Ocean currents and herbivory drive macroalgae-to-coral community shift under climate warming.

Coral and macroalgal communities are threatened by global stressors. However, recently reported community shifts from temperate macroalgae to tropical corals offer conservation potential for corals at the expense of macroalgae under climate warming. Although such community shifts are expanding geographically, our understanding of the driving processes is still limited. Here, we reconstruct long-term climate-driven range shifts in 45 species of macroalgae, corals, and herbivorous fishes from over 60 years of records (mainly 1950-2015), stretching across 3,000 km of the Japanese archipelago from tropical to subarctic zones. Based on a revised coastal version of climate velocity trajectories, we found that prediction models combining the effects of climate and ocean currents consistently explained observed community shifts significantly better than those relying on climate alone. Corals and herbivorous fishes performed better at exploiting opportunities offered by this interaction. The contrasting range dynamics for these taxa suggest that ocean warming is promoting macroalgal-to-coral shifts both directly by increased competition from the expansion of tropical corals into the contracting temperate macroalgae, and indirectly via deforestation by the expansion of tropical herbivorous fish. Beyond individual species' effects, our results provide evidence on the important role that the interaction between climate warming and external forces conditioning the dispersal of organisms, such as ocean currents, can have in shaping community-level responses, with concomitant changes to ecosystem structure and functioning. Furthermore, we found that community shifts from macroalgae to corals might accelerate with future climate warming, highlighting the complexity of managing these evolving communities under future climate change.

Incidence of Venous Thromboembolism in Patients Undergoing Major Hip Surgeries at a Single Institution: A Prospective Study.

BACKGROUND: Venous thoromboembolism (VTE) is one of the most significant complications after hip surgeries. Many studies have been reported about the incidence of VTE after THA, but a small number of reports were found concerning Periacetabular osteotomy, Revision THA and Surgery for hip fracture postoperatively. Furthermore, there exists no comparative study of the incidence of VTE among major hip surgeries at a single institution. We reported the incidence of VTE among hip surgeries performed at a single institution. METHODS: A total of 820 Hip surgeries were performed at same institution. The procedures included 420 hips that underwent primary total hip arthroplasties (THA), 91 revision or removal of total hip arthroplasties (Revision THA), 144 periacetabular osteotomy (PAO) and 165 surgery for hip fracture (SHF) between 2006 and 2012. VTE was detected by Multidetector computed tomography (MDCT) that scanned 768 cases and by ultrasound that scanned 52cases postoperative 10-14 days. RESULTS: The overall incidence of VTE was 12.2% (100 of 820). The incidence of VTE after THA was 13.1% (55 of 420), Revision THA was 13.2% (12 of 91), PAO was 2.1% (3 of 144) and SHF was 18.1% (30 of 165). The incidence of VTE was significantly higher in SHF than in PAO. CONCLUSION: This data indicates that the incidence of VTE after PAO is significantly lower than SHF and relatively lower than THA and Revision THA. A younger age and non-invasion of the bone marrow of the femur may have affected the result. Prophylaxis therapy was effective especially on SHF.

Phase II trial of panitumumab with irinotecan as salvage therapy for patients with advanced or recurrent colorectal cancer (TOPIC study).

Little is known about the clinical impact of salvage panitumumab with irinotecan for metastatic colorectal cancer (mCRC) patients. The present study conducted a single-arm, multicenter phase II trial for mCRC with skin toxicity prevention program. The subjects were mCRC patients with wild-type KRAS, who showed resistance to fluoropyrimidine, oxaliplatin and irinotecan. Panitumumab was administered at a dose of 6 mg/kg every 2 weeks by intravenous infusion over 60 min, and irinotecan was administered at a dose of 100-180 mg/m2 every 2 weeks by intravenous infusion over 90 min, depending on the preceding treatment dose. To prevent skin toxicities, a moisturizer was applied and oral antibiotics (100 mg minocycline twice daily) were initiated for 6 weeks. The primary endpoint was the response rate (RR) determined by independent reviewers. Secondary endpoints were the disease control rate (DCR), progression-free survival (PFS) time, overall survival (OS) time and adverse events. A total of 35 patients were enrolled between October 2010 and March 2012. The median age was 61 years (range, 41-76 years), with 25 male and 10 female patients. The initial irinotecan dose was 150 mg/m2 in 19 patients and 180 mg/m2 in 1 patient. The remaining patients were treated with ≤120 mg/m2. A central review indicated a partial response in 8 patients (22.9%) and stable disease in 6 patients (17.1%), with an RR of 22.9% (95% confidence interval, 12.1-39.0) and a DCR of 40%. The RR of the patients with standard-dose irinotecan (150 or 180 mg/m2) was 30%, although that of low-dose irinotecan (100-120 mg/m2) was 13%. The median PFS time was 2.7 months, and the median OS time was 6.3 months. A grade 3 or above acne-like rash developed in 25.7% of patients. In conclusion, panitumumab and irinotecan as salvage therapy for mCRC KRAS wild-type patients with skin toxicity prevention exhibits limited efficacy. In particular, the effect of low-dose irinotecan with panitumumab appears to be clinically insignificant. Routine use of skin toxicity prevention is currently under evaluation.

[How Jungian Psychology Has Been Developed in Japan].

Jungian Psychology was introduced to Japan in 1931 by Kokyo Nakamura for the first time in Sekai Daishiso Zenshu ("The Complete Works of Thoughts in the World") vol. 33. (Shunjusha Publishing Company). Yoshitaka Takahashi and others made Jungian Psychology more accessible to the Japanese public in the mid-1950s although they did not succeed in full repre- sentation of the fundamental ideas of C. G. Jung. It was Hayao Kawai who truly understood those ideas and initiated the Jungian movements in Japan in 1967. In my opinion, however, there are hardly any Jungian Analysts who develop Jung's ideas further enough to reach a new awareness of the human psyche except a very few people such as Neumann, E., and Gug- genbtihl-Craig, A., Kalff, D. M., Spiegelman, M., Meier, C. A. and Hillman, J., Giegerich, W, in the West and H. Kawai and me in Japan. Kawai develops and deepens Jungian thoughts to a cer- tain extent in his book, The Buddhist Priest Myoe : A Life of Dreams (Shohakusha Publishing Company), while his understanding of Buddhism does not exceed what D. T. Suzuki describes in his work, An Introduction to Zen Buddhism. That is to say the ideas of both Zen and Shin Buddhism are abstracted and assimilated in general Buddhism in his work, resulting in losing their unique features which could have been pursued further. Moreover, although Kawai translates Jung's idea of SynchronizitAt to "kyoji-sei" (synchronicity), I claim that "engi-ritsu" (the pratitya-samutpada principle) would be a more appropriate term to reflect the original concept as it would imply the opposite principle to"inga-ritsu" (the causal principle). It should be noted that the pratitya-samutpada principle is different from the Buddhist concept of pratitya- samutpada which includes causality. In addition I transcribed the Avatamsaka sutra, which originated in India and was developed in China. I also attended to the 2"d international confer- ence featuring the Avatamsaka sutra at Belesbat on the outskirts of Paris. Eventually I have reached an idea that when combined with the concept of the pratitya-samutpada principle, the Avatamsaka sutra could be considered as a-product of Eastern wisdom which would provide an insight beyond Jung. What was originally comprehended by Gautama Buddha was crystallised in abstract images of Amitabha and Vairocana in China during the second and fourth centuries. Amitabha is a celestial buddha that Shinran, the founder of Shin Buddhism, established his own understanding of in his school whereas Vairocana is a celestial buddha that appears in the Avatamsaka sutra. Vairocana could be taken as an image of the"rising sun", the creator of all things, while Amitabha as the "sinking sun", the saviour of all creatures. This picture of psychological cosmology gives a new perspective on the human psyche that would succeed Jungian Psychology. I believe this unique conception is equivalent to the findings in modern physical cosmology, such as Einstein's theories and the Alpha-Beta-Gamow paper, which provided a new understanding of the universe.

Adaptation pathways of global wheat production: Importance of strategic adaptation to climate change.

Agricultural adaptation is necessary to reduce the negative impacts of climate change on crop yields and to maintain food production. However, few studies have assessed the course of adaptation along with the progress of climate change in each of the current major food producing countries. Adaptation pathways, which describe the temporal sequences of adaptations, are helpful for illustrating the timing and intensity of the adaptation required. Here we present adaptation pathways in the current major wheat-producing countries, based on sequential introduction of the minimum adaptation measures necessary to maintain current wheat yields through the 21st century. We considered two adaptation options: (i) expanding irrigation infrastructure; and (ii) switching crop varieties and developing new heat-tolerant varieties. We find that the adaptation pathways differ markedly among the countries. The adaptation pathways are sensitive to both the climate model uncertainty and natural variability of the climate system, and the degree of sensitivity differs among countries. Finally, the negative impacts of climate change could be moderated by implementing adaptations steadily according to forecasts of the necessary future adaptations, as compared to missing the appropriate timing to implement adaptations.

Projecting the impacts of rising seawater temperatures on the distribution of seaweeds around Japan under multiple climate change scenarios.

Seaweed beds play a key role in providing essential habitats and energy to coastal areas, with enhancements in productivity and biodiversity and benefits to human societies. However, the spatial extent of seaweed beds around Japan has decreased due to coastal reclamation, water quality changes, rising water temperatures, and heavy grazing by herbivores. Using monthly mean sea surface temperature (SST) data from 1960 to 2099 and SST-based indices, we quantitatively evaluated the effects of warming seawater on the spatial extent of suitable versus unsuitable habitats for temperate seaweed Ecklonia cava, which is predominantly found in southern Japanese waters. SST data were generated using the most recent multiple climate projection models and emission scenarios (the Representative Concentration Pathways or RCPs) used in the Coupled Model Intercomparison Project phase 5 (CMIP5). In addition, grazing by Siganus fuscescens, an herbivorous fish, was evaluated under the four RCP simulations. Our results suggest that continued warming may drive a poleward shift in the distribution of E. cava, with large differences depending on the climate scenario. For the lowest emission scenario (RCP2.6), most existing E. cava populations would not be impacted by seawater warming directly but would be adversely affected by intensified year-round grazing. For the highest emission scenario (RCP8.5), previously suitable habitats throughout coastal Japan would become untenable for E. cava by the 2090s, due to both high-temperature stress and intensified grazing. Our projections highlight the importance of not only mitigating regional warming due to climate change, but also protecting E. cava from herbivores to conserve suitable habitats on the Japanese coast.

Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms.

Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI (bolus irinotecan, folinic acid, and fluorouracil followed by 46-hour fluorouracil infusion) followed by bevacizumab (5 mg/kg) in Cycle 1. In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2-week cycles. The area under-the-curves ratio (AUC0-last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN-38, SN-38G). Safety, efficacy, and drug-drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug-drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0-last ratios (with/without bevacizumab) of irinotecan, SN-38, and SN-38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression-free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. Bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status.

A microarray-based gene expression analysis to identify diagnostic biomarkers for unknown primary cancer.

BACKGROUND: The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. METHODS: Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). RESULTS: Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2-p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. CONCLUSIONS: The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP.

[An autopsy case of unresectable colon cancer who developed lung injury by cetuximab].

We report the case of a woman in her 60s with unresectable advanced colon cancer. After the first course of cetuximab as second-line therapy, she had developed drug-induced lung injury. Steroid pulse therapy had been ineffective, and she died of respiratory failure on day 9. The pathological examination of autopsy lung specimens revealed diffuse alveolar damage(DAD). Details of the cetuximab-induced lung injury are unclear. However, in 3 previous reports of lung injury by cetuximab, the postmortem findings were similar to this case. We concluded that DAD seems to be one of the pathological features of lung injury caused by cetuximab.

Intermediate- to long-term results after hybrid total hip arthroplasty in patients with rheumatoid arthritis.

There have been few reports describing intermediate- to long-term results after hybrid total hip arthroplasty in patients with rheumatoid arthritis. We followed up 52 hips in 44 patients aged 5 men and 39 women, with a mean of 11.5 years (range, 5-23.5 years). Revisions had been performed in 6 hips in 6 patients: 1 both acetabular and femoral components for infection, 1 acetabular component for aseptic loosening, 3 acetabular components for recurrent dislocation, and 1 acetabular component for dislodgement of the polyethylene liner from the metal shell. None of other acetabular or femoral components were revised or found to be loose at the final follow-up. Although postoperative dislocation remains a concern, hybrid total hip arthroplasty had an acceptable result in patients with rheumatoid arthritis.

Blockade of JNK and NFAT pathways attenuates orthopedic particle-stimulated osteoclastogenesis of human osteoclast precursors and murine calvarial osteolysis.

Particles released from orthopedic implants attract immune host defense cells to the bone-implant interface and contribute to development of inflammation. The inflammatory microenvironment supports recruitment and differentiation of osteoclasts, the primary culprit of osteolysis. Therefore, understanding the complex signals that contribute to osteoclastogenesis and osteolysis is a sensible approach to design strategies to inhibit bone loss. The signaling cascades that coordinate osteoclastogenesis have been widely investigated. These include MAP kinases, Akt/PI3K pathway, NF-κB signal transduction pathway, and NFAT pathway. We have recently reported that polymethylmethacrylate (PMMA) particles activate the NFAT pathway in murine osteoclast precursors and that NFAT inhibitors dose-dependently block PMMA-induced osteoclastogenesis. In the current study, we examined the role of JNK and NFATc1 in mice in response to PMMA particles using murine calvaria model. We show that locally administered MAPK/JNK inhibitor SP600125 and calcineurin/NFAT inhibitor cyclosporine-A effectively blocked PMMA-induced osteolysis in murine calvaria. To buttress the clinical relevance of JNK/NFATc1-based regulation of PMMA-induced osteoclastogenesis, we evaluated the effect of PMMA using human macrophages. We demonstrate that SP600125 and cyclosporine-A abolished particle-induced osteoclastogenesis in human osteoclast progenitors retrieved from patients undergoing total hip replacement. Thus JNK and NFATc1 appear to act as significant mediators of orthopedic particle-induced osteolysis in humans.

[A complete response of scirrhous gastric carcinoma treated with trastuzumab combination therapy].

Trastuzumab is the first molecular-target medicine for gastric cancer in acknowledgment of the effectiveness and safety in a randomized controlled trial for the HER2-positive gastric cancer. The HER2-positive rate of gastric cancer tends to be high for a well-differentiated adenocarcinoma. We report a case of HER2-positive scirrhous gastric carcinoma we treated, for whom a complete response was obtained by trastuzumab combination therapy. He was a 62-year-old man. In April, 2006, he was diagnosed with metastatic scirrhous gastric carcinoma(mainly poorly-differentiated adenocarcinoma). We become clear with HER2 strong positive in a pathology tissue and started capecitabine+cisplatin+trastuzumab therapy. We confirmed the disappearance of the lesion at the 10th cycle and judged it to be a complete response. The HER2 of advanced gastric cancer must be screened immediately without asking patients for their background or their clinical and pathologic features.

[Modified FOLFOX6(mFOLFOX6)in metastatic colorectal carcinoma patients with poor performance status].

Because mFOLFOX6 has few contraindications, it is useful for poor performance status(PS)cases. However, in Japan, there are some reports that the dose is reduced easily. We retrospectively examined the safety/usefulness of the full dose mFOLFOX6(first-line)for advanced colon cancer patients with poor PS. Four of five cases had improved PS. The response rate was 60%. Grade 3/4 adverse events were infection, leukopenia, and neutropenia. Treatment-related deaths within 60 days of starting treatment were absent. Full-dose mFOLFOX6 for poor PS may be beneficial. However, we must consider the increased risk of adverse events.

Lysine392, a K63-linked ubiquitination site in NEMO, mediates inflammatory osteoclastogenesis and osteolysis.

PMMA particles released from bone implants are considered major contributor to osteolysis and subsequent implant failure. Although the ensuing inflammatory response has been described, the mechanisms underlying PMMA particulate-induced osteolysis remain enigmatic. In previous studies, we have established that activation of Nuclear factor kappa-B (NF-κB) and MAP kinase pathways plays a central role in the pathogenesis of inflammatory osteolysis. Specifically, we have shown that impeding IKK complex assembly, and thus subsequent NF-κB activation, dampens particle-induced osteolysis. The IKK complex consists of IKKα, IKKß, and IKKγ, also known as NEMO. NEMO has no catalytic activity and serves as a scaffold protein facilitating assembly and distal activation of NF-κB signaling. In fact, blocking binding of NEMO with IKKα/ß abolishes NF-κB activity. In the current study, we identify Lysine 392 residue in NEMO as crucial mediator of PMMA particle-induced inflammatory osteoclastogenesis and osteolysis. Using mice in which NEMO-K392R mutation has been introduced, we provide evidence that PMMA-induced osteoclasts and osteolytic responses are impaired. Furthermore, we show that this impairment is likely due to poor activation of NF-κB and Erk, but not other MAP kinases. Our findings suggest that NEMO Lysine392, a well-established K63-linked polyubiquitination site, is an important mediator of PMMA-induced osteolysis. Therefore, this NEMO motif should be considered as a target to combat PMMA particle-induced osteolysis.

Intermediate to long-term results of periacetabular osteotomy in patients younger and older than forty years of age.

BACKGROUND: The treatment of middle-aged patients with periacetabular osteotomy remains controversial. The goal of the present retrospective study was to analyze the intermediate to long-term functional and radiographic results of periacetabular osteotomy in patients below and above the age of forty years. METHODS: Between February 1990 and December 2004, 166 periacetabular osteotomies were performed in 146 patients. We evaluated 158 hips in 139 patients who had a mean age of thirty-two years at the time of surgery. The mean duration of follow-up was eleven years (range, five to twenty years). We compared thirty-six patients (forty-one hips) who were forty years of age or older with 103 patients (117 hips) who were younger than forty years of age at the time of surgery. RESULTS: The average Harris hip score increased from 70 points preoperatively to 90 points postoperatively. The mean Harris hip scores at the time of the five-year follow-up were similar in the older and younger groups (p = 0.57), although the latest follow-up scores were significantly higher in the younger group than in the older group (91 compared with 88 points; p = 0.02). The average modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score (with 0 representing the worst score and 100 representing the best score) was higher for the younger group than for the older group (92 compared with 90 points; p = 0.03). Kaplan-Meier analysis with progression of the Tönnis grade of osteoarthritis as the end point showed a ten-year survival rate of 90.8% (95% confidence interval, 88.3% to 93.3%) and a fifteen-year survival rate of 83.0% (95% confidence interval, 78.5% to 87.5%); the ten-year survival rates in the younger and older groups were 94.4% and 81.3%, respectively, and the fifteen-year survival rates were 86.9% and 71.2%, respectively (p = 0.025). CONCLUSIONS: Periacetabular osteotomy yielded similar results for the two groups at the time of the five-year follow-up, although the results for the older group deteriorated thereafter. Decrease in physical function due to aging and increased susceptibility to the progression of osteoarthritis may be responsible for the poorer results over time in the older group.

[A case report of conversion therapy for initially unresectable colorectal cancer liver metastases after cetuximab as third-line treatment].

The introduction of monoclonal antibodies into the treatment protocols for metastatic colorectal cancer(mCRC)has significantly improved outcomes. There are some patients with mCRC, initially judged unresectable, who become resectable after chemotherapy. For patients with isolated liver metastases, surgical resection is recommended when feasible. We experienced a case in which an initially unresectable mCRC liver metastases converted into a resectable one after cetuximab monotherapy as third-line treatment. The sample from hepatectomy was a pathologically complete response; no remnants were detected. The management of liver metastases contributes to improvements in the clinical setting. For conducting a multimodal treatment of mCRC, the participation of various specialists such as medical oncologists, colorectal/hepaticsurgeons and diagnostic/therapeutic radiologists is indispensable. Furthermore, it is necessary to construct an evidence-based consensus on potentially resectable CRC liver metastases in each hospital.

Polyubiquitination events mediate polymethylmethacrylate (PMMA) particle activation of NF-kappaB pathway.

The pathologic response to implant wear-debris constitutes a major component of inflammatory osteolysis and remains under intense investigation. Polymethylmethacrylate (PMMA) particles, which are released during implant wear and loosening, constitute a major culprit by virtue of inducing inflammatory and osteolytic responses by macrophages and osteoclasts, respectively. Recent work by several groups has identified important cellular entities and secreted factors that contribute to inflammatory osteolysis. In previous work, we have shown that PMMA particles contribute to inflammatory osteolysis through stimulation of major pathways in monocytes/macrophages, primarily NF-κB and MAP kinases. The former pathway requires assembly of large IKK complex encompassing IKK1, IKK2, and IKKγ/NEMO. We have shown recently that interfering with the NF-κB and MAPK activation pathways, through introduction of inhibitors and decoy molecules, impedes PMMA-induced inflammation and osteolysis in mouse models of experimental calvarial osteolysis and inflammatory arthritis. In this study, we report that PMMA particles activate the upstream transforming growth factor ß-activated kinase-1 (TAK1), which is a key regulator of signal transduction cascades leading to activation of NF-κB and AP-1 factors. More importantly, we found that PMMA particles induce TAK1 binding to NEMO and UBC13. In addition, we show that PMMA particles induce TRAF6 and UBC13 binding to NEMO and that lack of TRAF6 significantly attenuates NEMO ubiquitination. Altogether, these observations suggest that PMMA particles induce ubiquitination of NEMO, an event likely mediated by TRAF6, TAK1, and UBC13. Our findings provide important information for better understanding of the mechanisms underlying PMMA particle-induced inflammatory responses.

[A case of metastatic colon cancer in which repetition of standard treatment proved effective].

In palliative chemotherapy, a focus on palliative treatment is recommended in cases that are unresponsive to multiple drugs. Careful judgment is needed, however, because when treatment is inadequate, cases that are considered to be unresponsive may include some in which chemotherapy would be effective. We treated a patient with metastatic colon cancer who was judged to be unresponsive to multiple drugs at another hospital, yet repetition of standard therapy proved effective. We report this case as an instructive example of the importance of maintaining dose intensity. The patient was a 60-year-old man. Lung metastasis appeared after he had undergone proctectomy and received adjuvant chemotherapy by his previous doctor. Low-dose intensity IFL therapy, FOLFOX4 therapy (once a month), and FOLFIRI therapy (once only) had been performed, but the patient's condition worsened and he was referred to our hospital. This case could not be considered unresponsive to multiple drugs because the treatment had been insufficient, and so we restarted FOLFIRI treatment with the international standard dose and obtained control of the disease. Treatment was then continued, and the patient died 2 years and 11 months after he was first examined at our hospital. Simple palliative treatment alone should not be given unthinkingly when patients are referred for outpatient palliative care. Full consideration of the dosing and schedule is needed.

Retrospective analysis of the international standard-dose FOLFIRI (plus bevacizumab) regimen in Japanese patients with unresectable advanced or recurrent colorectal carcinoma.

BACKGROUND: When applying the topoisomerase inhibitor irinotecan (CPT) with the infusional fluorouracil/levofolinate (FOLFIRI) ± bevacizumab chemotherapy regimen in cases of advanced colorectal carcinoma, the international standard dose for CPT is 180 mg/m(2). Despite this, 150 mg/m(2) CPT is widely prescribed and is the maximum dosage covered by Japanese health insurance. Consequently, the safety of dosing at the international standard has not been tested comprehensively and the efficacy of FOLFIRI in Japan may be underestimated. METHODS: To evaluate the safety of FOLFIRI (+bevacizumab) in clinical practice using international standards, we reviewed medical records of 53 patients who received FOLFIRI (+bevacizumab) with CPT 180 mg/m(2) as first-line treatment between September 2004 and August 2009. The primary endpoint of the study was to measure the relative dose intensity (RDI) of CPT after four courses. The secondary endpoint was to assess treatment completion rate, adverse events, response rate, progression-free survival (PFS) and overall survival (OS) among all patients. RESULTS: The RDI and the treatment completion rate were 88.9% and 69.8%, respectively, in the 53 patients. Accompanying grade 3 or 4 adverse events included neutropenia (35.8%), febrile neutropenia (7.5%), and diarrhea (3.8%). Supportive care managed all toxicity symptoms. Median durations for PFS and OS were 10.3 and 26.5 months, respectively. CONCLUSION: FOLFIRI (+bevacizumab) with the international standard dose of CPT is feasible in clinical practice. In order to minimize deviation of the Japanese regimen from global best practice, international dose standards should be followed.