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Objective To reveal the outcomes of initial active surveillance (AS), followed by deferred systemic target therapy, in a subpopulation of patients with indolent metastatic renal cell carcinoma (mRCC). Methods We retrospectively reviewed the clinical and pathologic data of patients with mRCC, who initially were monitored by planned AS before systemic therapy because of their preference and asymptomatic or slowly progressive disease, at our institution between 2000 and 2011. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). Results Twenty-nine patients with a metastatic lesion at start of AS were eligible for this analysis. The median age at the start of AS was 69 years. Of these patients, 65% had recurrent disease and 35% were in stage IV. All patients had undergone nephrectomy and 86% had clear-cell carcinoma. No patients were categorized into a poor risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) and Heng criteria. The median follow-up period was 35.4 months. Disease progression was observed in 72% of patients, but only 14% died during the follow-up period. The median PFS time was 26.1 months. After disease progression was observed, only 58% of these patients received treatment. The median OS had not been reached, but 12, 24, and 48 months OS rates were 96.4%, 88.7%, and 83.8%, respectively. Conclusion PFS and OS of patients who underwent AS were acceptable. AS might be a reasonable approach, particularly for patients with prolonged, indolent course of the disease. Further observational studies with a larger sample size might be needed.

Bortezomib is a proteasome inhibitor and is active against multiple myeloma. Most toxicities associated with bortezomib are mild to moderate and manageable; however, bortezomib-induced pneumonitis has been reported in some multiple myeloma cases. Bortezomib-induced pneumonitis was reported to occur relatively soon after the first administration of bortezomib. A 64-year-old Japanese man with multiple myeloma received low-dose dexamethasone followed by bortezomib monotherapy as the initial therapy. He had no pulmonary complications during bortezomib treatment. Thereafter, he was treated with high-dose chemotherapy, followed by autologous peripheral blood stem cell transplantation. Ten months after autologous peripheral blood stem cell transplantation, his disease relapsed and he received bortezomib retreatment. On the fifth day after the second dose of weekly bortezomib, he complained of mild dyspnea, dry cough and fever. High-resolution computed tomography of the chest showed bilateral infiltrates with partial ground glass appearance in the lower lobes. The diagnosis of bortezomib-induced pneumonitis was made. His bortezomib-induced pneumonitis responded to steroid therapy and his respiratory symptoms disappeared. This is the first report in which bortezomib-induced pneumonitis occurred during bortezomib retreatment for relapsed multiple myeloma. Careful management is needed during bortezomib retreatment, even after the previous course of bortezomib was administered safely.

Irradiation of conjugated imino ethers containing an adjacent 1,2-diazadicarboximide group in benzene afforded rearranged indole derivatives (3) and a novel dimer in good yields. The latter was formed by nucleophilic attack of 3 to a dipolar intermediate.

The purposes of this study were (1) to characterize psychological states and coping strategies after bereavement among spouses of cancer patients in Japan and (2) to explore the factors associated with psychological states in oncology settings. In March 2009, questionnaires to assess spouses’ psychological states, coping strategies, and mental health states (GHQ-28) were sent after patients died at the National Cancer Center of Japan. To address the first purpose, exploratory factor analysis, gender comparison, and calculation of correlation with age, time since bereavement, and mental health states were conducted. Hierarchical regression analysis was conducted to address the second purpose. A total of 821 spouses experiencing bereavement for 7 months to 7 years participated in the study. Psychological states revealed three factor structures: “Anxiety/Depression/Anger”, “Yearning”, and “Acceptance/Future-Oriented Feelings”. Coping strategies also revealed three factor structures: “Distraction”, “Continuing Bonds”, and “Social Sharing/Reconstruction”. Coping strategies represented 18 % to 34 % of each factor associated with psychological states, whereas the characteristics of bereaved spouses and deceased patients represented 6 % and less than 6 %, respectively. More “Distraction and Social Sharing/Reconstruction” and less “Continuing Bonds” were significantly associated coping strategies for achieving “Acceptance/Future-Oriented Feelings” (p

Information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B cell non-Hodgkin lymphoma (B-NHL), in particular for patients pretreated with rituximab, is limited. To evaluate the efficacy and safety of eight doses of rituximab monotherapy, 52 patients with relapsed or refractory indolent B-NHL were enrolled in the present study. Forty of 45 eligible patients (89%) had follicular lymphoma and 24 (53%) were at intermediate or high risk group according to the Follicular Lymphoma International Prognostic Index. The median number of prior chemotherapy regimens was 1 (range 1-7). At the median follow-up of 12.2 months, the overall response rate (ORR), complete response rate (%CR), and median progression-free survival (PFS) were 69% (95% confidence interval [CI] 53%-82%), 47% (95% CI 32%-62%), and 15.6 months (95% CI 10.6- months), respectively. In the 33 patients pretreated with rituximab, the ORR, %CR, and median PFS were inferior compared with values for the 12 patients who had not received rituximab previously (64%vs 83% for ORR; 39%vs 67% for %CR; and 13.8 vs 17.5 months for median PFS, respectively). All mild-to-moderate infusion-related toxicities were reversible. Grade 3/4 non-hematologic adverse events occurred in six of the 52 patients. Two patients developed Grade 4 late-onset neutropenia and a decrease (>50%) in serum immunoglobulin was observed in six patients. In conclusion, rituximab monotherapy with eight weekly infusions is effective in relapsed patients with indolent B-NHL, with acceptable toxicities, including in patients pretreated with rituximab; however, careful monitoring is recommended for infections associated with late-onset neutropenia and hypogammaglobulinemia. (University Hospital Medical Information Network no. UMIN000002974.)

Malignant pleural effusion is a common and devastating complication of metastatic breast cancer. This occurs in about 30% of patients with metastatic breast cancer during the clinical course, and chemical pleurodesis is sometimes performed to relieve dyspnea. However, the long-term outcome of pleurodesis and factors affecting successful pleurodesis have not been clarified.The aim of this analysis is to evaluate the long-term outcome of pleurodesis and to identify risk factors associated with success.Data on 75 patients who had undergone chemical pleurodesis with OK-432 for pleural effusion due to metastatic breast cancer were reviewed retrospectively. The primary outcomes were success rate and pleural progression-free survival (PPFS) rate.The median duration of follow-up was 134 days (range 8-975 days). During this period, 22 patients re-accumulated pleural fluid. The overall success rate was 70.5%. The 4-, 8- and 12-week PPFS rates were 88.0, 84.0 and 78.7% respectively. Multivariate analysis identified three unfavorable factors that were independently associated with unsuccessful pleurodesis, including estrogen-receptor negative status, a 24-h drainage volume of more than 100 mL before extubation and NSAID use. The PPFS rate at median follow-up was 93.5% in the low-risk group (n = 41, 0 or 1 unfavorable factor) and 55.1% in the high-risk group (n = 34, 2 or 3 unfavorable factors). The difference between the PPFS curves of the two risk groups was statistically significant (P0.001).Pleurodesis for metastatic breast cancer was efficacious in controlling malignant pleural effusion. Our simple new risk model warrants further studies.

ABL tyrosine kinase inhibitor (TKI), imatinib is used for BCR–ABL + leukemias. We developed an automatic method utilizing guanine-quenching probes (QP) to detect 17 kinds of mutations frequently observed in imatinib-resistance. Results were obtained from 100 μL of whole blood within 90 min by this method. Detected mutations were almost identical between QP method and direct sequencing. Furthermore, the mutation-biased PCR (MBP) was added to the QP method to increase sensitivity, resulting earlier detection of T315I mutation which was insensitive to any ABL TKIs. Thus, the QP and MBP-QP may become useful methods for the management of ABL TKI-treated patients.

Background: CHOP-21 has remained the standard chemotherapy for aggressive non-Hodgkin’s lymphoma (NHL), and dose intensification is a potential strategy for improving therapeutic results. We conducted a phase III trial to determine whether dose-dense strategy involving interval shortening of CHOP (CHOP-14) is superior to CHOP-21. Patients and methods: A total of 323 previously untreated patients (aged 15–69 years) with stages II–IV aggressive NHL were randomized. The primary end point was progression-free survival (PFS). Results: Treatment compliance was comparable in both study arms. At 7-year follow-up, no substantial differences were observed in PFS and overall survival (OS) between CHOP-21 (n = 161) and CHOP-14 (n = 162) arms. Median PFS was 2.8 and 2.6 years with CHOP-21 and CHOP-14, respectively (one-sided log-rank P = 0.79). Eight-year OS and PFS rates were 56% and 42% [95% confidence interval (CI) 47% to 64% and 34% to 49%], respectively, with CHOP-21 and 55% and 38% (95% CI 47% to 63% and 31% to 46%), respectively, with CHOP-14. Subgroup analyses showed no remarkable differences in PFS or OS for patients stratified as per the International Prognostic Index or by age. Conclusion: Dose-intensification strategy involving interval shortening of CHOP did not prolong PFS in advanced, aggressive NHL.

In hematological diseases such as myeloproliferative disorders (MPD) or myelodysplastic syndromes (MDS), some abnormalities in the chemiluminescence of neutrophils are observed. There are two groups; one includes chronic myelogenous leukemia (CML), essential thrombocythemia (ET) and MDS, which all have decreased chemiluminescence of neutrophils. The other group includes polycythemia vera (PV) which has increased neutrophil chemiluminescence. We studied the neutrophil function by analyzing the chemiluminescence in 35 patients with hematological diseases. In most of these cases the defects in chemiluminescence in 35 patients with hematological diseases. In most of these cases the defects in chemiluminescence in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) were correlated with those in response to phorbol 12-myristate 13-acetate (PMA). But there were exceptional cases in which the maximal light emission of chemiluminescence (Max CL) in response to FMLP was obviously lower than controls despite the fact that the Max CL in response to PMA was the same as the controls. These facts suggest a heterogenicity of the defect site in these diseases. There was a correlation between the level of chemiluminescence and the neutrophil alkaline phosphatase (NAP) activity in these patients. In vitro culture of CML neutrophils with granulocyte colony-stimulating factor (G-CSF) showed a correlation between the increase in the level of chemiluminescence and NAP activity. These results suggest that NAP may take part in the control of neutrophil function.

Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) is one of the most frequently applied initial treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL); however, information on its long-term outcome is limited. Untreated patients in the concurrent arm (Arm C) received six R (375 mg/m(2) ) treatments, 2 days prior to each cycle of CHOP, and patients in the sequential arm (Arm S) received 6 weekly R (375 mg/m(2) ) treatments following six cycles of CHOP. Sixty-nine patients were randomized but two patients were withdrawn before receiving the protocol treatment. Sixty-five patients (94%) had follicular lymphoma, and 37 (55%) were at low risk, 23 (34%) at intermediate risk and seven (10%) at high risk according to the Follicular Lymphoma International Prognostic Index. We previously reported that the overall response rate (ORR) in Arm C and in Arm S was 94% and 97%, respectively. The median progression-free survival (PFS)/7-year PFS rate in Arm C, Arm S and all 67 assessable patients was 2.4 years/23% (95% confidence interval [CI], 9-40%), 3.8 years/41% (95% CI, 23-57%) and 2.8 years/32% (95% CI, 20-45%), respectively. There was no significant difference between the two arms (P = 0.107). The overall survival (OS) of the 67 patients was 95% at 7 years. In conclusion, R-CHOP is a highly effective initial treatment for untreated indolent B-NHL in terms of ORR and OS; however, its long-term PFS is not good enough either in concurrent or sequential combination, warranting further investigations on post-remission therapy.

The reaction of 1-nitro-2-phenylethenes (β-nitrostyrenes) with aqueous titanium(III) chloride afforded substituted pyrroles in addition to the expected reduction products, oximes and carbonyl compounds. 2-Substituted 1-nitro-2-phenylethenes yielded divinylamine derivatives instead of pyrroles. The reaction mechanism has been rationalized by taking account of the electron transfer from titanium(III) species to the nitro olefins, followed by protonation, dimerization, cyclization, and/or hydrolysis.

3-Phenyl-2,4-dioxoimidazolidin-5-yl ribofuranoside (a hydantoin C-riboside) was synthesized from a Diels-Alder adduct of furan with methyl nitroacrylate.

The photochemical deacylation of 1,4-diacyl-2,5-piperazinediones was found to proceed through the type II ketene eliminating process

The reaction of substituted dicyanoalkenes with aqueous titanium(III) chloride was examined. The dicyanoalkenes, which showed irreversible reduction characteristics on cyclic voltammograms, (typically, 2-cyano-3-phenylpropenenitrile), afforded cyclized and/or uncyclized hydrodimers, while those characterized by reversible reduction behavior, (typically, 2-cyano-3,3-diphenylpropenenitrile), yielded the corresponding saturated dinitriles. The reduction mechanism has been rationalized by taking account of the electron transfer from the Ti(III) species to the dicyanoalkenes, followed by protonation, or dimerization and cyclization.

Irradiation of conjugated imino ethers containing an adjacent 1,2-diazadicarboximide group in benzene afforded rearranged indole derivatives (3) and a novel dimer in good yields. The latter was formed by nucleophilic attack of 3 to a dipolar intermediate.

The irradiation of oxime O-ethers 2, derived from N-substituted 3-acyl-1,2-dihydrocinnoline-1,2-dicarboximides in benzene, afforded rearranged products 3 possessing a [1,3,5]triazino[1,2-a]indole skeleton in good yields. Upon irradiation, 7-methoxy-substituted 1,2-dihydrocinnoline-1,2-dicarboximides 2 gave a novel dimer 5 together with the rearranged triazinoindole derivatives 3 in benzene, while in nucleophiles they gave the nucleophile-incorporated dihydrotriazinoindoles 6. However, the 7-nitro-substituted one was inert under the same conditions. The dimer and dihydrotriazinoindole derivatives were thought to be formed by a nucleophilic attack of the initial photoproduct 3 and nucleophiles to 2, respectively. From these results and the observation of a remarkable solvent-dependency of the fluorescence and UV spectra of 2, it was suggested that these photoreactions should occur through a nitrogen–nitrogen bond cleavage at polar excited states followed by skeletal rearrangements.

Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B-cell non-Hodgkin lymphomas (B-NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B-NHL or mantle-cell lymphoma (MCL). Patients received bendamustine (120 mg/m(2) ) on days 1-2 of a 21-day cycle, for up to six cycles. The primary endpoint was the overall response rate (ORR) as assessed by an extramural committee according to International Workshop Response Criteria (IWRC). Secondary endpoints included complete response (CR) rate, ORR according to Revised Response Criteria (revised RC), progression-free survival (PFS), and safety. Fifty-eight patients with indolent B-NHL and 11 with MCL were enrolled. By IWRC, bendamustine produced an ORR of 91% (95% confidence interval [CI], 82-97%; 90% and 100% in patients with indolent B-NHL and MCL, respectively), with a CR rate of 67% (95% CI, 54-78%). ORR and CR rates according to revised RC were 93% (95% CI, 84-98%) and 57% (95% CI, 44-68%), respectively. After a median follow-up of 12.6 months, median PFS had not been reached. Estimated PFS rates at 1 year were 70% and 90% among indolent B-NHL and MCL patients, respectively. Bendamustine was generally well tolerated. Reversible myelosuppression, including grade 3/4 leukopenia (65%) and neutropenia (72%), was the most clinically significant toxicity observed. Common non-hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single-agent bendamustine in relapsed patients with indolent B-NHL or MCL histologies.

The title compound, C 11 H 12 BF 2 NO, was found to be converted by irradiation to the anti and syn head-to-tail dimers {1,3.-bis(difluoroboronyloxy)-2,4-bis[1-(N-methylimino)ethyl]-1,3-diphenylcyclobutane, C 22 H 24 B 2 F 4 N 2 O 2 }. The enaminoketone group of each complex takes a ring structure chelated through the BF 2 group.

Although ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy has been regarded as a standard of care for advanced-stage Hodgkin lymphoma (HL) since 1992, there has been no prospective data of ABVD therapy in Japan. To investigate the efficacy and safety of ABVd therapy with the lower dose of dacarbazine (250 mg/m(2)) in patients with newly diagnosed stage II-IV HL, Lymphoma Study Group of Japan Clinical Oncology Group conducted a phase II study. The primary endpoints were complete response rate (%CR) and progression-free survival (PFS). A total of 128 patients with age less than 70 years were enrolled and received 6-8 cycles of ABVd followed by radiation to initial bulky mass. The %CR in 118 eligible patients was 81.4% [95% confidence interval (CI) 73.1-87.9%]. Major toxicity was grade 4 neutropenia (45.3%). Grade 3 nausea/vomiting was the most frequent non-hematological toxicity (10.9%). Transient grade 4 constipation, infection (abscess), hypoxemia and hyperbilirubinemia were observed in 4 patients. No treatment-related death was observed. PFS and overall survival at 5 years were 78.4% (95% CI 70.9-85.9%) and 91.3% (95% CI 86.1-96.5%), respectively. In conclusion, ABVd is effective in Japanese patients with stage II-IV HL with acceptable toxicities (UMIN-CTR Number: C000000092).

Peripheral T- and NK-cell lymphomas (PT/NKCLs) are relatively rare, and few studies have validated the International Prognostic Index (IPI) for PT/NKCLs in prospective clinical trials. Histopathological specimens from 136 patients, enrolled in six prospective multicenter trials of doxorubicin-containing regimens, with PT/NKCLs were reviewed by six hematopathologists following the WHO classification. This combined analysis demonstrated that the IPI was not predictive of prognosis for patients with PT/NKCLs as previously shown by GELA. In a univariate analysis, low total serum protein (TP) and albumin levels, gastrointestinal tract involvement, and histologic subtype (extranodal NK/T-cell lymphoma, nasal type, and peripheral T-cell lymphoma, unspecified) were significantly associated with reduced survival. In a multivariate analysis, TP (p = 0.004) and histologic subtype (p = 0.024) remained significant. We discuss the need to establish the importance and meaning of TP and to develop new strategies for patients with PT/NKCLs allowing for TP, especially with worse histologic subtypes.

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, antitumor activity, and recommended starting dose of axitinib in patients with advanced solid tumors. Twelve patients received single-dose axitinib 5 mg and were monitored for > or =48 h. Continuous 5 mg twice-daily dosing was then initiated. One patient had dose-limiting toxicity (grade 3 proteinuria and fatigue). Common treatment-related adverse events were anorexia, fatigue, and diarrhea. Grade 3 treatment-related adverse events were fatigue and hypertension. Maximum axitinib plasma concentration occurred 1-4 h after steady-state dosing. Eleven patients experienced thyroid-stimulating hormone elevation; time-course change and fatigue onset appeared to be related in some patients. Significant correlation was observed between thyroid-stimulating hormone change and area under the plasma concentration-time curve (AUC; r = 0.80, P = 0.005). Axitinib decreased plasma soluble vascular endothelial growth factor receptor 2 (s-VEGFR2), with significant correlation between change in s-VEGFR2 and AUC (r = -0.92, P < 0.0001). Fluorodeoxyglucose positron emission tomography revealed a substantial decrease in tumor metabolic activity associated with axitinib. Tumor size decreased in nine patients. The time-course of thyroid-stimulating hormone change appeared correlated with fatigue. There were significant correlations between thyroid-stimulating hormone or s-VEGFR2 and axitinib exposure. Axitinib 5 mg twice-daily is the recommended starting dose for Japanese patients. This trial is registered with ClinicalTrials.gov, identifier NCT00447005.

The reaction of substituted dicyanoalkenes with aqueous titanium(III) chloride was examined. The dicyanoalkenes, which showed irreversible reduction characteristics on cyclic voltammograms, (typically, 2-cyano-3-phenylpropenenitrile), afforded cyclized and/or uncyclized hydrodimers, while those characterized by reversible reduction behavior, (typically, 2-cyano-3,3-diphenylpropenenitrile), yielded the corresponding saturated dinitriles. The reduction mechanism has been rationalized by taking account of the electron transfer from the Ti(III) species to the dicyanoalkenes, followed by protonation, or dimerization and cyclization.

2-Methoxyfuran reacts with β-nitrostyrenes to give Michael adducts. Interestingly, isoxazoline N-oxides were obtained in the reactions with β-nitrostyrenes possessing additional electron-withdrawing groups (COPh and CO2Et).

2-Methoxyfuran reacts with β-nitrostyrenes to give Michael adducts. Interestingly, isoxazoline N-oxides were obtained in the reactions with β-nitrostyrenes possessing additional electron-withdrawin...

Oral fludarabine is more convenient than intravenous fludarabine in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma (B-NHL), we conducted a multicenter phase II study. Patients with relapsed indolent B-NHL with two or fewer prior regimens and up to 16 doses of rituximab were eligible. Patients received 375 mg/m2 rituximab on day 1, and 40 mg/m2 oral fludarabine once daily on days 1 through 5 every 28 days for up to six cycles. The primary endpoint was the overall response rate. Forty-one patients were enrolled, including 38 (93%) with follicular lymphoma. Thirty-four patients (83%) had received rituximab as prior therapy. Twenty-seven patients (66%) completed the planned six cycles. Dose reduction of oral fludarabine was required in 17 patients (41%). The overall response rate was 76% (31 of 41 patients; 95% confidence interval, 60–88%) with a complete response rate of 68% (28 of 41 patients; 95% confidence interval, 52–82%). Median progression-free survival for the 41 patients was 19.7 months (95% confidence interval, 12.3–26.5 months). Hematological toxicities, including grade 4 neutropenia (68%), were the most frequent toxicities. Non-hematological toxicities were mild, except for one patient who died of Pneumocystis jiroveci pneumonia 4 months after the protocol treatment. In conclusion, oral fludarabine in combination with rituximab is a highly effective and convenient therapy for patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab. (ClinicalTrials.gov number, NCT00311129.) (Cancer Sci 2009; 100: 1951–1956)

We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2-h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B-cell lymphoma. This was a dose-escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose-limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n = 3) and 2 (0.12 mg/kg/day, n = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35-65%), with 11% (2/18) complete response. With a median follow-up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non-hematologic toxicities were mild. In conclusion, cladribine with 2-h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B-cell lymphoma, including those pretreated with rituximab.

The reaction of 1-nitro-2-phenylethenes (β-nitrostyrenes) with aqueous titanium(III) chloride afforded substituted pyrroles in addition to the expected reduction products, oximes and carbonyl compounds. 2-Substituted 1-nitro-2-phenylethenes yielded divinylamine derivatives instead of pyrroles. The reaction mechanism has been rationalized by taking account of the electron transfer from titanium(III) species to the nitro olefins, followed by protonation, dimerization, cyclization, and/or hydrolysis.

There is no data about the efficacy and safety of radioimmunotherapy with 90Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma pretreated with rituximab-containing chemotherapy. We focused on this in a Japanese phase II study. Radioimmunotherapy with 90Y-ibritumomab tiuxetan (11.1 and 14.8 MBq) was evaluated in patients with 100–149 × 109 and >150 × 109 platelets/L, respectively. The primary endpoint was the overall response rate. Forty patients were treated with 90Y-ibritumomab tiuxetan (18 with 11.1 MBq/kg and 22 with 14.8 MBq/kg). Thirty-five patients (88%) had been pretreated with rituximab, including 27 (68%) pretreated with rituximab-containing chemotherapy. The overall response rate was 83% (33/40; 95% confidence interval, 67–93%), and the complete response rate was 68% (27/40; 95% confidence interval, 51–81%). The overall response rates in patients pretreated with rituximab-containing chemotherapy and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were 83% (19/23) and 94% (17/18), respectively. The median progression-free survival time of the 40 patients who received 90Y-ibritumomab tiuxetan was 9.6 months. Toxicity was primarily hematological and mostly transient. No grade 4 non-hematological toxicity was observed. In conclusion, radioimmunotherapy with 90Y-ibritumomab tiuxetan is safe and highly effective in patients with relapsed or refractory indolent B-cell lymphoma, including those pretreated with rituximab-containing chemotherapy. (ClinicalTrials.gov number NCT00220285) (Cancer Sci 2009; 100: 158–164)

To investigate the relationship between the degree of liver dysfunction and the pharmacokinetics of docetaxel, a population pharmacokinetic model was developed in an oncology practice without excluding patients with moderate to severe liver dysfunction. Two hundred patients were treated with docetaxel as a single agent or in combination chemotherapy. The plasma concentration-time course data were analyzed using a three-compartment open model with zero-order administration and first-order elimination on the NONMEM program. Sixty-one had elevated transaminase levels, and alkaline phosphatase was elevated in 40. Body surface area, albumin, alpha1-acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. Compared to patients with normal or minimal impairment of liver function, patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase had 22 and 38% lower clearances, respectively. Goodness-of-fit plots indicated that the model was fitted well with the observed data, and the bootstrap method guaranteed robustness of the model. We developed a population pharmacokinetic model for docetaxel, which can be used in the setting of an oncology practice. Based on the model, dose reduction by approximately 20 and 40% should be considered for patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase, respectively.

We report two cases of herpes simplex lymphadenitis without widespread organ involvement in a 60-year-old man and a 67-year-old woman. Their complaints were high fever and generalized erythema followed after few days by generalized lymphadenopathy. This report describes the findings obtained by light and electron microscopy, immunohistochemistry, and in situ hybridization. In both instances, Cowdry's type A intranuclear inclusion bodies were found in T-immunoblasts in the background of T-zone hyperplasia with focal necrosis. Electron microscopic investigation revealed intranuclear and cytoplasmic virus particles with characteristics of the herpes group. Immunohistochemical staining utilizing anti-herpes simplex virus (HSV) antibody was positive and in situ hybridization with HSV-DNA probe revealed positive signals in the nucleus and in the cytoplasm of T-immunoblasts. Although rare, HSV lymphadenitis in the absence of generalized infection can occur.

Background: The standard therapy for primary gastric diffuse large B-cell lymphoma (DLBCL) is chemotherapy of R-CHOP with/without involved-field radiation therapy. Although some reports indicated that gastrointestinal complications after chemotherapy for DLBCL occur at a rate of 0-26%, little is known about riskfactors for the complications. In addition, to detect DLBCL in gastric lesion, both of positron emission tomography-computed tomography (PET-CT) and esophagogastroduodenoscopy (EGD) are useful tools. However, there have been few reports comparing them. The aim of this study is to show the outcomes including treatment-related complications in patients with gastric DLBCL and risk factors for the gastric complications. Moreover, we evaluated whether PET-CT is sufficient to detect DLBCL in gastric lesion by comparing with EGD. Patients and methods: This retrospective study included consecutive patients with newly diagnosed DLBCL between October 2003 and July 2014 who underwent EGD and were treated with R-CHOP in our hospital. We classified the patients into three groups. Group A-1: patients who had documented DLBCL in gastric lesion by EGD and underwent PET-CT; group A-2: patients who had documented DLBCL in gastric lesion by EGD and did not underwent PET-CT; group B: patients who had no documented DLBCL in gastric lesion by EGD and underwent PET-CT. Suspected lymphomatous lesions by EGD were biopsied and immunopathologically examined. Gastric DLBCL was defined only when pathologically confirmed. In PET-CT, gastric lesions with SUV max ≥ 5 were considered positive. Outcomes and risk factors for complications among group A were analyzed using the logistic regression model. We evaluated significance of PET-CT and EGD in group A-1 and B by the positive predictive value (PPV) and the negative predictive value (NPV). Results: Among 448 patients diagnosed with DLBCL, 178 patients were enrolled for our study: 55 in group A-1, 28 in group A-2 and 95 in group B. Among 83 patients with gastric DLBCL (group A), the median age was 69 years (range, 29-85). The numbers of patients with clinical stage (Ann Arbor classification) I, II, III, and IV were 27, 18, 5, and 33, respectively. The rate of complete remission was 87%, and the median 3- and 5-year over survival (OS) were 81% and 75%, respectively. The median 3-year OS of patients with very good, good, and poor grade of Revised International Prognostic Index (R-IPI) was 100%, 77%, and 63%, respectively (Figure, p=0.025). Ten patients had gastric complications: 6 with bleeding that needed blood transfusion and 3 with gastrointestinal stenosis defined as ordinary endoscopy could not pass, no patients had gastrointestinal perforation. Most of bleeding (66.7%) occurred during the first cycle of R-CHOP (median, 15 days; range, 1-206). A multivariate analysis showed that low serum albumin (ALB) at diagnosis was an independent risk factor for gastric complications (odds ratio 10.75, p Conclusions: The present study showed that R-IPI was also predictive of survival in gastric DLBCL and low ALB at diagnosis as a significant risk factor for gastric complications following R-CHOP. In addition, our data suggested that PET-CT may be sufficient in the role of detecting gastric lesion of DLBCL because of high PPV and NPV. Disclosures No relevant conflicts of interest to declare.

2-Methoxyfuran as a diene fails to generate a Diels-Alder adduct when it reacts with β-cyanostyrenes (cinnamonitriles). However, in the reaction with β-cyanostyrenes possessing additional electron-withdrawing groups (CN, CO 2 Et, SO 2 Ph and COPh), it yielded two new phenylcyclopropanes. The formation of the cyclopropane ring may occur through the opening of the furan ring in the β-cyanostyrene-furan complex (zwitterion) formed. The product formation process involves a sterically controlled intramolecular reaction.

CHOP combined with rituximab (R-CHOP) is regarded as one of the most effective treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL), however, its optimal combination schedule remains unknown. We performed a randomized phase II study to explore a more promising schedule in untreated, advanced indolent B-NHL. Patients were randomized to receive either six courses of CHOP concurrently with rituximab (Arm C), or six courses of CHOP followed by six courses of weekly rituximab (Arm S). A total of 69 patients received the concurrent (n=34) or sequential (n=35) regimen. Overall response rate (ORR) in Arm C was 94% (95% confidence interval [CI], 79 to 99), including a 66% complete response (CR) compared with 97% (95% CI, 85-100), including a 68% CR in Arm S. Patients in Arm C experienced more grade 4 neutropenia (85%versus 70%) and experienced more grade 3 or greater non-hematological toxicities (21%versus 12%). Both arms were tolerated well. With a median follow-up of 28.2 months, the median progression-free survival (PFS) time was 34.2 months in Arm C, and was not reached in Arm S. R-CHOP is highly effective in untreated indolent B-NHL, either concurrent or in a sequential combination. Both combination schedules deserve further investigation.

Alpha(1)-acid glycoprotein, a plasma protein that binds docetaxel, is a significant determinant of the clearance and activity of docetaxel, but its serum levels in cancer patients are variable. This emphasizes the importance of investigating the pharmacokinetics of unbound drug rather than total drug in the plasma. In the present study, the pharmacokinetics and pharmacodynamics of unbound docetaxel were investigated in cancer patients. Docetaxel was infused over a 1-h period in 69 patients. The concentration of unbound docetaxel was measured in the plasma ultrafiltrate at the end of infusion and the unbound fraction (fu) was calculated. The pharmacokinetics of total docetaxel in the plasma was investigated. The area under the concentration-time curve (AUC) of unbound docetaxel was calculated by multiplying fu by the AUC of total docetaxel. The peak concentration at the end of infusion (Cmax) and AUC of total and unbound drug were compared between patients who did or did not experience grade 4 neutropenia. The median of fu was 4.0%, ranging from 1.2 to 22.6% (5-95% percentile; 1.4-10.5%). Grade 4 neutropenia was observed in 24 patients. Although Cmax and AUC of total drug were not different in patients with or without grade 4 neutropenia, patients who experienced grade 4 neutropenia had significantly greater Cmax (92.3 vs 63.3 ng/mL, P=0.01) and AUC (0.137 vs 0.104 microgxh/mL, P=0.05) of unbound docetaxel. In a logistic regression analysis, the unbound Cmax and alpha1-acid glycoprotein were determinants of grade 4 neutropenia. Pharmacokinetics of unbound drug rather than total drug is a better predictor of neutropenia for docetaxel.

A patient with lung metastasis of breast cancer was reported. The patient underwent surgery in December, 1999. Her breast cancer then recurred in December, 2000. After treatment failure with anthracycline and taxane antitumor drugs,she participated in a phase II study of S-1, a fluorinated pyrimidine anticancer drug, which was given orally at 80 mg/m2/day (2 doses). After completion of 4 courses of treatment,the target lesions of the lung metastasis markedly shrunk by 47.5% as compared with the pretreatment. Because salvage therapy with S-1 alone showed good antitumor efficacy and beneficial tolerability when the standard dosage was maintained, it was considered that this home therapy was effective for advanced/recurrent breast cancer that was resistant to anthracycline and taxane antitumor drugs.

To evaluate the efficacy and feasibility of rituximab monotherapy in Japanese patients with relapsed or refractory aggressive B-cell lymphoma.Sixty-eight patients were treated with rituximab at 375 mg/m(2) by eight consecutive weekly infusions. Pretreatment variables affecting overall response rate (ORR) and progression-free survival (PFS) and the relationship between pharmacokinetic parameters and efficacy were analyzed.The ORRs of 68 enrolled patients and 57 eligible patients were 35% [95% confidence interval (CI) 24% to 48%] and 37% (95% CI 25% to 51%), respectively. Median PFS of 53 evaluable patients was 52 days, whereas time to progression of 21 eligible responders was 245 days. Mild to moderate infusion-related toxicities were observed frequently at the first infusion, but all of them were reversible. Elevated lactate dehydrogenase (LDH) and refractoriness to prior chemotherapy were unfavorable factors affecting ORR and PFS (P0.01). Serum trough levels of rituximab and area under the concentration-time curve for responders were higher than for non-responders (P0.05).Eight consecutive weekly infusions of rituximab have significant anti-lymphoma activity for relapsed or refractory aggressive B-cell lymphoma. Several pretreatment variables and serum rituximab levels are useful for predicting its efficacy.

To investigate whether combination chemotherapy with vincristine, cyclophosphamide, prednisolone, and melphalan (COP/ MP) with the addition of ranimustine (MCNU) (MCNU-COP/MP) is superior to the slightly modified COP/MP (mCOP/MP) regimen in multiple myeloma (MM), a multicenter randomized study was performed. Two hundred ten patients with newly diagnosed, overt MM not treated with chemotherapy were enrolled from 32 institutions of the Lymphoma Study Group of the Japan Clinical Oncology Group and were randomized to receive either MCNU-COP/MP or mCOP/MP. The response rate (RR) to mCOP/MP was 43.7% (95% confidence interval [CI], 33.9%–53.8%] and to MCNU-COP/MP was 56.1 % (95% CI, 46.1 %–65.7%) (P = .097). The progression-free survival (PFS) was significantly longer for patients treated with MCNU-COP/MP than for patients treated with mCOP/MP (median, 23.0 months [95% CI, 18.9–25.8] versus 15.8 months [95% CI, 14.1–19.4]) (P = .014). However, no significant difference in overall survival rate (OS) was observed between the groups (median, 49.9 months [95% CI, 40.4-59.1] versus 44.0 months [95% CI, 32.8–59.8]) ( P = .75). Grades 3 and 4 hematological toxicities were more frequently observed with MCNU-COP/MP than with mCOP/MP, but the incidence of grades 3 and 4 nonhematological toxicities was low in both groups. In conclusion, MCNU-COP/MP in comparison with mCOP/MP improved RR and PFS in overt MM; however, this outcome did not contribute to prolonging OS, indicating that addition of MCNU to mCOP/MP has no benefit on survival.

Extragonadal germ cell tumors (EGCT) represent only 2-5% of adult germ cell malignancies. Some publications from Asia have reported inferior treatment outcomes compared to data from an international study group. To ascertain whether this is generally the case, here we analyze treatment outcomes for 30 Japanese patients with EGCT. The medical records of 30 patients (25 nonseminomas and 4 pure seminomas) treated from 1992 to 2002 were reviewed retrospectively. All patients with seminoma achieved long survival except one who died of chemotherapy-related sepsis. Ten and 11 patients with EGCT presented with mediastinal and retroperitoneal primary sites, respectively. The 5-year overall survival (OS) and progression-free survival (PFS) for nonseminoma was 71% and 42%, respectively. The 5-year OS and PFS was 60% and 44%, respectively, for 10 patients with mediastinal nonseminoma, and 91% and 48%, respectively, for patients with retroperitoneal nonseminoma. Tumor marker values on day 7 were available for 19 patients. Among the 19 patients in whom AFP or beta-HCG were measured on day 7, the values had declined in 12 patients and were transiently elevated in 7 patients compared to pretreatment values. The transient elevations of tumor markers were significantly associated with poor OS (P = 0.02) and PFS (P = 0.008). The treatment outcome of Japanese patients with EGCT seemed to be comparable to that reported from international studies, suggesting no difference between ethnic groups. Transient tumor marker elevations on day 7 predict poor survival in EGCT patients and may be a useful parameter for identifying patients requiring more aggressive treatment.

Objective: To evaluate the efficacy and toxicity of concurrent administration of doxorubicin and docetaxel, without prophylactic use of granulocyte colony-stimulating factor, as first-line chemotherapy in patients with metastatic breast cancer (MBC). Methods: This multi-institutional study enrolled 40 women; 37 were assessable for efficacy and all 40 patients were evaluated for toxicity. Treatment consisted of 50 mg/m2 doxorubicin and 60 mg/m2 docetaxel on day 1 every 3–4 weeks. Results: Patients received a total of 251 cycles of chemotherapy (median, 5 cycles; range, 1–13 cycles). Of the 37 patients assessable for efficacy, 2 had a complete response and 24 had partial responses, which accounted for a 70% objective response rate (95% confidence interval, 53–84%). The median time to treatment failure was 30.1 weeks (range, 3.3–80.7 weeks). Grade 4 neutropenia was observed in 88% of patients and was the most frequent haematological toxicity. Febrile neutropenia was seen in 40% of patients, but no severe infections were observed. Non-haematological toxicity was generally tolerable. There were 2 grade 4 adverse events, which included 1 bleeding duodenal ulcer and 1 hypersensitivity reaction, but grade 3 episodes were infrequent. None of the patients developed congestive heart failure or asymptomatic decrease of left ventricular ejection fraction to less than 50%. Fluid retention syndrome ≤ grade 2 was observed in 25% of patients at a median cumulative dose of docetaxel of 270 mg/m2. Conclusion: Concurrent administration of 50 mg/m2 doxorubicin and 60 mg/m2 docetaxel is active with a manageable toxicity profile as first-line chemotherapy for MBC.

Introduction Radical cystectomy plus platinum-based perioperative chemotherapy is a standard treatment for patients with clinically localized muscle-invasive bladder cancer. The standard perioperative chemotherapy is M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). There has been no prospective randomized trial that compare neoadjuvant and adjuvant chemotherapy for bladder cancer. And then, the efficacy of perioperative chemotherapy with gemcitabine–cisplatin (GC) has not been also clarified. We compared clinical outcomes between neoadjuvant and adjuvant chemotherapy in patients received GC. Methods We retrospectively reviewed the records of patients were planned to treat with radical cystectomy plus perioperative chemotherapy with GC from 2005 to 2010 at our institution. The eligible patients were diagnosed as clinical stage T2-4, N0-2, M0 bladder cancer. The primary outcome measure is recurrence-free survival (RFS). Results A total of 42 patients received perioperative chemotherapy with GC (25 neoadjuvants and 17 adjuvants). The median cycle number of GC between two groups was not statistically significant different. The median follow-up duration was 28.6 months. During the follow-up period, recurrence was observed in nine and three patients with neoadjuvant and adjuvant groups, respectively. The RFS rate at the median follow-up was 66.7 and 76.4% in neoadjuvant and adjuvant groups, respectively. No statistical difference in RFS at the median follow-up was observed between two groups (P = 0.124). Conclusions Form our result, there was no statistically significant difference in RFS between neoadjuvant and adjuvant GC chemotherapy for muscle-invasive bladder cancer. Our findings suggest the timing of perioperative chemotherapy is less important than whether or not a patient receives perioperative chemotherapy.

The purpose of this study was to investigate the treatable subsets in cancer of unknown primary origin (CUP). Fifty patients (27 males and 23 females; median age, 53 years) with CUP diagnosed between April 1992 and June 1999 were analyzed retrospectively. Of the 50 patients, 39 received chemotherapy: platinum-based in 31, non-platinum-based in 4, and clinical trials of new agents in 4. Of the 39 patients, 13 (33.3%; 95% confidence interval: 19.1 - 50.2%) showed objective responses, with 4 complete responders. Patients with poorly differentiated carcinomas in whom beta-subunit of human chorionic gonadotropin (beta-HCG) was elevated more than 10 mIU / ml and female patients with peritoneal adenocarcinomatosis achieved high response rates (83.3% and 80%, respectively) with platinum-based chemotherapy, as compared with only a 15.3% response rate in the remaining patients. Platinum-based chemotherapy provided promising results in patients with poorly differentiated carcinomas and in female patients with peritoneal adenocarcinomatosis. Significantly elevated serum levels of beta-HCG in patients with poorly differentiated carcinoma might predict a better response to platinum-based chemotherapy. However, the investigation of novel chemotherapeutic approaches is warranted for other groups of patients with CUP.

The crystal structure of bis(2-diethoxycarbonylethanyl-8-hydroxyquinolinato-N,O) copper(II), Cu(C17H18NO5)2, was determined by X-ray diffraction analysis. The compound crystallizes in the triclinic space group P1 with two molecules per unit cell. The cell parameters are a = 6.0177(10)A, b = 14.307(2)A, c = 19.848(3)A, α = 100.423(3)°, β = 97.987(3)°, γ = 93.783(3)°, V = 1657.1(5)A3. The structure was refined to the final R1 = 0.060, and revealed that a 2:1 complex between the ligand and Cu(II) is formed. The geometry of Cu(II) is distorted square-planar.

Latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA), NK-cell origin, and pretreatment bone marrow Epstein-Barr virus - encoded RNA by in situ hybridization (EBER-ISH) have been reported as prognostic biomarkers in patients with extranodal NK/T-cell lymphoma (NKTCL), nasal type when treated with conventional therapy (Kanemitsu N, et al. Clin Cancer Res 2012; Yoshino T, et al. Br J Haematol 2002; Kim GE, et al. Head Neck 2004; Lee J, et al. Clin Cancer Res 2007). Recently, concurrent chemoradiotherapy has become a standard management approach for newly diagnosed, localized, nasal NKTCL (Yamaguchi M, et al. J Clin Oncol 2009; Kim SJ, et al. J Clin Oncol 2009). Because it is a new treatment modality for lymphoma, little data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of known immunophenotypic biomarkers among patients treated with concurrent chemoradiotherapy, we conducted an ancillary clinicopathologic study of JCOG0211, which was a phase I/II trial of concurrent chemoradiotherapy (RT-DeVIC) for newly diagnosed, localized, nasal NKTCL (Yamaguchi M, et al. J Clin Oncol 2009 & 2012). The histological diagnoses of all 33 patients who were enrolled in JCOG0211 were confirmed as extranodal NKTCL, nasal type, by the Central Pathology Review. Pathological samples from 32 patients were available for the study. Patients received concurrent chemoradiotherapy comprising RT of 50 Gy and 3 cycles of DeVIC. The expression of LMP1 and CLA in tumor cells was examined using immunohistochemistry with paraffin sections of pretreatment lymphoma samples. Two monoclonal antibodies for TCRβ (βF1) and TCRγ (CγM1) were used to evaluate the cell of origin of lymphoma cells. Preliminary examination revealed that βF1 and CγM1 specifically recognized αβ and γδ T cells, respectively. Cases were considered to be of NK-cell origin if both TCRβ and TCRγ were negative. Cases showing positive staining for one or both of the antibodies (TCRβ and TCRγ) were determined to be of T-cell origin. Pretreatment bone marrow specimens from patients were examined for EBER-ISH. LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases, respectively. Among 32 cases examined for cell lineage, 27 (84%) cases were of NK-cell origin. Two (6%) cases were of αβ T-cell origin on the basis of positivity for TCRβ but not TCRγ, and 3 (9%) cases were of γδ T-cell origin on the basis of positivity for TCRγ but not TCRβ. Pretreatment bone marrow EBER-ISH was positive in 2 (7%) out of 29 cases examined. The median follow-up was 68 months (range, 61-94). The overall survival (OS) was better in the LMP1-positive (LMP1+) group than in the LMP1-negative (LMP1-) group [hazard ratio (HR), 0.240; 95% confidence interval (CI), 0.057-1.013; 80% CI, 0.093-0.615; P=0.035]. The OS at 5 years was 84% (95% CI, 59-95%) in the LMP1+ patients and 50% (95% CI, 18-75%) in the LMP1- patients. The progression-free survival (PFS) at 5 years was 74% (95% CI, 48-88%) in the LMP1+ patients and 50% (95% CI, 18-75%) in the LMP1- patients. The HR of PFS in the LMP1+ patients was 0.421 (95% CI, 0.121-1.463; 80% CI, 0.187-0.950). There were no significant differences in the OS and PFS between the CLA+ and CLA- patients (5-yr OS, 56% vs. 77%; 5-yr PFS, 56% vs. 68%). All 5 patients of T-cell origin achieved complete response by RT-DeVIC and were alive without relapse at the last follow-up. The OS and PFS at 5 years in the 27 patients of NK-cell origin were 67% (95% CI, 46-81%) and 59% (95% CI, 39-75%), respectively. Two patients who were positive for pretreatment bone marrow EBER-ISH survived more than 5 years without disease progression (5-yr OS and PFS, 100%). Our current study, for the first time, validated a favorable impact on the OS of LMP1 expression in newly diagnosed, localized, nasal NKTCL in a cohort uniformly treated with concurrent chemoradiotherapy. Further evaluation with a larger number of patients is warranted. (Supported in part by The National Cancer Center Research and Development Funds #21-6-3 & #23-A-17) Disclosures: Ishizuka: Sanofi: Employment. Oshimi:Eisai: Employment.

1113 Background: A pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) is well established predictive marker for long-term prognosis in patients (pts) with HER2 or triple negative (TN) breast cancer. However, predictive marker has not been established in pts with non-pCR after NAC yet. Reduction of Ki-67 value after NAC has been reported to be associated with a favorable prognosis. However, the association between the reduction rate of Ki-67 and prognosis has not been investigated in detail. This study investigates whether reduction rate of the Ki-67 could indicate a survival advantage in pts with non-pCR. Methods: A total of 450 pts who had received neoadjuvant anthracycline with or without taxane chemotherapy and surgery were analyzed retrospectively. Ki-67, hormone receptor and HER2 status were examined by immunohistochemistry (IHC) in pre-NAC biopsy samples and post-NAC surgical specimens. Pts with non-pCR were subdivided into threesubgroups according to Ki-67 change after NAC: High-reduction (absolute value of Ki-67 was reduced by > 80% compared with that prior to NAC), low-reduction (absolute value of Ki-67 was reduced by from 0% to 80% compared with that prior to NAC), and increase groups (absolute value of Ki-67 was increased compared with that prior to NAC). The relapse-free survival (RFS) rates were compared among subgroups. Results: pCR was observed in 19.5% of pts. In pts with non-pCR, a reduction in Ki-67 was observed in 64% (232/362 pts) and the median reduction rate was 60%. A total of 15% of pts were in the high-reduction, 63% in the low-reduction and 22% in theincrease group. The median follow-up was 64.5 months. The 5-year RFS rates among three groups were significantly different (p