Hilar/mediastinal and cutaneous drug-induced sarcoidosis-like reaction associated with immune checkpoint inhibitors in metastatic colorectal cancer: a case report.

Background: Immune checkpoint inhibitors (ICIs) are the standard treatment for metastatic colorectal cancer (mCRC) with high microsatellite instability (MSI-H). Among immune-related adverse events (irAEs), drug-induced sarcoidosis-like reactions (DISR) are often difficult to differentiate from cancer progression. Main Body: This is a case of a woman in her mid-60s, with mCRC (RAS wild/BRAF mutant/MSI-H) and abdominal lymph node metastasis, treated with four courses of ipilimumab + nivolumab every 3 weeks, followed by nivolumab every 2 weeks as third-line treatment. After treatment, the original lymph node metastases shrank, but hilar/mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epithelioid granulomas without necrosis, indicating a sarcoidosis-like reaction. Fluorodeoxyglucose-positron emission tomography scan showed abnormal subcutaneous accumulation in bilateral forearms and bilateral knee joints. Biopsy of the cutaneous lesions was also performed, which revealed epithelioid granulomas. As the patient had no symptoms in other organs, no specific therapeutic intervention was administered. After the discontinuation of immunotherapy, the sarcoidosis-like reaction regressed without cancer relapse. Conclusions: Clinicians should be aware of the possibility of DISR as an irAE during the ICI treatment of mCRC. In suspected cases of DISR following ICI therapy, it is important to differentiate between cancer progression and DISR through histological diagnosis for the subsequent strategy, as radiological and serological findings are not definitive.

Case Report: Longitudinal monitoring of clonal evolution by circulating tumor DNA for resistance to anti-EGFR antibody in a case of metastatic colorectal cancer.

Background: Treatment with anti-EGFR antibody has been shown to prolong survival in patients with RAS wild-type metastatic colorectal cancer (mCRC). However, even patients who initially respond to anti-EGFR antibody therapy, almost without exception, develop resistance to the therapy and then fail to respond. Secondary mutations in the mitogen-activated protein (MAPK) signaling pathway (mainly in NRAS and BRAF) have been implicated in anti-EGFR resistance. However, the process by which resistant clones develop during therapy has not been elucidated, and considerable intrapatient and interpatient heterogeneity exists. Circulating tumor DNA (ctDNA) testing has recently allowed the noninvasive detection of heterogeneous molecular alterations that underlie the evolution of resistance to anti-EGFR. In this report, we describe our observation of genomic alterations in KRAS and NRAS in a patient with acquired resistance to anti-EGFR antibody drugs by tracking clonal evolution using serial ctDNA anaylsis. Case presentation: A 54-year-old woman was initially diagnosed with sigmoid colon cancer with multiple liver metastases. After receiving first-line mFOLFOX + cetuximab, second-line FOLFIRI + ramucirumab, third-line trifluridine/tipiracil + bevacizumab, fourth-line regorafenib, and fifth-line CAPOX + bevacizumab, she was rechallenged with CPT-11 + cetuximab. The best response to anti-EGFR rechallenge therapy was a partial response. RAS in the ctDNA was assessed during treatment. The RAS status changed from wild type to mutant type, back to wild type, and again to mutant type (NRAS/KRAS codon 61) during the course of treatment. Conclusion: In this report, tracking of ctDNA allowed us to describe clonal evolution in a case in which we observed genomic alterations in KRAS and NRAS in a patient who acquired resistance to anti-EGFR antibody drugs during treatment. It is reasonable to consider repeat molecular interrogation during progression in patients with mCRC by using ctDNA analysis, which could help to identify patients who may benefit from a rechallenge strategy.

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma.

BACKGROUND: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer. METHODS: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given. RESULTS: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies. CONCLUSION: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347).

Identifying Early Predictive Markers for Immune-Related Adverse Events in Nivolumab-Treated Patients with Renal Cell Carcinoma and Gastric Cancer.

BACKGROUND: Neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios can indicate poor disease prognosis and are inflammation markers. We investigated the role of NLR and PLR as effective predictive markers of immune-related adverse event (irAE) onset in patients treated with nivolumab. METHODS: We retrospectively analysed 73 gastric and renal cancer patients treated with nivolumab at the Hokkaido Cancer Centre from January 2017 to June 2020. NLR and PLR were calculated at the initiation of nivolumab treatment and irAE onset. We identified the risk factors for Grade 3-4 irAE onset using NLR, PLR, sex, cancer type, and age. Overall survival (OS) and progression free survival (PFS) were calculated from the initiation of nivolumab treatment to the date of death or censored at last follow-up. RESULTS: Among the 73 patients included, 17 (18%) had at least one grade3-4 irAE. Multivariable logistic regression analyses revealed that pretreatment NLR<4.3 was significantly associated with a reduced risk for onset of grade3-4 irAEs, whereas rate of NLR change after treatment, ΔNLR>120% was significantly associated with an increased risk. CONCLUSIONS: NLR is an effective marker for prognosis and onset of grade 3-4 irAEs.

Analgesic effects of indomethacin spray on drug-induced oral mucositis pain in patients with cancer: A single-arm cross-sectional study.

AIMS: Symptomatic treatment is insufficient for chemotherapy- or targeted therapy-induced oral mucositis (OM) pain, and benzydamine mouthwash is not commercially available in Japan. We evaluated the analgesic effects of an in-hospital preparation of 0.25% indomethacin spray (IMS) on anticancer drug-induced OM pain. METHODS: This single-arm prospective trial enrolled 20 patients (median age 62.0 years) with OM and numerical rating scale scores of ≥5 who were undergoing chemotherapy or targeted therapy in our hospital. Pain scores were recorded using a visual analog scale (VAS) before and 30 min after IMS administration. Pain relief (PR) scores were recorded at 15, 30, and 60 min after IMS administration; total PR after 60 min (TOTPAR60 ) was calculated, and the mean PR score after 3 days (PR3days ) was determined. RESULTS: The median (interquartile range) OM grade of the participants was 2.0 (2.0-2.3). The VAS score decreased significantly at 30 min after IMS administration (p = .001). The median (interquartile range) TOTPAR60 and PR3days were 6.0 (3.8-7.3) and 2.0 (2.0-3.0), respectively. CONCLUSIONS: IMS helped improve patients' quality of life. The risk of systemic adverse effects was low because of the low dose administered. IMS effectively relieved anticancer drug-induced OM pain and may be useful for immediate self-medication.

Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab.

The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27-0.74; p < 0.001]. In patients with left-sided tumours, treatment with chemotherapy plus cetuximab yielded longer OS than chemotherapy plus bevacizumab (50.6 vs 27.8 months, HR 0.55; 95% CI 0.32-0.97; p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32-0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28-0.68, p < 0.001, respectively). Moreover, ETS and/or high DpR achieved in patients with right-sided mCRC receiving chemotherapy plus cetuximab were associated with significantly better OS than in those lacking ETS and with low DpR (34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.

A dose-escalation study of docetaxel, oxaliplatin, and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer.

PURPOSE: The aim of this study was to determine the recommended dose (RD) for a docetaxel/oxaliplatin/S-1 (DOS) regimen in patients with unresectable gastric cancer and to preliminarily evaluate its efficacy. METHODS: Previously untreated patients with histologically proven unresectable metastatic gastric cancer were enrolled (n = 16). Docetaxel and oxaliplatin were administered intravenously on day 8 and S-1 was administered orally twice a day on days 1-14. Each cycle was repeated every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle. Three dose escalations of DOS were employed in this study: level 1 (50/100/80 mg/m2), level 2 (50/130/80 mg/m2), and level 3 (60/130/80 mg/m2). RESULTS: According to the 3 + 3 dose-escalating schedule, we determined that the RD and maximum tolerated dose for this regimen were level 1 and level 2, respectively. The DLTs were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) for patients with measurable lesions and consisted of two complete responses and five partial responses. Five patients underwent conversion surgery. The median follow-up time was 19 months with median survival time and progression-free survival being 19.6 months and 7.6 months, respectively. CONCLUSIONS: The results from this study demonstrated the safety and tolerability of DOS in unresectable metastatic gastric cancer patients and revealed promising preliminary efficacy with a high conversion rate. A phase II trial of DOS regimen using the identified RD is ongoing.

[CapeOX Therapy as a Salvage Treatment for Advanced Gastric Cancer Refractory to S-1, Cisplatin, Irinotecan, and Taxanes].

AIM: This study aimed to retrospectively evaluate the efficacy and safety of capecitabine plus oxaliplatin(CapeOX)for heavily pretreated advanced gastric cancer(AGC)refractory to S-1, cisplatin, irinotecan, and taxanes. METHODS: Twelve patients with AGC refractory to S-1, cisplatin, irinotecan, and taxanes were enrolled in this study.Treatment comprised capecitabine(1,000mg/m / 2 twice a day on days 1-14)and oxaliplatin(130mg/m2 on day 1).Cycles were repeated at 3- week intervals. RESULTS: The overall response rate was 16.7%, and the disease control rate at 6 weeks was 75.0%. The progression free survival was 3.1 months, and the overall survival was 8.3 months after initiation of CapeOX therapy. The most common hematological toxicity was grade 3 neutropenia(50%).Peripheral neuropathy of Grade 1 or 2 was found in 50%of cases, but no Grade 3 or 4 neuropathy was found. CONCLUSIONS: CapeOX showed some activities as salvage therapy for heavily pretreated AGC patients.We suggest that CapeOX therapy should be considered a treatment option for pretreated AGC with good performance status.

Phase Ib study of irinotecan and ramucirumab for advanced gastric cancer previously treated with fluoropyrimidine with/without platinum and taxane.

PURPOSE: Optimal salvage chemotherapy for patients with treated advanced/metastatic gastric cancer (AGC) is unknown. Irinotecan is commonly used in Japan. Ramucirumab, a human IgG-1 monoclonal antibody targeting the extracellular domain of VEGF receptor 2, is the first molecularly targeted agent proven to be effective in second-line therapy for AGC in combination with chemotherapy. We sought to determine the maximum tolerated dose (MTD) and recommended dose (RD) of ramucirumab plus irinotecan for AGC previously treated with fluoropyrimidine with/without platinum and taxane. METHODS: Patients received systemic chemotherapy with ramucirumab (8 mg/kg) and irinotecan on day 1, repeated every 2 weeks. A decrease in irinotecan dose was planned from start level 1 (irinotecan 150 mg/m2). This trial was registered with the University Hospital Medical Network (UMIN no. 000018606). RESULTS: Six patients were enrolled from August 2015 to September 2017. No dose-limiting toxicity (DLT) was observed, and the maximum tolerated dose (MTD) was not reached at level 1. Irinotecan 150 mg/m2 in combination with ramucirumab 8 mg/kg was administered with acceptable toxicity, and all patients were treated at these doses. No treatment-related deaths were observed. Adverse events of Grade 3/4 were neutropenia (17%), anemia (17%) and hypertension (17%). Patients were evaluated using the RECIST criteria, and response rate and disease control rate were 17% and 83%, respectively. CONCLUSIONS: Salvage chemotherapy with irinotecan plus ramucirumab was well-tolerated by patients previously treated for AGC. RD was defined as irinotecan 150 mg/m2 in combination with ramucirumab 8 mg/kg.

Skin Disorders and Primary Tumor Location as Prognostic Factors in Patients with Metastatic Colorectal Cancer Treated with Cetuximab and Chemotherapy

Background: Cetuximab-induced skin disorder is common in colorectal cancer (CRC), and is known to affect prolonged overall survival (OS). Patients with left-sided CRC survive longer than those with right-sided CRC, among those treated with combination cetuximab and chemotherapy. However, no study has evaluated patient prognosis in terms of OS and progression-free survival (PFS) in relation to both tumor location and skin disorder. This study aimed to determine the incidence of skin disorder according to tumor location and analyze the relationship of tumor location and skin disorder with OS. Methods: Patients with metastatic colorectal cancer (mCRC) treated with standard chemotherapy and cetuximab as first-line therapy were included. Differences in the incidence of skin disorders due to the location of the primary tumors were compared in the same patient. The OS and PFS in relation to the location of the primary tumors and presence or absence of skin disorder were also compared. Results: Total frequency of each skin disorder as rash acneiform, paronychia, and dry skin in patients with left- and right-sided mCRC was 70%, 70%, and 43% and 27%, 36%, and 27%, respectively. The median OS was 8.9 months for mCRC on the left-sided without skin disorder and 56.3 months for mCRC on the left-sided with skin disorder. In comparison, the median OS was 10.4 months for mCRC on the right-sided without skin disorder and 11.3 months for mCRC on the right-sided with skin disease (left-sided with skin disorder versus other three group; P<0.001). Conclusions: Primary tumor location and the presence of skin disorder are important factors in patients with mCRC who receive cetuximab. In particular, our results show the new fact that the left-sided and right-sided mCRC survival time were comparable if there is no skin disorder caused by cetuximab.

Neoadjuvant chemotherapy with docetaxel, nedaplatin, and fluorouracil for resectable esophageal cancer: A phase II study.

Cisplatin plus 5-fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how definitive chemoradiotherapy with docetaxel, nedaplatin, and 5-fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib-III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2 ) and nedaplatin (50 mg/m2 ) on days 1 and 8, and a continuous infusion of 5-fluorouracil (400 mg/m2 /day) on days 1-5 and 8-12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end-point was the completion rate of the protocol treatment. Twenty-eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty-five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment-related deaths and major surgical complications did not occur. Estimated 2-year progression-free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305).

A phase II study of modified docetaxel, cisplatin, and S-1 (mDCS) chemotherapy for unresectable advanced gastric cancer.

PURPOSE: Triplet therapy using docetaxel, cisplatin, and S-1 (DCS) against unresectable gastric cancer as previously reported by us showed high clinical efficacy, with a 87.1% total response rate; however, it also showed a high incidence of grade 3/4 toxicity. With the aim of reducing toxicities, we conducted a phase II study of modified DCS (mDCS), using a reduced dose of docetaxel, and evaluated the clinical efficacy and adverse events of this regimen. METHODS: Patients with unresectable gastric cancer received chemotherapy with S-1 (40 mg/m2 b.i.d) on days 1-14, and docetaxel (50 mg/m2) plus cisplatin (60 mg/m2) on day 8 every 3 weeks. The primary endpoint was the response rate (RR). Overall (OS) and progression-free survival (PFS), and toxicities were also evaluated. RESULTS: Forty-nine patients were enrolled from November 2011 to April 2014, and 43 were eligible. The overall RR was 79.1%, including two cases of a complete response (4.7%), and 32 cases of a partial response (74.4%). Nine cases had stable disease (20.9%) but none showed progressive disease. Of the 43 cases, 15 cases (34.9%) underwent curative conversion surgery. The median PFS was 350 days (95% CI 240-416 days) and median OS was 722 days (95% CI 411 days-not reached). Grade 3/4 neutropenia developed in 79.1%, and febrile neutropenia in 34.9%, of patients. Non-hematological grade 3/4 adverse events were anorexia (25.6%), nausea (4.7%), and diarrhea (9.3%). CONCLUSION: Modified DCS therapy showed high clinical efficacy sufficient enough to attempt conversion therapy against unresectable gastric cancer. Modified DCS showed fewer toxicities, but careful management of these is still essential.

Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study.

Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization. Results Thirty patients enrolled in Part A (dose range: 40 mg twice daily [bid] to 120 mg bid; 160 mg once daily [qd]), four in Part B (80 mg bid). No dose-limiting toxicities were observed and maximum tolerated dose was not determined. Most common adverse events (AEs; any grade) were: dysgeusia (50% of patients); stomatitis (41%); diarrhoea (38%); hyperphosphataemia (38%); dry mouth (35%). Common grade ≥3 AEs were nausea (12% of patients) and neutropenia (9%). No complete or partial responses were observed: 21/30 patients had stable disease ≥4 weeks in Part A, and 1/4 patients had stable disease ≥10 weeks in Part B. Following single and multiple dosing, absorption rate appeared moderate; peak plasma concentrations generally occurred 3-4 h post-dose, then declined biphasically with terminal half-life ~30 h. Steady state was reached by day 8. Compared with single dosing, plasma concentrations were, on average, 2.4- and 3.3- to 5.4-fold higher after qd and bid dosing, respectively. Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease ≥4 weeks.

Conversion therapy for inoperable advanced gastric cancer patients by docetaxel, cisplatin, and S-1 (DCS) chemotherapy: a multi-institutional retrospective study.

BACKGROUND: Conversion therapy is an option for unresectable metastatic gastric cancer when distant metastases are controlled by chemotherapy; however, the feasibility and efficacy remain unclear. This study aimed to assess the feasibility and efficacy of conversion therapy in patients with initially unresectable gastric cancer treated with docetaxel, cisplatin, and S-1 (DCS) chemotherapy by evaluating clinical outcomes. METHODS: One hundred unresectable metastatic gastric cancer patients, enrolled in three DCS chemotherapy clinical trials, were retrospectively evaluated. The patients received oral S-1 (40 mg/m2 b.i.d.) on days 1-14 and intravenous cisplatin (60 mg/m2) and docetaxel (50-60 mg/m2) on day 8 every 3 weeks. Conversion therapy was defined when the patients could undergo R0 resection post-DCS chemotherapy and were able to tolerate curative surgery. RESULTS: Conversion therapy was achieved in 33/100 patients, with no perioperative mortality. Twenty-eight of the 33 patients (84.8 %) achieved R0 resection, and 78.8 % were defined as histological chemotherapeutic responders. The median overall survival (OS) of patients who underwent conversion therapy was 47.8 months (95 % CI 28.0-88.5 months). Patients who underwent R0 resection had significantly longer OS than those who underwent R1 and R2 resections (P = 0.0002). Of the patients with primarily unresectable metastases, 10 % lived >5 years. Among patients who underwent conversion therapy, multivariate analysis showed that the pathological response was a significant independent predictor for OS. CONCLUSIONS: DCS safely induced a high conversion rate, with very high R0 and pathological response rates, and was associated with a good prognosis; these findings warrant further prospective investigations.

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours.

PURPOSE: This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed. METHODS: In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation. RESULTS: Twenty-eight patients were enrolled and 23 were treated (n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response. CONCLUSIONS: Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies. CLINICAL TRIAL REGISTRATION NUMBER: NCT01813474.

[Four cases of esophageal metastasis from breast cancer].

The 4 patients with esophageal metastasis from breast cancer were women aged 55 to 68, who had multiple metastases and long term survival (9 to 13 years) from diagnosis of primary breast cancer. All of them presented with progressive dysphagia. Computed tomography revealed a circumferential wall thickening of the upper to middle esophagus without enlarged mediastinal lymph nodes or other lesions that would cause esophageal obstruction through external compression. Endoscopic examination revealed circumferential stricture without mucosal abnormality. In 3 cases, biopsy or EMR specimens revealed adenocarcinoma, which suggested metastasis of breast cancer resected previously. In the other case, biopsy failed to detect any malignancy. Metastatic cancer to the esophagus is a rare occurrence. We report these rare cases with references to the literature.

Prospective phase II study of FOLFIRI for mCRC in Japan, including the analysis of UGT1A1 28/6 polymorphisms.

OBJECTIVES: This is the first phase II study to evaluate the efficacy and tolerability of the first-line FOLFIRI, as well as the influence of uridine diphosphate glucuronosyl transferase 1, family polypeptide A1 gene (UGT1A1) 28/6 polymorphism, in Japanese metastatic colorectal cancer patients. METHODS: Fifty-two patients were enrolled in this study and were administrated FOLFIRI (irinotecan; 150 mg/m(2)) as first-line chemotherapy. Thirty-nine patients accepted the evaluation of UGT1A1 genotypes. In patients with UGT1A1 28 homozygosity, the starting dose was reduced (100 mg/m(2)) according to the Food and Drug Administration recommendation and our previous phase I study. RESULTS: After a median follow-up period of 22 months, complete response was achieved in 1.9%, partial response in 38.5 %, stable disease in 51.9% and progressive disease in 3.9%. The overall response rate was 40.4%, the disease control rate was 92.3% and the median overall survival time was 22.3 months. The major toxicity was grade 3-4 neutropenia in 44.2%. There was no definite relation between UGT1A1 28, 6 polymorphisms and toxicity. However, homozygosity for UGT1A1 28 or UGT1A1 6 and double heterozygosity for both UGT1A1 28 and UGT1A1 6 were significantly associated with severe neutropenia in metastatic colorectal cancer patients (P< 0.001). CONCLUSIONS: FOLFIRI is effective and tolerable for Japanese metastatic colorectal cancer patients. Homozygosity for UGT1A1 28 or 6 and heterozygosity for both UGT1A1 28 and 6 are associated with severe neutropenia.

Iron/IRP-1-dependent regulation of mRNA expression for transferrin receptor, DMT1 and ferritin during human erythroid differentiation.

OBJECTIVE: We investigated iron regulatory protein (IRP)-dependent expression of transferrin receptor (TfR), divalent metal transporter-1 (DMT1) and ferritin during erythroid differentiation system using an in vitro three-phase liquid culture. METHOD: Peripheral blood hematopoietic progenitor cells were cultured with interleukin-3 and stem cell factor (SCF) for 7 days (first phase), subsequently with SCF, erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) for 5 days (second phase), and finally with EPO and IGF-I for 3 days (third phase). Cells were subjected to colony assay, flow-cytometric analysis, mRNA assessment, electrophoretic mobility shift assay (EMSA), immunoblotting, and immunoprecipitation. RESULTS: In the second/third phases, erythroid cells serially differentiated. Expression of TfR and DMT1 mRNA, which have iron-responsive elements (IREs) at 3'-UTR, reached a maximum on second phase, and thereafter decreased, while expression of ferritin mRNA, which has an IRE at the 5'-UTR, decreased reciprocally on second phase. IRP in the cytosol after precipitation of polysome decreased on second phase, suggesting that IRP bound to IREs of these mRNAs in the polysome. When cells were incubated with (59)FeCl(3), (59)Fe-bound IRP-1 immunoprecipitated with anti-IRP-1 antibodies was detected on first phase and third phase, but was not detected on second phase. CONCLUSION: These results suggest that IRP-1/IRE interactions, which are supposedly induced after sensing a decrease of the intracellular non-Heme iron levels, play a crucial role on the posttranscriptional regulation of TfR, DMT1, and ferritin mRNAs during differentiation of normal human erythropoietic cells.

[A case of recurrent biliary cystadenocarcinoma successfully treated with 5FU/CDDP systemic chemotherapy].

We report a case of biliary cystadenocarcinoma which recurred 41 months postoperatively. A 60-year-old woman was admitted for further examination of multiple metastatic tumors and a large amount of ascites. Systemic administration of 5FU and CDDP caused her CEA level to decrease gradually and abdominal computed tomography revealed considerable reduction of the metastatic tumors and ascites. Since her general condition had improved, chemotherapy was continued in the outpatient clinic.