Effects of newly introduced chemotherapeutic agents on a cytogenetically highly malignant neuroblastoma, xenotransplanted in nude mice.

A human neuroblastoma xenograft, designated TNB9, was used in this experiment. This xenograft is known to have a homogeneously staining region (HSR) on chromosome 20 and to exhibit 60- to 100-fold amplification of clones 8, G21 and N-myc, and showed a rapid tumor weight doubling time of 5.9 days; it represents one of the most malignant strains of human neuroblastoma. The effects of nine different chemotherapeutic agents on this xenograft were studied according to the standard Battelle Columbus Laboratories protocol, and the in vivo chemotherapeutic sensitivity assessment disclosed that Mitomycin C, Ifosfamide, and Carboplatin were highly effective against it, while VP-16, NK-171, 5-Fluorouracil, and THP-Adriamycin were ineffective. Cytogenetic and molecular-cytogenetic analyses suggest that the present data may accurately predict the clinical results with these chemotherapeutic agents in treating patients in advanced stages, as did those from our previous studies. Inclusion of Mitomycin C, Ifosfamide, and/or Carboplatin into a new chemotherapeutic protocol may be recommended.

[A multicenter comparative study in patients with liver metastasis to compare tegafur in new forms with existing drugs. SF-RC.SF-SP Comparative Study Group].

A multicenter comparative study was carried out in 101 patients with liver metastasis to compare tegafur in a new oral form (Sunfural S) and tegafur in a new soft-capsule suppository form (Sunfural Rectal Capsules) with existing drugs. Sunfural S showed a tendency toward high plasma and tissue levels as compared to existing drugs, and clinically, Sunfural S produced survival times that surpassed those of existing drugs. Liver metastasis at the present time has few effective treatments, but we expect that anticancer effects will be obtained through the administration of new drugs with improved bioavailability.

[A resected case of recurrent carcinoma of the right colon ten years after the initial operation].

A 59 year-old female complained of right lower abdominal mass. She underwent radical operation 10 years ago for the right colonic cancer staged Dukes C. She had passed 10 years without any sign or symptom of recurrence. She noticed a egg-sized tumor in the right lower abdomen unexpectedly one month ago when she got a bruise on that region, and then the tumor grew rapidly. Preoperative examinations, including barium enema, abdominal computerized tomography and so on, suggested a extraluminal tumor with infiltration to the colon. Laparotomy revealed that the tumor originated from the right paracolic gutter. The tumor sized 18 X 11 X 8 cm was resected and histological diagnosis was adenocarcinoma with the similar structural pattern to the initial specimen. On the basis of both operations and histological findings, we concluded that free tumor cells might be implanted in the large raw surface of the right dorsolateral abdominal wall, which was created by surgical incision at the initial operation, and subsequently appeared as a local recurrence after 10 years interval.

[A case of multiple aneurysms originated from the superior mesenteric artery branch, and a review of literature].

A case of multiple aneurysm of superior mesenteric artery (SMA) branch is presented. A 54-year-old man with sudden onset of back pain was admitted to our hospital. Severe abdominal pain was developed and he fell into shock. Selective angiography of the SMA demonstrated aneurysm of the accessory middle colic artery to splenic flexure. Laparotomy disclosed much intraperitoneal blood and a large clot under the pancreatic body with a gushing hemorrhage. The bleeding vessel was ligated and sutured. The postoperative course was uneventful, but the subsequent angiography revealed another aneurysm of SMA branch, which was not able to be seen in the previous angiography because of overlapping with main SMA trunk. Resection of the aneurysm was done. The etiology of the latter aneurysm was suggested to be medial degeneration histologically. Fourty-nine cases of SMA aneurysm from the Japanese literature were reviewed and discussed. Emphasis is placed on early diagnostic laparotomy for appropriate management and the role of angiography in confirmation of bleeding site in case of spontaneous intraabdominal hemorrhage.

[Mixed ductal and acinar cell cancer of the pancreas head; report of a case].

A 63 year old Japanese man was admitted in Feb. 1983, with his chief complaint of upper abdominal pain. Physical examination showed only resistance in the right hypochondrium on palpation, but no icteric conjunctiva and skin. A large global tumor of the pancreas head was visualised as a hyperechoic mass with irregularly shaped cystic cavity in ultrasonography, as a hypervascular mass with lucent area in celiac arteriography, and as a mass lesion with low density area in body computerized tomography. Cancer cells were histologically confirmed on specimens taken by fine needle aspiration biopsy under ultrasonic guidance. Cancer of 6.5 X 6.0 X 4.0 cm in size was resected by pancreaticoduodenectomy. Four months after operation, two liver metastatic nodules were resected by right hepatic lobectomy. Histologically, tumor was composed of two characteristic patterns, acinar cell cancer and duct cell cancer, which were confirmed by immunohistochemical techniques. The patient is doing well 3 years and 3 months postoperatively without evidence of recurrent cancer. To our best knowledge, this case is the seventh of mixed ductal and acinar cancer in the world, but the previous 6 cases were reported on autopsy specimens.

[Clinical study on glucose intolerance and insulin response in obstructive jaundice].

Insulin responses to oral glucose loads were studied in patients with obstructive jaundice and compared with those of other liver diseases (fatty liver, chronic hepatitis and liver cirrhosis), pancreatic diseases, and definite diabetes mellitus. Compared with their corresponding glucose intolerance, high insulin responses were characteristic in fatty liver, chronic hepatitis and liver cirrhosis, and insulin responses and insulinogenic index decreased in chronic hepatitis and liver cirrhosis as glucose intolerance progressed. In obstructive jaundice with the pancreatic ducts stenotic or obstructed, insulin responses were suppressed in comparison with their corresponding glucose intolerance, and also insulinogenic index were below 0.5 in most of the cases. However, in obstructive jaundice with the pancreatic ducts intact, high insulin responses were observed in almost half of the cases with insulinogenic index above 0.5, and insulin response and insulinogenic index decreased as glucose intolerance progressed. While most cases of fatty liver, chronic hepatitis and liver cirrhosis with insulinogenic index above 0.5 were distributed in non-diabetes zone in sigma BS-sigma IRI plane (Kosaka's), those with insulinogenic index below 0.5 were distributed in intermediate zone. Most cases with obstructive jaundice with pancreatic ducts stenotic or obstructed, had insulinogenic index below 0.5 and were distributed in diabetes zone. However, half of cases with obstructive jaundice with pancreatic ducts intact, had insulinogenic index above 0.5 and their distribution in non-diabetes zone, while the other half had insulinogenic index below 0.5 and their distribution in diabetes zone. Therefore, it may be concluded that insulin responses increase at the early stage of obstructive jaundice mainly under influence of liver dysfunction itself, but that insulin response is suppressed at later stage of obstructive jaundice as pancreatic islets are affected.

Characterization of mice bearing subclones of colon 26 adenocarcinoma disqualifies interleukin-6 as the sole inducer of cachexia.

A subclone (clone 20) of chemically induced, murine colon adenocarcinoma with a potent ability to induce cachexia and another subclone (clone 5) without such an activity were transplanted to syngeneic mice (CDF1) and their tissue weights, blood components and cytokine levels in sera were compared. Mice transplanted with clone 20 showed a profound body-weight loss by 15 days after inoculation when the tumor accounted for less than 1% of the body weight, along with marked reduction of food and water intakes. Thereafter, they transiently gained in body weight with restoration of food and water intakes. Thus, the change in body weight was biphasic and not proportional to the tumor size. Body fat was lost preferentially, accompanied with a decrease in plasma triglyceride levels. The thymus contracted remarkably, and the peripheral lymphocyte count decreased extensively. Mice transplanted with clone 5, in contrast, did not show any of these changes characteristic of cachexia. Serum concentration of interleukin-6, which has been proposed as the principal inducer of cachexia in mice with colon 26, increased in mice with clone 5 to levels comparable to those in mice with clone 20. The changes in mice bearing clone 20 could not all be explained in terms of known biological activities of interleukin-6. Additional unknown factors, therefore, are presumed to contribute to cachexia in mice with clone 20. Identification of them should be helpful in the care of cachectic patients.

Manifestations of cancer cachexia induced by colon 26 adenocarcinoma are not fully ascribable to interleukin-6.

In order to further clarify the role of interleukin 6 (IL-6) in the pathogenesis of cachexia, recombinant human IL-6 (hIL-6) was administered s.c. by osmotic pump for 9 days at a dose of 1 or 10 micrograms/day into CDF1 mice inoculated with a non-cachexia-inducing subclone of colon 26 adenocarcinoma (clone 5), or with a cachexia-inducing subclone (clone 20) of this malignancy. The serum level of IL-6 in non-cachectic mice with clone-5 tumors was 35% lower than in cachectic mice bearing clone 20 of colon 26 adenocarcinoma on the 19th day after tumor inoculation. IL-6 administration induced anemia, thrombocytosis and visceral organ hypertrophy not only in mice with clone-5 tumors but also in control mice with no tumor burden. Lipolysis and proteolysis became conspicuous when a large dose (10 micrograms/day) of IL-6 was infused into mice with clone-5 tumors. However, IL-6 supplementation did not induce loss of body weight, a decline in food intake or lymphocytopenia, which were characteristically observed in cachectic mice with clone-20 tumors. In conclusion, IL-6 appears to be a permissive factor for the development of cachexia but, while it can induce some of the symptoms typical of cachexia, it cannot in itself induce the full cachectic syndrome.

A newly developed fine-caliber endoscope for peroral cholangiopancreatoscopy.

We have developed a new fine-caliber (2.09 mm outer diameter) endoscope for peroral cholangiopancreatoscopy. The endoscope contains one image transmission fiber, 12 light guide fibers (the transmitter of light from the light source) and a working channel (a lumen for the guide wire and rinsing). The working channel, whose bore is 0.72 mm, is located centrally within the endoscope. The endoscope can be introduced reliably into the bile and pancreatic ducts using the same techniques as those for endoscopic nasobiliary drainage through the instrumental channel of a duodenoscope for examination without pretreatment of the papilla of Vater. Two patients with lesions of the pancreatic duct and seven patients with lesions of the bile duct suspected or detected by endoscopic retrograde cholangiopancreatography (ERCP) were examined. Direct inspection of the biliopancreatic duct not only provided enough information to make a definite diagnosis, but also revealed lesions that were not detectable by ERCP or other examinations.

Factors influencing insulin secretion after pancreatoduodenectomy.

Preoperative patients with periampullary cancer had a higher mean sigma IRI value than that of normal controls, and also had a delayed pattern of insulin response and a lower insulinogenic index during oral-GTT. sigma IRI levels after pancreatoduodenectomy were similar to those of normal controls when the pancreatic remnants were histologically intact at the time of surgery. Postoperative sigma IRI levels could not be predicted based on the extent of histological fibrosis of the distal pancreas at the time of surgery. Patency of pancreatojejunostomy was obtained with the modified Warren's method in 39 out of 40 patients, and sigma IRI levels were maintained up to 5 years postoperatively. No significant difference was found in sigma IRI levels between pancreatoduodenectomised patients with the conventional Roux-en-Y procedure and those with the inverted Roux-en-Y with jejunal interposition. The mean insulin peak value and sigma IRI level were higher in pancreatoduodenectomised patients than in normal controls, and higher in gastrectomised patients than in pancreatoduodenectomised patients. Pancreatoduodenectomy with superior mesenteric arterial dissection resulted in remarkably low sigma IRI levels.

Lidocaine metabolite formation as a measure of perioperative liver function.

In order to determine whether lidocaine metabolism, as the formation of monoethylglycinexylidide (MEGX), could be used as a quantitative index of perioperative liver function, serum levels of MEGX in 31 surgical patients were measured and compared with the results of conventional liver function tests. A significant correlation was found between the values of MEGX and ICGR15 in 20 of the 31 patients. The values of ICGR15 were lower than 20% in patients whose MEGX values were above 60 ng/ml and 20% or higher in those with MEGX values of lower than 60 ng/ml. There was also a significant correlation between MEGX values and antithrombin III values, and between MEGX values and the postoperative maximum levels of aspartate aminotransferase. However, no correlation was found between MEGX values and other preoperative conventional liver function tests in any of the 31 patients. We suggest that a cut-off MEGX value of 60 ng/ml be used as an indicator for satisfactory preoperative liver function. MEGX formation could be a useful prognostic index for patients who have undergone surgical procedures for liver disease, and employed as a quantitative assessment of perioperative liver function.