction to 45 Gy and administration of only two preoperative cycles of chemotherapy is recommended.

Coexpression of the melatonin receptor 1 and nestin in human breast cancer specimens.

Activation of the G-protein-coupled receptor (GPCR) for melatonin (MT1) suppresses breast cancer cell growth in experimental models. To elucidate whether MT1 might play a role in cancer cells positive for the stem cell marker nestin, we assessed paired carcinomatous (Ca) and adjacent noncancerous (NCa) samples from 42 patients with primary breast cancer for MT1 and nestin by double immunofluorescence staining and quantitative image analysis with Tissue-Quest software. MT1 was located in luminal and myoepithelial cells in milk ducts and in tumor cells in 40/42 and 39/42 of NCa and Ca specimens, respectively, independent of hormone receptor and HER-2 status. Nestin was located together with MT1 in myoepithelial cells in 38 NCa specimens (total n = 42) and in 18 Ca specimens with intact milk ducts. Quantitative evaluation of selected 16 NCa and Ca samples revealed that MT1 levels were higher in invasive Ca sections than in NCa specimens in eight and lower in six cases. Specimens from higher tumor stages (TII/III) with a higher risk of relapse were associated with MT1/nestin co-staining in more than 10% of tumor cells, whereas a lack of co-staining correlated with lower tumor stages. Abundant expression of MT1 and, particularly, coexpression of MT1 with nestin in invading tumor cells in more advanced tumors suggest an important role for this GPCR in the pathogenesis of breast cancer.

Cryoscience and cryomedicine: new mechanisms of biological tissue injury following low temperature exposure. Experimental study.

UNLABELLED: A number of theoretical and experimental studies, both in vitro and in vivo, have been performed to explain the action of low temperatures on tissue. It is now evident that the thermal parameters used in the past for freezing during cryosurgery were not precise; this may have resulted in the failure of treatment. For the first time, this report describes the early ultrastructural features of pancreatic parenchyma after low temperature exposure, i.e, cryosurgery, in vivo. MATERIALS AND METHODS: Of investigation 48 animals were used for the experiment. A temperature range of -80 degrees C and -180 degrees C in contact with pancreas tissue was selected for cryosurgical exposure. The cryosurgical response of pancreas parenchyma, i.e. ultrastructural cellular changes in pancreas tissue, was investigated. For transmission electron microscopy, the specimens from the pancreas parenchyma were taken immediately, one hour and 24 hours after the finishing of the freeze-thaw cycles intraoperatively. RESULTS: The electronic microscopic analysis showed that, after local cryodestruction at temperatures of -80 degrees C and -180 degrees C, similar processes occurred within the pancreas tissue in the early postcryosurgical phase-immediately and up to 24 hours after low temperature exposure on tissue. The exocrine pancreatic cells in the center of the cryozone changed upon thawing. Ultrastructural changes in the exocrine pancreatic cells, where the first signs of dystrophic processes had been noticed, were increased. These ultrastructural changes in the pancreatic cells provide a platform to better understand the mechanisms of damage and the pathogenesis of frostbite after cryosurgery. The properties of the pancreas parenchyma response after low temperature exposure provide important insights into the mechanisms of damage and the cryogenic lesion immediately after thawing in cryosurgery. CONCLUSION: Our new insights prove on the cell level that suddenly and progressively damaged pancreatic cells in the postcryosurgical zone lead to aseptic cryonecrosis and then to aseptic cryoapoptosis of vital normal tissue. The vascular capillary changes and circulatory stagnation demonstrate the anti-angiogenesis mechanism, which, together with cryonecrosis and cryoapoptosis, are some of the main mechanisms of biological tissue injury following the low temperature exposure.

Well or poorly differentiated nonfunctioning neuroendocrine carcinoma of the pancreas: a single institution experience with 17 cases.

AIM: To evaluate the influence of distinguishing between well and poorly differentiated nonfunctioning neuroendocrine pancreatic carcinomas (PC). METHOD: Six well differentiated and 11 poorly differentiated nonfunctioning neuroendocrine PC were retrospectively analyzed for differences and compared with 340 ductal PC. RESULTS: 1. There was no difference in pT categories between well differentiated and, poorly differentiated nonfunctioning neuroendocrine PC and ductal PC. 2. The rate of the pN1 category was lower in well differentiated lesions (20%) than in poorly differentiated lesions (66%) and in the ductal PC group (75%). 3. The outcome of patients with R0 resections was significantly better for well differentiated neuroendocrine PC with all patients alive than for poorly differentiated ones and for ductal PC (5-year survival rate 0% and 18%, respectively). 4. The outcome following R1/R2 resections for poorly differentiated neuroendocrine PC tended to be similar than for ductal PC (1-year survival rate 20% vs. 33%). 5. There was no difference in mean survival time (9 months) between poorly differentiated lesions and ductal PC after palliative procedures. CONCLUSIONS: The better outcome of surgical treatment of nonfunctioning neuroendocrine PC vs. that of ductal PC was confined to well differentiated neuroendocrine lesions. For poorly differentiated lesions the outcome was as poor as for ductal PC. These results underscore the importance to distinguish between well and poorly differentiated nonfunctioning neuroendocrine PC.

Implications of histological grade of tumour for the prognosis of radically resected periampullary adenocarcinoma.

OBJECTIVE: To study the influence of histological grade of tumour on the prognosis of radically resected periampullary cancers. DESIGN: Retrospective study. SETTING: Teaching hospital, Austria. SUBJECTS: 156 patients (papilla of Vater, n = 34, head of the pancreas, n = 105, and distal common bile duct, n = 17) who underwent partial pancreaticoduodenectomy for periampullary adenocarcinoma between 1 January, 1967 and 31 December, 1996. OUTCOME MEASURES: The relation between grade of tumour and site, T and N classification, extramural growth, invasion of vessels and resection margins, tumour volume, and survival time. RESULTS: Well differentiated lesions were significantly more common in the papilla of Vater (n = 15, 44%, p = 0.01) than in the pancreatic head or the common bile duct (n = 20, 19%, and n = 5, 29%, respectively). Only in ampullary lesions did the grade of tumour significantly affect the incidence of other histopathological risk factors (T p = 0.003; nodal status p = 0.01; extramural growth p = 0.0001; tumour volume p = 0.02) and survival time (p = 0.02); no significant correlations were found in cancers of the head of the pancreas or common bile duct. CONCLUSIONS: There was a significant difference in the distribution of grade of tumour between the different sites of origin of resected periampullary cancers. Grade of tumour correlated with T and N classification, tumour volume, extramural growth, and survival only in ampullary lesions.

Chemotherapy for germ cell tumors relapsing after high-dose chemotherapy and stem cell support: a retrospective multicenter study of the Austrian Study Group on Urologic Oncology.

BACKGROUND: In most patients with advanced refractory germ cell tumors undergoing high-dose chemotherapy with stem cell support (HDCT) the disease progresses after HDCT. This study was designed to shed light on the unestablished role of post-HDCT chemotherapy. PATIENTS AND METHODS: In a retrospective multicenter study data of 47 evaluable patients from nine centers subjected to post-HDCT chemotherapy for progression of their germ cell tumors were collected in a questionnaire survey and analyzed for treatment response and survival. RESULTS: Of 191 patients pretreated by HDCT, 48 (25%) were subjected to post-HDCT chemotherapy for disease progression. Remission was achieved in 17 (36%) and marker-negative remission in eight (17%). The median survival time was 26 weeks, 65 weeks for responders and 13 weeks for non-responders. Only one of 47 evaluable patients achieved sustained complete remission. Remissions significantly correlated with the post-HDCT interval, the use of ifosfamide and the combination regimens of cisplatin + etoposide i.v. or ifosfamide and of paclitaxel + ifosfamide or cisplatin. On univariate analysis a longer post-HDCT interval, the use of cisplatin, paclitaxel and ifosfamide and the combined use of paclitaxel + ifosfamide and/or cisplatin significantly improved the chances of survival. On multivariate analysis only treatment with paclitaxel and ifosfamide retained independent prognostic significance for survival. CONCLUSIONS: One third of the patients considered to be candidates for further chemotherapy once progressive after HDCT went into remission with a gain in survival time. Sustained remissions may occur, but are rarely seen. Paclitaxel and ifosfamide appear to be the most effective drugs in these heavily pretreated patients.

Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial.

PURPOSE: To assess the impact of short-term adjuvant chemotherapy on relapse rates, treatment-related morbidity, and long-term toxicity in patients with clinical stage I nonseminomatous testicular germ cell tumor (NSGCT I) who carry a high risk of relapse, ie, who show blood-vessel invasion (VI) by the primary tumor. PATIENTS AND METHODS: From January 1985 to January 1995, 42 NSGCT I patients with VI were treated with two courses of cisplatin, etoposide, and bleomycin (PEB) after orchidectomy. Of these, 29 patients with a follow-up time of more than 2 years are the subject of this report. NSGCT I patients without VI were assigned to a surveillance program and served as controls for the assessment of long-term toxicity. RESULTS: During a median follow-up time of 79 months (range, 27 to 119), two patients relapsed. One developed fully differentiated mature teratoma; the other was a true chemotherapy failure and again developed embryonal carcinoma. Twenty-seven patients (93%) are alive without evidence of disease; one patient (3%) died of progressive testicular cancer and another of lung cancer. The two courses of PEB did not cause any severe acute adverse reactions. The assessment of late sequels of adjuvant chemotherapy based on clinical and laboratory evidence of cardiovascular and pulmonary disease, fertility, and secondary neoplasms, as well as on a psychosocial questionnaire, did not show any significant disadvantages versus the control group. CONCLUSION: Adjuvant chemotherapy with two courses of PEB is an effective and reasonable treatment option for patients with clinical stage I NSGCT who carry a high risk of relapse. No adverse late sequelae were detected within a median follow-up time of more than 6 years.

The importance of tumour volume in the prognosis of radically treated periampullary carcinomas.

OBJECTIVE: To assess the influence of tumour volume on clinicopathological findings and survival time after radical operation for periampullary carcinoma. DESIGN: Retrospective study. SETTING: Kaiser-Franz-Josef-Hospital, Vienna, Austria. SUBJECTS: 72 of 75 consecutive patients who underwent pancreaticoduodenectomy for periampullary carcinoma between 1 January 1979 and 31 December 1991. OUTCOME MEASURES: Cancers were divided into four groups according to volume (mm3) and the incidence of lymph node involvement, infiltration of surrounding tissues and of visceral vessels, and histologically non-radical resections were calculated, as was the length of survival after resection. RESULTS: There were 22 tumours with a volume of 0-2500 mm3 (group 1), 12 with a volume of 2,501-5,000 mm3 (group 2), and 19 each in groups 3 (5,0001-10,000 mm3) and 4 (more than 10,000 mm3). All carcinomas of the common bile duct (n = 5) and the papilla of Vater (n = 18) were in groups 1 and 2, whereas 38 of the 49 carcinomas of the head of pancreas were in groups 3 and 4. Lymph nodes were involved in 3 (14%), 6 (50%), 13 (68%) and 14 (74%); the surrounding tissues were infiltrated in 6 (27%), 8 (67%), 11 (58%) and 12 (63%); the main visceral vessels were involved in 0, 3 (25%), 5 (26%) and 8 (42%); and the resections were histologically not radical in 0, 2 (17%), 7 (37%) and 9 (47%), respectively. There was significant negative correlation (p < 0.0001) between tumour mass and survival. CONCLUSIONS: These results explain at least in part the poorer prognosis after radical resection of carcinoma of the head of the pancreas.

Investigations on the significance of the adenoma-carcinoma sequence in the small bowel.

In view of the rarity of small-bowel epithelial neoplasms as compared with the case for the large bowel, evidence for an adenoma-carcinoma sequence in the small bowel was studied based on a search for data in the medical literature for the years 1927 through 1986. Sufficiently defined data were found for comparison of 185 benign adenomas, 76 adenoma-with-carcinomas, and 1333 carcinomas in patients without familial polyposis disease and for 63, five, and 30, respectively, in patients with disease. For patients without polyposis, it was found that (1) 29.8% of all small-bowel adenomas (33.6% if those at Vater's ampulla are excluded) showed malignancy; (2) the mean and median ages were lower for benign adenoma than for adenoma-with-carcinoma and carcinoma, although the ratios by sex were the same; (3) there is a nearly identical spatial distribution of the three types of epithelial neoplasms within the small bowel; and (4) both the frequency of finding adenomatous residues existing in continuity with carcinoma and the life history of the adenoma-carcinoma sequence are similar in the small bowel as in the large. In comparing these results with those from patients with familial polyposis disease, it was particularly noted that (1) the only difference was that adenomas in familial polyposis occurred earlier and multiply, and (2) the spatial distributions of adenomas and carcinomas for both cases were closely similar. It is therefore postulated that the adenoma-carcinoma sequence is as significant in the small bowels as in the large. A hypothesis regarding the relationship of epithelial neoplasms in people with and without familial polyposis disease is suggested.

[Correlation of tumor site and tumor volume in radical surgery of cancer of the peripapillary area]. / Untersuchungen zur Wechselwirkung von Tumorlokalisation und Tumorvolumen bei radikal operierten Karzinomen der peripapillären Region.

In a group of 52 partial duodenopancreatectomies (34 cancers of the head of the pancreas, 14 cancers of the papilla and 4 cancers of the common bile duct) the dependence of tumour volume and tumour localisation on carcinomatous lymph node involvement, infiltration of surrounding tissues, infiltration of great visceral vessels and not radical resection was determined. The analysis demonstrates that there is significant difference in volume between radically treated carcinomas of the common bile duct, the papilla of Vater and the head of the pancreas with mean volumes of 463:1,851:11,835 mm3 or 1:4:26! Furthermore the investigation shows that for every analysed parameter median volume is larger for positive observations than for negative ones: lymph node involvement 10,606:6,459 mm3, infiltration of surrounding tissues 10,444:6,703 mm3, infiltration of great visceral vessels 14,923:7,144 mm3, not radical resection 18,130:5,343 mm3. From these results it is concluded, that early stages of periampullary carcinomas with a good chance for cure are only present in radically treated cancers of the papilla and the common bile duct. In cancers of the head of the pancreas the significant larger primary cancers and the more advanced staging results in a dismal prognosis.

[Change in the value of palliative interventions in cancer of the head of the pancreas]. / Zum Wandel des Stellenwertes palliativer Eingriffe beim Pankreaskopfkarzinom.

An analysis of 412 patients with carcinoma of the head of the pancreas treated only with palliative procedures revealed remarkable differences in the results following internal anastomosis procedures and external T-tube drainage. The anastomosis group showed in comparing the years 1963-1982 with the years 1983-1987 a decline in the frequency of such procedures from 89% to 54% and a decline of the mortality from 12% to 4% while the survival time (220 days) showed no change. According to the low mortality rate we prefer internal anastomosis procedures to PTCD. However, as the results of T-tube drainage are still poor (mortality rate 36%; survival time 190 days) an attempt of PTCD seems indicated if the untreatable situation is recognized preoperative, as PTCD achieves similar results as T-tube drainage.

Factors affecting mortality in transduodenal sphincteroplasty.

An analysis of 1,200 consecutive transduodenal sphincterotomies performed between 1967 and 1985 is presented herein. The over-all mortality rate was 3.75 per cent. Since 1980, however, the mortality rate has decreased to 2.1 per cent. The mortality rate was influenced by the age of the patient at the time of the operation (p less than 0.005). Furthermore, the mortality rate increased from decade to decade (less than 30 years, zero per cent; greater than 70 years, 6 per cent). The operative mortality rate was also influenced by general risk factors--hypertony (mortality rate of 5.8 per cent, not significant), diabetes (mortality rate of 6.5 per cent, p congruent to 0.05), renal failure (15.5 per cent, p less than 0.005), jaundice (bilirubin level in survivors, 78.3 micromoles per liter and in those who died, 120.4 micromoles per liter, p less than 0.005) and vital indication (mortality rate of 15 per cent, p less than 0.01). Although the indication for sphincterotomy had a small influence on the mortality (papilla stenosis without bile duct stones, 1.7 per cent; papilla stenosis with common duct stones, 3.6 per cent, and impacted stones in the papilla, 5.0 per cent), these small differences are not significant. A significant influence, however, was due to complicating intraoperative findings, such as bilioenteral fistulas (a mortality rate of 10.8 per cent, p less than 0.0005). The fact that the mortality rate increased in patients with T-tube insertion shows that operative problems and complications influence the mortality rate for sphincterotomy. From these results, we concluded that, in the aforementioned risk groups, a preoperative endoscopic sphincterotomy should be strongly considered, as the risk from the surgical procedure is diminished by the endoscopic relief of the obstruction of the biliary tract.

[Hypothesis on the existence of an adenoma-carcinoma sequence in the small intestine]. / Untersuchungen zur Hypothese der Existenz einer Adenom-Karzinom-Sequenz im Dünndarm.

An analysis of a literature survey of 104 adenomas of the ampulla of Vater, 94 of the duodenum and 20 of the jejunum and ileum, as well as 735 carcinomas of Vater's ampulla, 180 carcinomas of the duodenum and 72 carcinomas of the jejunum and ileum, demonstrated, in spite of small case collectives, that there is probably a similar close relationship between adenomas and carcinomas in the small intestine, as in the large intestine. In adenomas of the small intestine signs of malignancy sometimes can be seen, as well as in some case of carcinoma of the small intestine rests of adenomas have been described. The age and sex distribution of the epithelial neoplasms of the small intestine permits an adenoma-carcinoma-sequence. The relative distribution of the adenomas over the different parts of the small intestine corresponds with that of the carcinomas. The adenomas and carcinomas of the small intestine in patients with adenomatosis coli have the same relationship to the neoplasms of the small intestine in patients without adenomatosis coli, as it is valid in the large intestine. The hypothesis of an adenoma-carcinoma-sequence in the small bowel with a great significance, which explains the results best, is therefore proposed. As the distribution of adenomas and carcinomas of the small bowel in patients with and without familial polyposis is equal, the theory is suggested, that the principle of the adenomatosis intestine disease is a general increase of the overall liability to adenomas in the large and small intestine.

[Development of carcinoma of Vater's ampulla in an adenoma. Analysis of a personal case load and review of the literature]. / Zur Entstehung der Karzinome der Papilla Vateri über eine Adenom-Karzinom-Sequenz. Eine Analyse des eigenen Krankengutes und eine Literaturübersicht.

A retrospective analysis was undertaken of our case material of 40 histological preparations of carcinoma of the ampulla of Vater, as well as a survey of the literature of 103 adenomas of the ampulla of Vater. Signs of malignant transformation were detected in 25% of the adenomas, whilst adenomatous residues were identified in 72% of the examined carcinomas of the ampulla of Vater. Thus, an adenoma-carcinoma sequence seems to be as significant in the case of Vater's papilla as in the colo-rectal region. An epidemiological investigation confirms this hypothesis since 1. adenomas of the papilla Vateri develop 4 years prior to a carcinoma and 2. the relative sex distribution of the two diseases is approximately equal.

[Adenomas and carcinomas of the small intestine in familial polyposis and Gardner syndrome--analysis of a literature survey]. / Untersuchungen über Adenome und Karzinome des Dünndarms bei familiärer Polypose und Gardner Syndrom--eine Analyse einer Literaturübersicht.

An analysis of 70 case records from the literature of patients with familial polyposis or Gardner syndrome and adenomas or carcinomas of the small bowel demonstrated that there is no difference between the neoplasms of the small bowel in familial polyposis or in Gardner syndrome. Between the adenomas and the carcinomas of the small bowel it was possible to show, that there exists a similar close relation as in the large intestine. In some carcinomas of the small bowel rests of adenomas can be observed. The peak incidence of small bowel adenomas is more than a decade earlier than that of carcinomas. The distribution of adenomas in the small bowel is quite similar to that of carcinomas. Therefore it can be supposed, that the significance of familial polyposis coli and Gardner syndrome for the importance of an adenoma-carcinoma-sequence in the large bowel is also existing in the small bowel.

[Changes in the value of papilla excision in papilla cancer. A retrospective study]. / Die Wandlung der Wertigkeit der Papillenexstirpation beim Papillencarcinom. Eine retrospektive Analyse.

A retrospective analysis of 56 patients with a carcinoma of Vater's ampulla in the years 1956-1983 demonstrated a steadily increasing resection index of duodenopancreatectomy from 34% (1961-1965) to 86% (1981-1983), although the rate of mortality was 0% since 1975. The reason for the increasing resection index was the treatment of all patients since 1975 by only one team of operators and the improvement of peri- and postoperative medicine treatment. Thus it was possible to perform a duodenopancreatectomy without operative mortality even in patients in the 8th decade of life. Therefore an indication for a local excision of the ampulla no longer seems to be justified.

[Gallbladder cancer with and without cholelithiasis--a comparative study of 19,167 autopsy records]. / Das Gallenblasenkarzinom mit und ohne Cholelithiasis--eine vergleichende Untersuchung von 19.167 Obduktionsprotokollen.

An analysis of 19,167 autopsies revealed, as a conformity of gallbladder carcinomas with and without cholelithiasis a statistical proved preference of women in gallbladder carcinomas. The difference in the age and relative sex distribution of gallbladder carcinomas with and without concrements demonstrates the influence of cholelithiasis in gallbladder carcinomas.

[Primary gallbladder cancer]. / Das primäre Gallenblasenkarzinom.

118 surgically-treated patients with gall bladder carcinoma and 407 autopsies recording this diagnosis were reviewed and analysed with a view to investigating the reasons for the bad prognosis of this disease. An early tumour stage was seen in only 5.9% of the surgical patients. A possible reason for the bad results even at an early tumour stage is undertreatment by simple cholecystectomy. In advanced stages of gall bladder carcinoma palliative operations have a better prognosis than diagnostic laparotomies. Prevention of gall bladder carcinoma through prophylactic cholecystectomy in the case of documented lithiasis failed to prevent gall bladder carcinoma in our group of patients because only 9% of the patients with gall bladder carcinoma had been diagnosed as having lithiasis in time to consider cholecystectomy as a preventive measure.

[Incidence of fatal, biliary pancreatitis--an analysis of 19167 autopsy protocols]. / Zur Häufigkeitsverteilung der letalen, biliären Pankreatitis--eine Analyse von 19167 Obduktionsprotokollen.

19 167 autopsy records are analysed to the frequency and to risk-groups for a lethal biliary pancreatitis. In cholecystolithiasis biliary pancreatitis was the far most stone caused lethal complication, in choledocholithiasis the 4. An increased incidence of the lethal biliary pancreatitis was found in younger individuals, in male individuals and in choledocholithiasis.