Miki Tateyama

Phase II Study of Combined Treatment with Irinotecan and S-1 (IRIS) in Patients with Inoperable or Recurrent Advanced Colorectal Cancer (HGCSG0302)

Objectives: This phase II study was designed to evaluate the efficacy and safety of oral fluoropyrimidine S-1 plus irinotecan (IRIS regimen) in patients with previously untreated metastatic colorectal cancer. Methods: The response rate was the primary endpoint. Safety, progression-free survival time, and median survival time were secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15). S-1 (40 mg/m2) was administered for 2 weeks (on days 1 to 14) and followed by a 2-week rest. Results: Forty patients were enrolled. Four patients had grade 4 neutropenia, and six patients had grade 3 diarrhea. No other serious hematologic or nonhematologic adverse reactions occurred, and all patients received IRIS safely on an outpatient basis. The response rate was 52.5% (95% confidence interval [CI], 36.1–68.5%). Median progression-free survival was 8.6 months (95% CI, 5.3–11.9), and median survival time was 23.4 months (95% CI, 15.9–30.8). Conclusions: IRIS produced a high response rate and could be given safely. IRIS may become a first-line treatment for inoperable or recurrent advanced colorectal cancer.

SO-CALLED NASAL GLIOMA

Nasal glioma is heterotopic brain tissue which usually presents as a tumor around the nose of children and infants. We have encounterd two cases of nasal glioma during the past nine years at Hokkaido University Hospital. One showed a tumor in the subcutis of the nasal bridge and the other a polypoid mass arising in the soft palate. Both consisted of proliferation of fibrillary spindle cells consistent with fibrillary astrocytes divided by fibrovascular septa. This was reminiscent of “gliosis” of the central nervous system. Occasional protoplasmic astrocytes were present in both and, in addition, one case showed neuronal cells and choroid plexus. The glial nature of the lesion was confirmed by the presence of glial fibrillary acidic protein demonstrated by the immunoperoxidase method. Nasal glioma is not neoplastic contrary to its name and is considered heterotopic brain tissue which was displaced during fetal development by similar pathogenetic mechanisms of sincipital and basal encephalocele, although its communication to the brain was lost.

Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study; J-STEPP

AIM We planned a randomized, open-label trial to evaluate differences between pre-emptive and reactive skin treatment for panitumumab (Pmab)-associated skin toxicities in Japanese patients with metastatic colorectal cancer. PATIENTS & METHODS Patients receiving third-line Pmab-containing regimens were randomized to pre-emptive or reactive treatment. The primary end point was the cumulative incidence of ≥grade 2 skin toxicities during 6 weeks. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner. RESULTS A total of 95 patients were enrolled (pre-emptive: 47, reactive: 48). The primary end point was achieved (21.3 and 62.5% [risk ratio: 0.34; p < 0.001], for pre-emptive and reactive treatment, respectively). A similar trend was observed in central review. CONCLUSION Pre-emptive skin treatment could reduce the severity of Pmab-associated skin toxicities in Japanese metastatic colorectal cancer patients.

Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer

Abstract Background. In Japan, a study comparing the effectiveness and safety of irinotecan plus S-1 (IRIS) with those of a combination of 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line treatment in patients with advanced or recurrent colorectal cancer demonstrated that IRIS was non-inferior to FOLFIRI. We previously reported that IRIS is also effective as first-line treatment. Patients and methods. Eligibility criteria included inoperable recurrent colorectal cancer with a confirmed diagnosis of adenocarcinoma, age ≥20 years, and no history of prior chemotherapy. S-1 (40–60 mg twice daily) was given orally on Days 1 to 14, and irinotecan (100 mg/m2) and bevacizumab (5 mg/kg) were given intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS). Results. A total of 52 eligible patients were enrolled from October 2007 through March 2009. In safety analysis, the incidences of grade 3 or 4 adverse reactions were as follows: neutropenia, 27%; hypertension, 21%; and diarrhea, 17%. The overall response rate was 57.7%. Median progression-free survival was 16.7 months. Conclusion. IRIS plus bevacizumab is a well-tolerated, highly effective chemotherapeutic regimen that is easy to administer.

MUCORMYCOSIS IN DIABETIC KETOACIDOSIS: Role of Unbound Iron Binding Capacity of Transferrin

Increased susceptibility to Rhizopus oryzae in diabetes was investigated using mice in which diabetic ketoacidosis was experimentally induced. All of the diabetic mice which had developed ketoacidosis died within four days after inoculation of R. oryzae and their serum UIBCs (Unbound iron binding capacity) were significantly lower than those of the normal control mice. This study suggested that the decreased serum UIBC produced by diabetic ketoacidosis enhances the growth of R. oryzae in vivo. ACTA PATHOL. JPN. 36: 1507‐1512, 1986.

DISSEMINATED FUNGAL INFECTION A Review of 20 Autopsy Cases

In the study of disseminated fungal infection, in consecutive autopsy cases between 1974 and 1982, we have found this infection in 20 cases (2.55% in all autopsy cases and 16.8% of deep‐seated fungal infection). Candidiasis was present in 11 cases, aspergillosis in 8 cases, and mucormycosis and cryptococcosis in 1 case each. One case showed the disseminated infection by both Candida and Aspergillus. All of the 20 cases had underlying disorders. Hematologic disorders were most frequent and were present in 15 cases. In contrast to the small yellow disseminated foci of candidiasis, the lesion by Aspergillus and Mucor were relatively larger, hemorrhagic, and necrotic. Cryptococcal lesion showed a small gelatinous appearance. All of the fungal lesion were devoid of significant inflammatory reaction. Lymphocytopenia (less than 500/mm3) was present in 13 cases out of 16 cases (not examined in the remaining 4 cases). Eight cases had long‐standing indwelling intravenous catheters, including two cases in which the catheters apparently played an important role in the development of disseminated candidiasis. Ante‐mortem diagnosis was established or suspected in only seven cases. Possible means of the prevention of fungal infection is also discussed. ACTA PATHOL. JPN. 34: 1201–1208. 1984.

Open‐label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron

The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1–3 in combination with palonosetron (PALO), a second‐generation 5‐HT3 receptor antagonist, for chemotherapy‐induced nausea and vomiting (CINV) in non‐anthracycline and cyclophosphamide (AC) moderately‐emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi‐center, randomized, open‐label, non‐inferiority design. Patients who received non‐AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2–3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non‐inferiority margin was set at −15% (study treatment group − control group). From April 2011 to March 2013, 305 patients who received non‐AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group (N = 151) and 63.6% in the control group (N = 154). PALO plus DEX day 1 was non‐inferior to PALO plus DEX days 1–3 (difference, 2.5%; 95% confidence interval [CI]: −7.8%–12.8%; P‐value for non‐inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti‐emetic DEX administration on days 2–3 may be eliminated when used in combination with PALO in patients receiving non‐AC MEC.

Phase 1/2 clinical study of irinotecan and oral S-1 (IRIS) in patients with advanced gastric cancer

BackgroundIrinotecan and S-1, an oral fluoropyrimidine composed of tegafur, gimeracil, and oteracil potassium, have demonstrated antitumor activity against advanced gastric cancer. We performed a phase 1/2 study to determine the recommended dose, antitumor activity, and safety of a combination of S-1 and irinotecan in patients with advanced gastric cancer.MethodsPatients with previously untreated advanced gastric cancer were enrolled. Patients received irinotecan intravenously on days 1 and 15 plus oral S-1 twice daily on days 1–14 of a 28-day cycle. In the phase 1 part, the dose of irinotecan was escalated from 100 mg/m2 to 125 mg/m2 and then to 150 mg/m2.ResultsA total of 24 patients were enrolled. Overall, the median number of treatment cycles per patient was 5.9, and 92% of the patients completed at least two cycles. The overall response rate was 54.2% (13 of 24). The response rates in differentiated and undifferentiated cancer were 56.3% (nine of 16) and 50.0% (four of eight), respectively. Median survival time was 581 days. The maximum tolerated dose of irinotecan was not reached at the highest level. However, grade 4 neutropenia occurred at 125 mg/m2. We concluded that the recommended dose of irinotecan for the present regimen was 125 mg/m2.ConclusionTreatment with S-1+irinotecan is considered effective in patients with advanced gastric cancer who have not previously received chemotherapy. A combination of irinotecan and S-1 was well tolerated in patients with advanced gastric cancer and could be given on an outpatient basis.

Modified-irinotecan/fluorouracil/levoleucovorin therapy as ambulatory treatment for metastatic colorectal cancer: results of phase I and II studies.

AbstractBackground: Combined therapy with irinotecan/fluorouracil/levoleucovorin (calcium levofolinate) [IFL] has lost its position as the standard regimen for metastatic colorectal cancer because its toxicity and effectiveness have become controversial. Objective: To (i) identify the optimal regimen for IFL therapy in terms of irinotecan dosage, and (ii) determine the maximum tolerated dose and efficacy of the modified-IFL regimen in patients with histologically confirmed advanced colorectal cancer. Methods: In a phase I study, nine patients with advanced colorectal cancer received IFL treatment modified such that irinotecan was administered every 2 weeks, as opposed to the more toxic once-weekly administration. The study evaluated three escalating dose levels of irinotecan (100,125 and 150 mg/m2). Each treatment cycle consisted of irinotecan on days 1 and 15; fluorouracil 600 mg/m2 on days 1,8, 15 and 22; and levoleucovorin 250 mg/m2 on days 1, 8, 15 and 22. Data from the phase I study were used to determine the recommended dose of irinotecan for the phase II study. The latter study evaluated the effectiveness (overall response rate, median time to disease progression and median survival time) and tolerability of this modified-IFL therapy as ambulatory treatment in 22 patients with advanced colorectal cancer. Results: The dose-limiting toxicity of irinotecan was grade 3 neutropenia, which occurred in three patients at dose level 2 (125 mg/m2); furthermore, a fourth patient developed grade 4 neutropenia at this dose level. Therefore, 125 mg/m2 was considered to be the maximum tolerated dose, and the dose of irinotecan for the phase II study was set at 100 mg/m2. Fourteen patients achieved partial response using this modified-IFL regimen, and the overall response rate was 63.6% (95% CI 43.5, 83.7). The median time to progression was 197 days (range 111–283 days) and the median survival time was 414 days (95% CI 116, 712). Toxicities were acceptable and manageable. Conclusions: Modified-IFL therapy is a practical, effective and tolerable option for ambulatory treatment of advanced colorectal cancer.

Renal Actinomycosis Associated With A Duodenorenal Fistula Caused by Foreign Body

We are reporting a case of a rare renal actinomycosis in a 12‐year‐old mentally‐retarded girl. Proteinuria and hemopyuria were pointed out one year before the operation by an annual medical check‐up and IVP subsequently performed showed foreign bodies at the upper pole of the right kidney. The patient continued to have pyuria and right nephrectomy was performed. There was a fistula between the duodenum and the upper portion of the right kidney. Foreign bodies (two bobby pins) were found in the kidney. Subsequent pathologic examination of the resected kidney revealed an actinomycotic lesion.