Intensive Chemotherapy with Cisplatin, Doxorubicin, Cyclophosphamide, Etoposide and Granulocyte Colony-stimulating Factor for Advanced Thymona or Thymic Cancer: Preliminary Results

A study was conducted to evaluate the impact of cisplatin, doxorubicin,cyclophosphamide and etoposide (PACE) with granulocyte colony-stimulatingfactor (G-CSF) on advanced thymoma or thymic cancer. BetweenAugust 1989 and December 1994, 14 patients with invasive, metastaticor recurrent thymoma or thymic cancer were treated with cisplatin(80 mg/m², on day 1), doxorubicin (45 mg/m², on day 1), cyclophosphamide(800 mg/m², on day 1) and etoposide (80 mg/m², on day 1–3)with G-CSF (90 mg/m², on day 5–18) at the National CancerCenter Hospital, Tokyo. Courses were repeated every 3 or 4 weeksfor a maximum of 4 cycles. Twelve patients were treated with2 or more courses of PACE. Two patients were treated with onlyone course, one refused and another required emergency thoracicradiotherapy after one course of PACE. Six patients had partialresponses (3 thymomas and 3 thymic cancers) but there were nocomplete remissions (response rates, 42.9%; 95% confidence interval,17.7% to 71.1%). Moderate hematological toxicities were observed:grade 3 or 4 leukopenia, neutropenia, anemia and thrombocytopeniain 10, 13, 8 and 6 patients, respectively. Six patients developedinfections that required antibiotics. Surgical resection orthoracic radiotherapy after PACE treatment was performed in2 and 7 patients, respectively. The overall median survivaltime was 14.7 months (range, 5.9 to 59.7 months). For 9 patientswho had received no prior treatment before chemotherapy, themedian survival time was 8.9 months, and one patient survivedfor 4 years and is still alive. In conclusion, PACE with G-CSFfrequently produces objective remissions in patients with advancedthymoma or thymic cancer. A large-scale intergroup study isnecessary to determine the impact of this regimen on advancedthymoma and thymic cancer.     

Frequent Genetic Instability in Small Intestinal Carcinomas

To determine whether genetic instability plays a part in the development of digestive tract carcinomas, we analyzed 3 microsatellite loci isolated from tumors and surrounding normal tissue samples obtained during surgery. The polymerase chain reaction (PCR) technique was used to assess differences between tumor and matched normal DNAs. Replication errors (RERs) were observed in 3 of the 29 cases (10%) of gastric carcinoma and in 11 of the 72 cases (15%) of colorectal carcinoma. None of the 13 (0%) esophageal carcinoma cases showed any RER, but 5 of the 11 cases of small intestinal carcinoma (45%) had RERs, a significantly frequent finding. These results suggest that genetic instability plays an important role in the pathogenesis of small intestinal carcinomas.     

Reactivity of anti-AraC-resistant cell monoclonal antibody, YU-311, in formalin-fixed paraffin-embedded specimens of various hematopoietic disorders

YU-311 is a monoclonal antibody reacting with cytosine arabinoside (AraC)-resistant human leukemic cell line and identifies a 92 kDa membrane protein. We have examined YU-311 reactivity with various hematopoietic disorders by an immunohistochemical method and evaluated a correlation between YU-311 expression and refractoriness to chemotherapy, retrospectively. YU-311 reacted with AraC-resistant human leukemia cell lines, in which a 92 kDa membrane protein was identified by Western blotting, whereas drug-resistant cell lines to other than AraC failed to express YU-311 antigen. The frequency of YU-311 positivity was significantly increased in relapsed cases. Only five cases were positive for YU-311 at diagnosis and 24 cases at relapse. Unexpectedly, only eight cases of relapsed leukemia/lymphoma expressed YU-311 and P-glycoprotein simultaneously. Most of the YU-311-positive relapsed cases showed clinical refractoriness for chemotherapy and then failed to induct complete remission or relapsed at short periods with short disease-free duration. These findings indicate that YU-311 expression is closely associated with some aspects of drug resistance, especially with AraC resistance.     

Inhibitory Effect of a Traditional Chinese Medicine, Juzen-taiho-to, on Progressive Growth of Weakly Malignant Clone Cells Derived from Murine Fibrosarcoma

We have investigated the inhibitory effect of oral administration of Juzen-taiho-to , a Kampo (Chinese herbal) medicine, on progressive growth of a mouse fibrosarcoma. Spontaneously regressive QR-32 tumor cells were able to grow progressively in vivo when coimplanted s.c. with a foreign body, gelatin sponge, whereas QR-32 cells alone gradually grew for over 15 days after inoculation and thereafter regressed for up to 25 days. Oral administration of Juzen-taiho-to (40 mg/day/mouse) for 7 days after inoculation of QR-32 cells with gelatin sponge resulted in significant inhibition of tumor growth and prolongation of the survival of the tumor-bearing mice. This growth-inhibitory effect of Juzen-taiho-to observed on day 25 was dose-dependent over the dose range from 4 to 40 mg/day. Treatment with Juzen-taiho-to for 7 days before tumor inoculation with gelatin sponge also significantly suppressed tumor growth examined on day 25, as did the administration of bismuth subnitrate, which is well known to induce metallothionein, an antioxidant. On the other hand, inoculation of progressed tumor cells (QRsP) resulted in growth without gelatin sponge, leading to death in syngeneic mice. Administration of Juzen-taiho-to for 7 days after inoculation of QRsP cells resulted in a decrease of the tumor growth and prolongation of the survival of mice, but the effect was less than that on the growth of QR-32 regressor tumor after coimplantation with gelatin sponge. These results suggest that the inhibitory effect of Juzen-taiho-to is partly associated with prevention of gelatin sponge-elicited progressive growth, probably mediated by endogenous factors including antioxidant substances, in addition to the augmentation of host-mediated antitumor activity.     

Extracorporeal membrane oxygenation — succesful treatment after repair of congenital diaphragmatic hernia

A case of congenital diaphragmatic hernia successfully treated by extracorporeal membrane oxygenation (ECMO) is reported. A female baby weighing 3.4 kg was admitted 3 h after birth because of respiratory distress. Her left diaphragmatic hernia was repaired 5 h after birth by laparotomy. The AaDO₂ levels were higher than 500 mmHg before and after the operation. She was managed by high-frequency ventilation and administration of tolazoine for the first 58 h. These effects were temporary, however, and she reverted into persistent fetal circulation three times. Therefore, ECMO was started at 59 h after birth. When the flow rate of ECMO reached 320 ml/min, the newborn entered a state of complete lung rest. Her general condition improved slowly, and ECMO was successfully terminated after 60 h of bypass. This was the first successful case in Japan. Offprint requests to: M. Nagaya     

Computed tomography in the diagnosis of primary tumors of the petrous bone

This paper constitutes an evaluation of 23 patients with signs and symptoms of 4 types of tumors: 6 congenital epidermoids, 3 cases of meningiomas presenting within the temporal bone, 2 cases of jugular fossa schwannomns, 3 cases of glomus tympanicum, and 9 selected cases of glomus jugulare tumors. Since these tumors occur insidiously and are located in an inaccessible region of the skull, they are usually not diagnosed until they reach considerable size and cause multiple cranial nerve deficits or intracranial complications. Assessment of these tumors and subsequent surgical management depend primarily on the preoperative radiographic findings. CT and dynamic CT study have proven to be extremely valuable and accurate in the diagnosis of these lesions. Epidermoids have a characteristic CT appearance. Dynamic CT is often helpful in differentiating glomus tumors from meningiomas and schwannomas. Involvement of the middle ear, labyrinth, intracranial, and extracranial components of these tumors can be best evaluated by CT. This paper places special emphasis on congenital cholcsteatoma (epidermoid) and draws relevant conclusions about the diagnostic work-up.     

Effects of growth hormone on testicular dysfunction induced by cyclophosphamide (CP) in GH-deficient rats

Growth hormone (GH) is known to accelerate spermatogenesis and maintain gonadal function. In this study, we evaluated the effect of GH on recovery from testicular damage induced by cyclophosphamide (CP). Eleven- to fourteen-week-old GH-deficient Lewis rats (dw/dw) were divided into 4 groups (n = 10 each), with one group serving as controls. In the CP group, CP was intravenously administered in daily doses of 50 mg/kg for 2 days, followed by daily doses of 10 mg/kg for the next 3 days. In the GH group, rat GH was subcutaneously administered at a daily dose of 0.3 mg/kg until the rats were sacrificed. In the CP/GH group, GH and CP administration were started simultaneously. In the CP/preGH group, GH administration was started 14 days before CP administration. Five rats from each group were sacrificed at days 14 and 28 after administration of CP. Spermatogenesis was then evaluated morphometrically by counting numbers of cells at several stages of the spermatogenic cycle. On day 14, there were no significant differences in the numbers of the spermatocytes between CP and CP/GH group. On day 28, the numbers of spermatocytes and motility of spermatozoa in CP/GH group were greater than those of CP group were. In the CP/preGH group, these effects of GH administration were not observed. These results suggested that administration of GH improved testicular function damaged by CP under GH-deficient condition, when GH and CP administration are started simultaneously.     

Functional analysis of the tissue-engineered stomach wall

We have established a method for in situ tissue engineering of the stomach in a canine model using an acellular collagen scaffold graft. The current study was conducted to evaluate the functional aspects of the tissue-engineered stomach wall. The anterior wall of the stomach in beagle dogs was replaced with a collagen sponge scaffold measuring 4 x 4 cm. At 16 weeks after implantation, the animals were sacrificed and the stomach specimens were evaluated immunohistochemically and physiologically. Regeneration of the proton pump and thin muscle layer, which are essential for mechanical and chemical digestion by the stomach, was observed in the tissue-engineered gastric tissue. However, acetylcholine-induced contraction was not observed in the tissue-engineered stomach wall. Although there is still room for improvement, the tissue-engineered stomach wall had a highly organized structure, and it is anticipated that this approach could eventually become an alternative for stomach reconstruction after gastrectomy.