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We established a transition program from hospital to home administration of blinatumomab using the CADD-Legacy® pump and evaluated its safety and feasibility in 2 pediatric patients. The program recommended that repeated overnight stays with continued hospitalization would help patients safely transition to home administration of blinatumomab. Pediatric patients who do not attend school, such as preschoolers, or who return to their original school, can be transited to an outpatient setting if people caring for pediatric patients, including teachers in the school, are educated.

5-aminolevulinic acid hydrochloride is a highly effective drug in reducing tumor residuals in transurethral resection of the bladder tumors; however, hypotension is a serious side effect that causes clinical problems. To avoid serious side effects, a pharmacist, in consultation with a physician, decided to discontinue the antihypertensive medication, and the effect of this pharmaceutical intervention was examined retrospectively. This study included patients who received 5-aminolevulinic acid hydrochloride at Gifu Municipal Hospital and were instructed to continue receiving their usual antihypertensive medication on the day of surgery. The control group comprised 17 patients before the pharmaceutical intervention, and the intervention group comprised 18 patients after the pharmaceutical intervention. The difference in systolic blood pressure before and after 5-aminolevulinic acid hydrochloride administration was -19.4±22.5 mmHg in the control group and -2.8±16.0 mmHg in the intervention group. The intervention group showed a significantly lower decrease in blood pressure(p=0.019). Intervention to avoid hypotension through the collaboration between physicians and pharmacists may be effective in improving the safety of 5-aminolevulinic acid hydrochloride.

This study aimed to identify the risk factors of febrile neutropenia(FN)onset associated with melphalan(L-PAM)therapy. Thirty-nine patients(21 men, 18 women)were administered L-PAM intravenously for multiple myeloma(MM)from April 2011 to February 2022 at the Department of Hematology of Gifu Municipal Hospital. Patients were classified into those with and without FN(Grade 3 or higher), complete blood count and liver function tests were performed immediately before starting therapy. Univariate analysis with Fisher's exact probability test was performed. Factors with p<0.2 were considered as independent variables for multivariate analysis in the multiple logistic regression analysis. A multivariate analysis with 2 independent variables, lactate dehydrogenase(LD)level>222 U/L(upper limit of the facility reference value)and white <3.3×103/μL(lower limit of the facility reference value)from the univariate analysis, and FN onset(Grade 3 or higher)as the dependent variable showed that LD level>222 U/L(odds ratio: 6.33, 95% confidence interval: 1.12-35.8, p=0.037)was a significant factor. In conclusion, patients with LD levels >222 U/L immediately before starting therapy require adequate monitoring for FN onset following L-PAM administration.

Skin complication caused by anti-programmed cell death-1(PD1)antibody is a typical immune-related adverse event. We designed this study to clarify the correlation between risk factors(patient's background and laboratory data)and skin toxicity( rash and eruption, excluding itch)after administration of either nivolumab or pembrolizumab. From February 2016 to January 2018, we evaluated the clinical outcomes of 54 patients who were administered anti-PD1 antibody. The patients were divided into 2 groups: 9 patients with skin eruption caused by anti-PD1 antibody(skin eruption group)and 45 patients without skin eruption caused by anti-PD1 antibody(non-skin eruption group). Univariate analysis revealed a significant difference in eosinophil counts in both the groups before anti-PD1 antibody administration(>300/µL)(p=0.020). Factors with p<0.2 in the univariate analysis and 4 factors, age(<65 years of age), sex(male), allergy(+), and pembrolizumab, likely to be related to the appearance of skin eruption, were examined by multivariate analysis. Consequently, eosinophil count before anti-PD1 antibody administration(>300/µL)was identified as a risk factor (odds ratio: 9.530, 95% confidence interval: 1.260-71.80). In conclusion, we suggest that cases with an increased eosinophil count before anti-PD1 antibody administration(>300/µL)may be associated with the appearance of skin eruption.

Using electronic medical charts at the department of pharmacy of Gifu Municipal Hospital, we constructed a new support system for the prescription inspection of anticancer drug injection preparation via quality control. The system comprises: (1)a "regimen inspection sheet" that can be easily used to check the regimen and clinical laboratory data of patients before the administration of anticancer drugs and(2)an "instruction sheet confirming implementation" that can conveniently confirm the latest clinical laboratory data used to decide the administration of anticancer drugs. Using this system, the safety of anticancer drug administration and work efficiency may be improved.

Skin reactions to nivolumab are typical immune-related adverse events. We investigated the relation between patient background and test values before nivolumab administration and skin reactions. From February 2016 to February 2017, we evaluated the clinical outcomes of 21 patients who were administered nivolumab. Patients were divided into 2 groups: 3 cases of skin reactions to nivolumab(skin reaction group)and 18 cases without skin reactions to nivolumab(non-skin reaction group). In the skin reaction group, the numbers of eosinophils and basophils before nivolumab administration were significantly higher than those in the non-skin reaction group(p=0.0015 and p=0.0075, respectively). It was suggested that the numbers of eosinophils or basophils before nivolumab administration might be associated with the appearance of skin reactions.

A 68-year-old woman with a 5-year history of an untreated left breast tumor presented to our hospital. She was admitted for untreated diabetes and severe anemia. The cause of the anemia was bleeding from the tumor, and she was referred to our department. She was diagnosed with T4bN0M0, stage IIIb breast cancer. First, we initiated hormonal therapy. However, the tumor did not decrease in size. We then administered chemotherapy. The tumor markedly decreased in size, and mastectomy and axillary lymph node dissection were performed. The response was a pathological complete response. She is currently undergoing hormonal therapy at the time of this writing.

We report 3unusual cases of cancer of unknown primary(CUP)with a long-term survival after chemotherapy. A 56-yearold man was diagnosed as having CUP with invasion of an enlarged carcinoma 20 cm in size to the pancreas and peritoneal dissemination. He received chemotherapy with paclitaxel, carboplatin, and gemcitabine. After the chemotherapy, CT scan and PET-CT revealed no evidence of disease, so tumor resection was performed. The subsequent pathological findings revealed no cancer and a complete pathological response. The patient is currently alive 4 years after the first surgery, without evidence of recurrence and adjuvant chemotherapy. A 60-year-old man was diagnosed as having CUP with an undifferentiated carcinoma and lymph node metastasis. He received chemotherapy with paclitaxel, carboplatin, and gemcitabine. However, unanticipated adverse events(finger ulcer)occurred. Thus, the chemotherapy was changed to paclitaxel, carboplatin, and etoposide. The patient is currently alive 4.2 years after the first chemotherapy, without evidence of recurrence. A 59-year-old man was diagnosed as having CUP with neuroendocrine carcinoma(NEC)and lymph node metastasis. He received chemotherapy with irinotecan and cisplatin. The lymph node metastases disappeared, but bone metastasis was found. The chemotherapy was changed to paclitaxel, carboplatin, and etoposide. The patient is currently alive 3.5 years after the first chemotherapy, without evidence of recurrence. We report 3rare cases of high-grade malignant CUP with complete pathological response, partial response, stable disease, and long-term survival after chemotherapy.

A 44-year-old woman was diagnosed cT4bcN3cM1(LYM), Stage IV triple-negative breast cancer.Enhanced computed tomography revealed ipsilateral axillary lymph node metastasis, 10 cm in diameter.The supraclavicular and cervical lymph nodes also had metastases.She received paclitaxel(90mg/m2, on days 1, 8, and 15 every 4 weeks)in combination with bevacizumab(10mg/kg, on days 1 and 15 every 28 days).Her height was 165 cm, and her body weight was 100 kg.After 1 course of chemotherapy, a metastatic axillary lymph node with necrotic changes was removed spontaneously.A few days later, she experienced severe bleeding from her axillary artery, and she went into hypovolemic shock.Despite undergoing surgical hemostasis, the bleeding recurred twice, so we performed coil embolization of her subclavian artery.Thirty -five days after the first occurrence of bleeding, the patient died of sepsis and ARDS due to left arm necrosis.Bevacizumab is effective for the treatment of large tumors, but when the tumor is close to an artery, clinicians should be wary of fatal bleeding after necrosis.

Risk factors for hypokalemia were analyzed in patients who received anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs) at Gifu Municipal Hospital between February 2010 and March 2013. Subjects were 51 patients (27 men and 24 women) with the median age (interquartile range) of 66 (63-72) years. The study period started from the initiation of anti-EGFR MoAbs administration and ended 4 weeks after administration was completed. Patients were categorized into the side effect group if both minimum serum potassium (Min S-K) grade and b grade (pre-treatment S-K grade-Min S-K grade) were B1; otherwise, they were placed into the no side effect group. Univariate analysis for factors to prevent the side effect identified the "concomitant use of hyperkalemia-inducing drugs" to be statistically significant (p=0.010). Multivariate analysis was conducted on factors with a p value of <0.25 in the univariate analysis and on "concomitant use of hyperkalemia-inducing drugs," which was likely to clinically affect S-K decrease, although its p value was >0.25. It showed that "concomitant use of hyperkalemia-inducing drugs" was a significant risk-prevention factor (odds ratio: 0.138, 95% confidence interval[CI]: 0.033-0.581, p=0.007). In conclusion, "concomitant use of hyperkalemia-inducing drugs" is a factor associated with preventing hypokalemia accompanying anti-EGFR MoAbs administration.

The onset of thrombocytopenia and related factors was analyzed in patients with multiple myeloma (MM) who were receiving lenalidomide (Len) therapy at the Department of Hematology, Gifu Municipal Hospital between July 2010 and March 2014. We included 28 MM patients (18 males and 10 females) with a median age of 70.5 (range: 55-84) years. The patients were examined from the start of Len therapy until treatment discontinuation, prolongation, or dose reduction. A significant correlation was observed between platelet (Plt) count prior to the start of Len therapy (pre-treatment Plt) and the difference between pre-treatment Plt and the minimum Plt up to the point in time of treatment discontinuation, prolongation, or dosage reduction (min-Plt) (r=0.674, p<0.001). Univariate analysis revealed that factors causing thrombocytopenia of grade 2or above as a side-effect showed a significant difference when the Plt count was below the lower limit of the normal value (<14.0×10(4)/µL)(p=0.011). Factors with p<0.25 in the univariate analysis and daily dosage of Len were examined by multivariate analysis; thus, a Plt count below the lower limit of the normal value was identified as a factor (odds ratio: 15.12, 95% confidence interval [CI]: 1.712-133.5, p=0.015). In conclusion, we suggest that a Plt count below the lower limit of the normal value prior to the start of Len therapy is a prognostic factor for thrombocytopenia as a side-effect of Len therapy.

Imatinib was administrated to a 38-year-old woman with chronic myeloid leukemia(CML). A major molecular response (MMR)(≤5 copies/0.5 μgRNA in Amp-CML detected using the transcription mediated amplification/hybridization protection assay(TMA/HPA)method)was achieved in 18 months. She maintained MMR for 10 months, and wished to become pregnant. Imatinib was stopped intentionally because she wished to plan a pregnancy, but we prescribed interferon alpha (IFN-a)due to the likelihood of the CML recurring after pregnancy. The nausea caused by IFN-a was improved by administrating it during the night, and she gave birth to a healthy baby by a normal delivery, whilst maintaining MMR. In this case, IFN-a treatment gave good clinical results, the patient's prognosis was improved, and she could maintain a good quality of life. We consider this to be an informative example of IFN-a therapy for CML during pregnancy.

We investigated factors influencing the occurrence of infusion reactions after initial treatment with rituximab. We included patients who were administered rituximab for the treatment of B-cell non-Hodgkin's lymphoma at the Gifu Municipal Hospital Hematology from February 2010 to March 2013. Fifty-one patients were included; their median age was 72(44-87)years, and 31 were men and 20 were women. We defined the index of infusion reaction as the maximal change in body temperature within 24 hours from the administration of rituximab and evaluated the correlation with change in body temperature and each factor, and differences of change in body temperature between the upper and lower groups divided by standard value of each factor by using the t test without correspondence. The "2,000 U/mL or less group"of soluble interleukin-2 receptor(sIL- 2R)levels and the "over 2,000 U/mL group"showed significant different(p=0.014). The "double value or less group"of a standard value(211 IU/L)and "over double value group"showed significantly different lactate dehydrogenase(LDH)levels (p=0.017). The "lower limit or less group"of the standard value(men: 13 g/dL, women: 12 g/dL)and the "over lower limit group"showed significantly different hemoglobin(Hb)levels(p=0.020). In conclusion, the levels of sIL-2R, LDH, and Hb may predict the occurrence of infusion reaction after the initial administration of rituximab in patients with B-cell non-Hodgkin's lymphoma.

Myeloid-derived suppressor cells(MDSCs) have been reported to be induced by inflammation, to suppress immune function, and promote tumor progression, and to be found in circulating blood, tumor tissue, and lymph nodes. MDSCs were found in pleural effusions and ascites of patients with malignant diseases and these results are described in this report. Changes in the levels of MDSCs during clinical responses to cancer chemotherapy are also reported. MDSC levels in malignant effusions have also been shown to change with the levels of MDSCs in peripheral blood and with clinical responses. MDSCs seem to play an important role in inflammation that is strongly related to advancing malignant diseases. The results also suggested that MDSCs may be reduced after effective chemotherapy, which may be effective as an adjuvant treatment with cancer immunotherapy.

Myeloid-derived suppressor cells (MDSCs) are one of the major cell populations responsible for regulating immune responses. MDSCs have been reported to accumulate in the blood, lymph nodes, and at tumor sites in most patients during tumor progression and chronic infection, where they potentially suppress T cell functions. We analyzed MDSCs (CD11b+ CD14- CD33+) in peripheral blood mononuclear cells by flow cytometry in 222 patients with esophageal, gastric, colorectal, hepatocellular, cholangiocellular, pancreatic, breast, ovarian, thyroid, and lung cancer, and 18 healthy volunteers. MDSCs were significantly higher in patients with esophageal, gastric, colorectal, hepatocellular, pancreatic, and breast cancer than in healthy volunteers, and the differences were not significant in patients with cholangiocellular, ovarian, thyroid, and lung cancer. Production of the cytokines IFN-γ and IL-6 in response to phytohemagglutinin was assayed using enzyme-linked immunosorbent assay (ELISA) test kits. Serum concentrations of sIL-2R were measured by ELISA. The percentages of MDSCs in patients with colorectal cancer positively correlated with neutrophil counts and the concentration of sIL-2R(both p<0.05), and inversely correlated with the production of IFN-γ( p<0.0001), serum albumin concentration(p<0.005), and lymphocyte counts (p<0.05). These data suggested that MDSCs are strongly related to chronic inflammation and nutritional impairment.

Myeloid-derived suppressor cells (MDSC) are one of the major cell populations responsible for regulating immune responses. These cells have been reported to accumulate in the blood, lymph nodes, and tumor sites in most patients during tumor progression and in chronic infection. They are also reported to potently suppress T-cell functions. We studied MDSC in the peripheral blood mononuclear cells(PBMC)by flow cytometry using blood samples from 29 patients with breast cancer, and from 11 healthy donors. The cell level was significantly high for patients compared to the 11 healthy donors (5. 68±6. 09% vs. 0. 91±0. 54%). MDSC was significantly higher in all of the breast cancer patients (5. 68±6. 09%), preoperative patients (5. 79±4. 92%) and recurrent disease patients (5. 59±7. 28%), compared to healthy donors, but not for postoperative patients (1. 50±0. 95%). Thus, MDSC was elevated in patients with breast cancer, but decreased to the range of healthy individuals after the removal of the tumor mass. However, MDSC increased again with recurrence. We also report that in 2 cases, MDSC in the peripheral blood and pleural effusion of patients with metastatic breast cancer decreased after chemotherapy with gemcitabine.

The efficacy of local steroid injection on the extravasation of vesicant anticancer drugs is controversial. In this study, the efficacy of local steroid injection was evaluated macroscopically and histologically in the extravasation models of doxorubicin (DXR), vinorelbine (VNR), and paclitaxel (PTX)in rats. Macroscopically, gross skin lesions were reduced by local steroid injections in rats treated with DXR and VNR. PTX did not cause gross skin lesions in most rats regardless of local steroid injection. Histologically, however, DXR, VNR, and PTX all induced deep tissue lesions such as edema, inflammation, and necrosis. Therefore, the effect of local steroid injection seemed to be minimal. In particular, DXR induced extensive necrosis in the subcutaneous and muscle tissues. VNR-induced skin lesions were milder than those induced by DXR, but had full thickness. Lesions caused by PTX were the mildest. These findings suggest that although local steroid injections could serve a primary role in diluting anticancer drugs and reducing gross skin lesions by their anti-inflammatory effect, they have less ability for suppressing deep-tissue lesions developing over time.

Patients: The subjects were 65 stage IV or relapsed breast cancer patients who received vinorelbine monotherapy or combination therapy at Fukushima Medical University between May 2002 and November 2006., Method: Chemotherapy was divided into the following 3 groups Vinorelbine monotherapy (group A), Trastuzumab combination therapy (group B), MMVC (mitomycin C, methotrexate, vinorelbine and cyclophosphamide) therapy(group C)., Results: There were 33 patients in group A, 15 patients in group B, and 17 patients in group C. The percentage of patients who had received more than 3 prior chemotherapy regimens were 69. 7% in group A, 66. 7% in group B, and 82. 4% in group C. No complete responses were observed. Partial responses was observed 6 patients in group A, 5 patients in group B, and 2 patients in group C. Overall response rate was 18. 2% in group A, 33. 3% in group B, and 11. 8% in group C. Clinical benefit rate was 24. 2% in group A, 46. 7% in group B, and 23. 5% in group C. The median overall survival time was 267, 522, and 275 days in group A, B, and C respectively., Discussion: Vinorelbine-based chemotherapy was considered as a new treatment option for patients with metastatic or relapsed breast cancer. It is necessary to examine the use at the early stage or more to obtain a high response rate and duration of response.

Background: Recently, aromatase inhibitors (AI) are widely used in postoperative adjuvant therapy for breast cancer. Nevertheless, studies of postoperative therapeutic strategies for recurrent breast cancer are insufficient., Subjects and Method: Data on 12 post-menopausal advanced/recurrent breast cancer patients in our department during June 2003- April 2007 were used for this study. No patient had responded to high-dose toremifene (TOR), a third-generation AI. Their therapeutic outcomes were analyzed retrospectively. The median observation period of the subjects was 16.1 months (4.0-40.9 months). Subjects were all hormone-sensitive. Overexpression of HER2 protein was found in only one case. During AI therapy immediately prior, exemestane (EXE) and anastrozole (ANA) had been given in nine and three cases, respectively., Results: The complete response rate of AI therapy was 16.7% (2/12). The clinical benefit rate was 58.3% (7/12). The median of time to progression (TTP) was 33.8 weeks. Neither the presence nor absence of past history of treatment with tamoxifen (TAM) or other chemotherapies affected the anti-tumor effect. Analysis by the site of metastasis or recurrence revealed that the therapeutic effects were better for non-life-threatening cases in the lung, pleura, soft tissue, etc. The severities of adverse effects were all less than grade 2; the major ones were flushing and sweating., Conclusion: Results show that high-dose TOR given at an early stage can provide clinical benefits for post-menopausal advanced/recurrent breast cancer not responding to AI.

Standard chemotherapy for endometrial cancer, including therapy with adriamycin and cisplatin (AP therapy), has not been established. However, recently, many studies have reported the efficacy of taxanes. We retrospectively investigated 46 patients with endometrial cancer who were diagnosed and treated in our hospital. As a rule, 6 courses of TC therapy (paclitaxel (PTX): 180 mg/m2, carboplatin (CBDCA): AUC 5), as initial chemotherapy, were performed at 3-week intervals in 18 patients with advanced or recurrent cancer from whom informed consent was obtained. In endometrioid adenocarcinoma patients, the response rate was 66.6%. A complete response for celomic fluid was achieved in 1 patient (1/1). Overall, the response rate was 50.0%. Adverse reactions such as digestive symptoms, alopecia, and peripheral neuropathy were observed in all patients. Concerning Grade 3 or higher blood toxicity, thrombopenia was noted in 1 patient. There was no hypersensitivity. Two patients with a partial response (PR) (1 with endometrioid adenocarcinoma, 1 with serous adenocarcinoma) achieved a disease-free survival of more than 30 months. Relapse was detected in 1 patient with a stage I c G3 lesion (response period: 20 months). Thus, TC therapy may be effective for endometrial cancer. However, in the future, the long-term outcome should be further investigated.

The current initial standard chemotherapy for advanced ovarian cancer is a regimen with a combination of platinum and taxane. However, the 5-year survival rate remains at 40% or lower, and the recurrence rate is as high as 70-80%. Second-line chemotherapy for recurrent cases has not yet been established. We conducted a phase I study of combined chemotherapy with paclitaxel (TXL) and carboplatin (CBDCA) administered weekly for recurrent and refractory ovarian cancer. The subjects were patients with a histopathologically confirmed diagnosis of malignant epithelial ovarian cancer, with recurrent or refractory disease after the initial chemotherapy. TXL was administered at escalating concentrations up to 60-100 mg/m(2), while the dose of CBDCA was fixed at an AUC of 2. In regard to the dosing schedule, premedication was performed as defined before TXL administration, and TXL and CBDCA were administered, in that order, by intravenous infusion for over at least 1 hour. The 4-week period, including the administration of both drugs on Day 1, 8, and 15, was regarded as one course of treatment. No cases developed grade 4 hematoxicity, but leukopenia and neutropenia occurred. All cases of leukopenia of step 4 and step 5 developed grade 3 leukopenia. Grade 2 thrombocytopenia was one example at a low rate. Non-hematological toxicity included neuropathy, arthralgia and muscle pain, but none of the patients developed grade 3 or 4. The response rate was 41.7% (5/12). The response rate of cases administered over TXL 80 mg was 66.7% (4/6). Based on these results,the following dose schedule was recommended for planning and designing a phase II study in the future: CBDCA AUC 2+TXL 80 mg/m(2) (Days 1, 8, and 15 q 4 weeks).

The patient was a 70-year-old woman, who became aware of a mass in her right breast in 2001, but left it untreated. On March 10, 2003, she visited a nearby doctor with the chief complaint of dyspnea. Since a large painful mass was palpable in the right breast, advanced right breast cancer was suspected, and the patient was referred to our department. Examination revealed the presence of right axillary lymph node metastasis, left pleural effusion, and left atelectasis, and the patient was admitted to our hospital on an emergency basis. Two cycles of CMF were begun on April 2, but CT indicated NC to PD. Therefore, exemestane (EXE, 25 mg/day), was administered on May 13. While the size of the primary lesion was partially decreased, the tumor marker levels were increasing markedly. Administration of EXE was therefore discontinued, and toremifene (TOR, 120 mg/day), was begun. The systemic condition began to improve one month after the start of TOR administration. Two months later, the primary lesion had decreased in size. At after 9 months of TOR treatment, the size of the primary lesion and the tumor marker levels continued to decrease, and both the left pleural effusion and the left atelectasis disappeared.

We report herein on the efficacy and toxicity of docetaxel and carboplatin in patients with epithelial ovarian cancer. Fifteen patients with FIGO stage I c-IV epithelial ovarian cancer were administered docetaxel (70 mg/m2) and carboplatin (AUC 5) every 3 weeks as 1 course. Eleven patients received this regimen as a first-time chemotherapy, and the other 4 as therapy for recurrence. Seven patients were evaluated for response. Of these, 6 achieved complete response and the other a partial response. CA 125 response was seen in 2 of 8 patients who did not have visible tumors. Our toxicity findings include the following: grade 3 and 4 neutropenia (86.7%), hypersensitive reaction (13.3%), grade 2 alopecia (13.3%), and no edema. Docetaxel and carboplatin are actively used in ovarian cancer, with the major toxicity being bone marrow suppression. But we were able to control myelosuppression with G-CSF. Hypersensitivity reactions were frequent, we thought pre-medication. This chemotherapy combination appears effective for epithelial ovarian cancer.

A 41-year-old male complaining of epigastric discomfort visited another hospital for a medical checkup. Gastrointestinal fiberscopic examination revealed a type 3 lesion on the lesser curvature of the lower portion, and biopsy specimens showed tubular adenocarcinoma. Abdominal CT demonstrated multiple liver metastases. After receiving a low-dose FP chemotherapy via IVH catheter for 1 week, the patient undertook a distal gastrectomy accompanied by D2 lymph node dissection. From the 19th postoperative day (POD), hepatic arterial infusion chemotherapy (HAIC) using 5-FU (500 mg/day) plus CDDP (10 mg/day) was performed for about 14 months. On the 47th POD, oral administration of UFT began and continued for 2 years. After 4 months of HAIC, the metastatic lesions of the liver disappeared completely. The patient has been free from recurrence since then for about 2 years. In the peripheral blood, Th1/Th2 ratio and activity of NK/LAK (IL-2 induced) kept increasing during this period. IHAC using 5-FU plus CDDP seems to be an efficient and worthy therapeutic modality if there are no other lesions except multiple liver metastases and a curative gastric resection is indicated.

It is well known that the 5-year survival rate of advanced ovarian cancer patients greatly improved after the appearance of cisplatin. Recently, paclitaxel has been reported to be effective in the treatment of cisplatin-resistant ovarian cancer. However, control of intraperitoneal lesions is still the biggest problem in this treatment, and attention is focused on the development of effective approaches. Intraperitoneal chemotherapy is considered to be a mode of administration expected to have a direct effect on ovarian cancer by penetrating the tumor and an indirect effect via blood vessels. We examined the outcome and adverse drug reactions in 102 ovarian cancer patients who underwent repeated intraperitoneal administration of cisplatin in our hospital between April 1987 and April 1999. We confirmed that this method may greatly improve the five-year survival rate compared to intravenous administration.

We conducted a dose-finding study for combination therapy of paclitaxel (Taxol; TXL) and carboplatin (Paraplatin; CBDCA). TXL is a novel plant-derived anticancer agent that is a diterpene derivative possessing the taxane ring. The subjects were patients with ovarian carcinoma, who were evaluated by a modified Fibonacci method. The dosage of TXL was 150 to 180 mg/m2. CBDCA was administered by dose escalation from AUC = 4 to 7. The administration schedule was as follows. Pre-medication was administered before TXL was given. TXL was then administered by intravenous infusion over 3 hours, followed by CBDCA. The dose of CBDCA was determined using the Calvert formula: [AUCX (GFR + 25)]. GFR was calculated with the Jelliffe equation. The non-hematological toxicities observed in 15 eligible cases were mainly grade 1, with no grade 3 or above, and no increase in severity was observed with stepping up. The hematological toxicities were grade 3 leukopenia in 5 of 15 cases, neutropenia in 5 cases and thrombocytopenia in 0 cases. No grade 4 toxicity was observed. The lowest counts of leukocytes and neutrophils were reached after 10.8 and 11.7 days, respectively. The toxicities were reversible in most cases with subsequent recovery. The above findings indicate that the recommended dosages for TJ therapy for Japanese ovarian cancer patients should be TXL 180 mg/m2 and CBDCA at a target of AUC = 6.

We performed a retrospective long-term study to evaluate the efficacy of intravesical instillation of Tokyo 172 strain Bacillus Calmette-Guerin (BCG) on carcinoma in situ (CIS) of the bladder. Between 1989 and 1998, 42 patients with CIS of bladder underwent intravesical instillation of BCG. In the follow-up period from 6 to 116 months (mean: 37.3 months), the efficacy rate of intravesical BCG instillation for CIS of the bladder was 81.0%. Two patients died from the bladder cancer. The non-recurrence rate in patients with grade 2 carcinoma (19 cases) was not significantly different from that in those with grade 3 carcinoma (23 cases). However, the recurrence rate in patients with secondary CIS (15 cases) was significantly higher than in those with primary CIS (27 cases). The recurrence of CIS was observed in 7 of 42 cases. In 6 of 7 patients, CIS recurred within one year after treatment. Total cystectomy was performed in 10 of 42 patients, and pathological findings of muscle layer invasion were detected in 8 patients. Although side effects occurred in 33 patients (77.5%), no clinically significant side effects were observed. Our results suggest that intravesical BCG therapy may be useful for the treatment of CIS of the bladder.

We reported a 36-year-old woman with metastatic liposarcoma originating in the retroperitoneum, which responded well to adjuvant chemotherapy. The primary tumor was removed by surgery. Two months later, the patient developed metastasis to the brain, and to the lung four months later. Metastatic liposarcomas to the brain generally are extremely rare. The patient was treated with combination chemotherapy using cyclophosphamide, vincristine, adriamycin, and dacarbazine (CYVADIC). After she was examined, the former two drugs were alternated with vindesine and ifosfamide, and another regimen with cisplatin and etoposide was given after a three-week interval. As a result, both of the metastases totally disappeared. No recurrent lesion has been noted for two years. Although the role of chemotherapy for liposarcoma has not been well defined and little data support its use in an adjuvant setting, this combination chemotherapy seemed to be effective for advanced liposarcoma.

A clinical study was performed on the efficacy of intraarterial chemotherapy using reservoir system for far-advanced urological malignancy. The reservoir system was indwelled in the femoral subcutaneous layer using Seldinger's method. Fifteen cases with inoperable complicated advanced bladder cancer and ten cases with postoperative local recurrent bladder cancer received intraarterial chemotherapy using the reservoir system. Then, 23 cases with local relapsed prostate cancer and two cases with endocrine-resistant prostate cancer received chemotherapy. The administered anti-cancerous agents were methotrexate, cis-platinum and adriamycin, and 5-FU or carboplatin were administered as maintenance therapy. The mean courses of chemotherapy were six for bladder cancer and four for prostate cancer. During stabilization of the local lesion, no distant deterioration was recognized. Overall clinical efficacy was as follows: PR:18 cases and NC:7 cases for bladder cancer; then, PR:11 cases and 14 cases for prostate cancer. The median duration of stabilization was as follows: 23 months for bladder cancer and 12 months for prostate cancer. Complications were fewer than with systemic chemotherapy.

Intra-arterial infusion chemotherapy combined with leucovorin (LV) and 5-fluorouracil (5-FU) was performed in two patients with multiple metastases from rectal and gastric cancer. In each patient LV 45 mg was infused as a bolus just before and after 5-FU 1,000 mg/4 hrs administration. Thereafter 5-FU dose was decreased gradually. This regimen was principally repeated weekly on an outpatient basis. In both patients PR was detectable 3 and 4 months after the beginning of chemotherapy, and CR was obtained in 21 and 6 months, respectively. Neither patient showed any signs of recurrence and are in good health 35 and 30 months after initiation of chemotherapy. These findings suggest that our protocol has an excellent anti-tumor effect and improves the QOL in some patients for a long time.

Seventy cases of surgically resected specimens of large-bowel carcinomas were used. DNA ploidy was determined by flow cytometry for step-wise sections in each carcinoma. Intratumor DNA ploidy distribution pattern was classified into 5 types: Type A showing diploidy in all sections; Type B showing aneuploidy in all sections with the same DNA index (DI); Type C showing diploidy in the majority of the sections and aneuploidy in a part; Type D showing aneuploidy in the majority of the sections and diploidy in a part; and Type E showing aneuploidy in all sections with different DI in some parts. Ki-67 in cell nuclei was stained immunohistochemically for the 4 microns-thick paraffin section using MIB1 monoclonal antibody, and the Ki-67 index expressing the growth fraction was calculated. Ki-67-index (Mean +/- SD) of 4 cases in Type A showed 20.6 +/- 4.88, that of 16 cases in Type B showed 37.5 +/- 9.62, that of 2 cases in Type C showed 42.4 +/- 0.21; that of 26 cases in Type D showed 41.8 +/- 10.6 and that of 22 cases in Type E showed 41.7 +/- 8.58. Thus, the aneuploidy group (type B, C, D, E) revealed a significantly higher Ki-67 index than the diploidy group (Type A) (p < 0.01). In the predominantly diploidy group (Type A, C), the cases in Type C also revealed a significantly higher value than the cases in Type A (p < 0.01). Therefore, there seemed to be some difference in the Ki-67 index or proliferative activity of cancer cells in large-bowel carcinomas relating to the intratumor DNA ploidy distribution pattern.

Esophageal carcinoma is classified as one of the most malignant neoplasms owing to the difficulty of early detection, frequent lymph node metastasis, and high incidence of recurrence even after curative resection of the lesion. According to the increase of early cases of esophageal carcinoma with the progress of the diagnostic technique, endoscopic mucosal resection and blunt resection of the esophagus have come to be performed in cases with quite early carcinoma or poor risk factors. Hyperthermo-chemo-radiotherapy (HCR) is extremely effective for esophageal carcinoma, especially for the advanced cases. The 1-, 3- and 5-year survival rates of the cases treated with preoperative HCR and chemo-radiotherapy (CR) were 64.6, 35.0 and 23.9%, against 46.9, 20.0 and 3.4%, respectively. The prognosis of the cases treated with HCR was significantly better than that for cases treated with CR. Moreover, for far-advanced esophageal carcinoma cases, palliative therapy such as intubation should be performed to assure quality of life (QOL). Strict follow-up including postoperative combined therapies is required for an improved prognosis in esophageal carcinoma.

This study examined the role of oxygen-derived free radicals for antitumor effects of intra-arterial injection with adriamycin (ADR). The effect of chemoembolization using ADR and degradable starch microspheres (DSM) was studied in rabbits with VX2 carcinoma of the hind leg. The tumor growth in rabbit treated with chemoembolization (ADR: 3.0 mg/kg + DSM 20mg/kg) was completely suppressed, but the therapeutic effect of chemoembolization combined with dimethylsulfoxide (DMSO) was reduced. On the other hand, the therapeutic effect of chemoembolization combined with superoxide dismutase and catalase was not reduced. These results indicate that the production of oxygen-derived free radicals, especially hydroxyl radical in the cancer cell, plays an important role in the antitumor effect of adriamycin.

In vitro tests were performed to assess the sensitivity to six anticancer agents-ACT-D, ADM, CDDP, CQ, 5-FU and MMC-of a JOHYL-1 (ascites type) cell line from human dysgerminoma which was used as challenge strain. For comparative assessment, anticancer sensitivity was expressed as the ratio of IC50 and IC90 to LD50 (i.v.) in mice. Drug dose-response and time-response curves were plotted, and the IC50 ratio was calculated, for each test compound in order to investigate the mechanism of anticancer action. The results obtained were as follows. CQ proved to be remarkably active and ADM fairly active against JOHYL-1 (ascites), but 5-FU, CDDP and MMC varied remarkably with the parameter of measurement employed. Analysis of IC50 ratio data and patterns of cell growth inhibition indicated the growth-inhibitory effect of CDDP to be concentration-and time-dependent. The results of the present study are in close accord with the pattern of action reported in the literature.

Endometrial hyperplasia (EH) was found to coexist in 13 of 21 patients (cystic glandular hyperplasia, 13; adenomatous hyperplasia, 9) with endometrial adenocarcinoma (EC), but in only 44 of 940 patients with other than EC. In this study, blood type (A, B, H), c-myc translation products, estrogen receptor and DNA polymerase alpha were examined on endometrium of proliferative phase (EPP), EH and EC. Patient blood type products were shown in EH surrounding EC, and yet they were detected in only small portion or none of EC itself. H products were detected in EC of other than O type. c-myc translation products were shown in only a small portion of cancer cells. EPP had many ER positive cells and a few proliferating cells as they were shown by staining with anti-DNA polymerase alpha monoclonal antibody. EC can be divided into two types, one has few ER positive cells and many proliferating cells, other many ER positive cells and a few proliferating cells. In EH, the numbers of ER positive cells and DNA polymerase alpha positive cells were between those of EPP and EC. In a patient with atypical hyperplasia, high dose Medroxyprogesterone acetate (MPA) therapy induced that stratification and papillary growth of gland lining epithelia disappeared, and that cytoplasmic enlargement and vacuolation appeared. These findings were important histopathological changes in high dose MPA administration to EH and EC.