A 87-year-old man was diagnosed with prostate cancer (cT2aN0M0 Gleason score 4＋4 with initial prostate specific antigen of 23.4 ng/ml). Prostate cancer was treated with combined androgen blockade (goserelin acetate plus flutamide). He was administered goserelin acetate depot injection without any complications as an outpatient. However, 5 hours after he left the hospital, he came back to the hospital, complaining of lower abdominal pain. Abdominal computed tomography revealed a giant subcutaneous hematoma in the lower abdomen. Hemoglobin was 6.9 g/dl and blood pressure was lower than 80 mmHg. He was admitted and given a blood transfusion. Because of pre-disseminated intravascular coagulation score 6, it was hard to antagonize warfarin by Vitamin K (he had taken warfarin because of atrial fibrillation). Arteriography was performed and injury to a branch of the lower epigastric artery was found. Transcatheter arterial embolization was performed at the same time. Injecting goserelin acetate may cause severe arterial injury.

Molecularly targeted anticancer agents cause a variety of adverse reactions compared with conventional anticancer agents because of their unique mechanisms of action. Sources of drug information such as package inserts (PIs) provide primarily document-based and numerical information. Therefore it is not easy to obtain a complete picture of drugs with similar effects, or to understand differences among drugs. In this study we used the self-organizing map (SOM) technique to visualize the adverse reactions indicated on PIs of 23 molecularly targeted anticancer agents as of March 2013. In both the presence/absence version and the frequency version, SOM was divided into domains according to mechanism of action, antibody drug or low-molecular weight drug, and molecular target. The component planes of the 753 adverse reaction items in the frequency version enabled us to grasp all available information and differences among the drugs. In some component planes in the presence/absence version, an adverse reaction that had not been reported for a drug but had already been reported for its proximally positioned drug(s) as of March 2013, was found to be reported thereafter by the Drug Safety Update (DSU) or the Adverse Event Report Search System "CzeekV," which is based on FDA Adverse Event Reporting System (FAERS). Our results suggest that visualization of the adverse reactions of molecularly targeted anticancer agents by the SOM technique is useful not only to acquire all available information and differences among drugs, but also to predict the appearance of adverse reactions.

We encountered cases of capecitabine-induced increase in blood triglyceride (TG) levels, which is relatively rare in routine medical practice. Although capecitabine-induced hypertriglyceridemia (CI-HTG) has been occasionally reported in other countries, such cases have not been reported in Japan. Therefore, the details of this condition remain to be clarified. To obtain evidence that would be useful in routine medical practice, we conducted a retrospective study of patients with CI-HTG. The study included 56 patients, of whom, 14 (25.0%) had TG levels < 150 mg/dL before capecitabine treatment that increased to ≥ 150 mg/dL after treatment. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, v4.0, Japanese edition, Japan Clinical Oncology Group version (CTCAE v4.0-JCOG). We found that TG levels were markedly elevated (≥ Grade 3) in 2 patients (3.6%). Thus, CI-HTG also affects Japanese patients, although its frequency is relatively low. Detailed studies including a larger number of facilities should be conducted in future.

This review describes the synthesis and evaluation of novel nucleic acid derivatives performed by our research group to date. We developed a new method for the synthesis of 2-alkoxyadenosine analogs via nonaqueous diazotization-dediazoniation reactions. By applying these reactions, we effectively synthesized four types of carbocyclic oxetanocin analogs (2-alkoxy-C.OXT-A). The angiogenic activities of these compounds were evaluated using human umbilical vein endothelial cells. This resulted in increased activities of the analogs, especially of 2-methoxy-C.OXT-A and 2-isopropoxy-C.OXT-A, at a concentration of 100 μM; they showed angiogenic potency similar to or greater than that of vascular endothelial growth factor. We also synthesized and evaluated a novel series of uracil derivatives carrying a 3,5-dimethylbenzyl group at the N(3)-position and acting as non-nucleoside HIV-1 reverse transcriptase inhibitors. Some of these compounds showed good-to-moderate inhibitory activity, with EC₅₀ values in the submicromolar range. Among them, the analog 6-amino-1-(4-picolyl)-uracil showed significant HIV-1 reverse transcriptase inhibition, with an EC₅₀ value of 0.03 μM and a high selectivity index of 2863.

Little attention has been paid to the hazards that healthcare professionals may be exposed to when administering drugs to patients. Hazardous drugs, even in very low concentrations, can produce adverse reactions in patients and in healthcare professionals who handle the drugs or work in the vicinity. Small amounts of hazardous drugs have been detected in the urine of healthcare professionals who prepare or administer these drugs even with the use of safety protection. Moreover, environmental contamination of hazardous drugs has been reported in a survey of patient care surroundings even when handling guidelines have been followed. The academic subcommittee of the Japanese Society of Hospital Pharmacy has established guidelines for the handling of hazardous drugs; however, reports suggest that there are problems with compliance to the guidelines. Recently, closed system devices have been marketed for use in healthcare settings to reduce environmental contamination during drug preparation. However, these devices have not gained widespread use because of their high cost and incompatibility with certain products like ampules. In addition, it is not clear whether the hazardous drugs are deactivated by these devices. In an effort to prevent healthcare professionals from being exposed to hazardous drugs, it is important to clean up contaminated surfaces and also to prevent dangerous drugs from spreading.

A 51-year-old man with a history of an abdominoperineal resection of the rectum and colostomy for rectal cancer underwent chemotherapy for multiple liver metastases.Twenty -two courses of the folinic acid, 5-fluorouracil(5-FU)and oxaliplatin(FOLFOX4)/bevacizumab(BEV)regimen and 39 courses of 5-FU/Leucovorin/BEV were administered.Progressive splenomegaly and stomal varices were observed during the course of chemotherapy.The patient was admitted due to excessive bleeding after colostomy.Angiography revealed bleeding stomal varices secondary to portal hypertension.Splenectomy was performed with subsequent reduction in the size of the stomal varices and no rebleeding was observed.Oxaliplatin -based chemotherapy could lead to hepatic sinusoidal dilation and induce splenomegaly and varix formation secondary to portal hypertension.Our experience with this case suggests that careful attention should be paid to stomal varices in colostomy patients receiving oxaliplatin-based chemotherapy.

The efficacy of docetaxel, vinorelbine, or gemcitabine monotherapy in previously untreated elderly patients with non-small cell lung cancer has been reported.Pemetrexed monotherapy has shown clinically equivalent efficacy to docetaxel, a standard therapeutic option, in patients with previously treated non-small cell lung cancer and in those with a lower incidence of toxicity such as febrile neutropenia.

Prostate cancer is a heterogeneous disease that responds variably to available agents, particularly androgen receptor(AR)- targeting agents. In preclinical models, cabazitaxel, a second-generation taxane, demonstrated enhanced antitumor activity when compared with docetaxel. In subsequent clinical trials, cabazitaxel was associated with pharmacokinetic, safety, and tolerability profiles consistent with those of previous taxanes. In the pivotal phase III study(TROPIC; NCT00417079), cabazitaxel led to significantly improved overall survival in patients with metastatic castration-resistant prostate cancer(mCRPC), compared with mitoxantrone, when both were administered in combination with prednisone/prednisolone(median survival: 15.1 months[95%confidence interval(CI): 14.1-16.3]vs 12.7 months[95% CI: 11.6-13.7], hazard ratio(HR): 0.70[95% CI: 0.59-0.83], p<0.0001), and it also extended progression-free survival. Furthermore, a long-term analysis of the TROPIC trial revealed that the survival benefit with cabazitaxel was maintained at 2 years, with 60(15.9%)patients in the cabazitaxel group and 31(8.2%)patients in the mitoxantrone group surviving for B2 years(odds ratio: 2.11, 95% CI: 1.33-3.33). Cabazitaxel also provides pain palliation similar to that provided by using mitoxantrone. The safety profile of cabazitaxel is consistent with that of first-generation taxanes, and gastrointestinal(predominantly diarrhea)and hematologic(mainly neutropenia)adverse events are the most frequently reported. Clinical trial data suggest that these events can be managed with careful monitoring and dose reduction where necessary. In addition, treatment with granulocyte colony-stimulating factor(G-CSF)can mitigate hematologic adverse events, whereas supportive treatment with antiemetic and antidiarrheal agents may ameliorate gastrointestinal symptoms. The treatment paradigm for mCRPC is evolving rapidly with the emergence of data for new agents, leading to maximization of patient benefits. The proven efficacy and tolerability profiles of cabazitaxel suggest the promising role of this agent within this paradigm.

The patient was a 73-year-old Japanese female diagnosed with stage IIIc primary peritoneal cancer. After undergoing total hysterectomy and bilateral oophorectomy, she received regimens consisting of paclitaxel (PTX) and carboplatin (CBDCA). She subsequently developed recurrence four years after the disease onset and was treated with PTX, CBDCA and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Bev). Although clinical remission was maintained with the administration of Bev monotherapy every three weeks, proteinuria was detected six months later, and gradually increased. The findings of a renal biopsy showed diffuse wrinkling and double contouring of the glomerular tufts under light microscopy, although no immune complex deposition was observed on immunostaining. Additionally, electron microscopy showed hypertrophy of glomerular endothelial cells and widening of the subendothelial spaces. These histopathological findings were fully consistent with those of reported patients treated with VEGF inhibitors. The proteinuria attenuated following the initiation of treatment with losartan. Therefore, the administration of renoprotective therapy contributed to the patient's ability to continue the anticancer regimen with Bev in this case.

Panitumumab was approved in June 2010 for use in the treatment of unresectable advanced/recurrent colorectal cancer. Here, we report outcomes and adverse events of panitumumab combination therapy or single-agent chemotherapy for K-ras wild-type unresectable or recurrent colorectal cancers. Our study focused on first-line treatments. The study involved 18 patients who started receiving panitumumab in October 2010. Nine patients received panitumumab as a first-line treatment; 4, as a second-line treatment; and 5, as a third-line or subsequent treatment. The overall response rate was 27.8%. Among the patients who received panitumumab as a first-line treatment, the response rate was 55.6%. Grade 1 and 2 skin disorders were common adverse events. Grade 2 interstitial pneumonia was observed in 1 patient(5.6%). Grade 3 or higher events comprised peripheral neuropathy in 1 patient(5.6%)and neutropenia in another patient(5.6%). The treatment was beneficial, and metastatic foci were resected in 3 patients. In this study, the only adverse events of Grade 3 or higher were 1 case each of peripheral neuropathy and neutropenia. Accordingly, adequate control seemed possible. The specific line of treatment that panitumumab should belong to remains controversial. However, active initiation as first-line treatment should be considered for cases in which resection of metastatic foci can be expected from tumor reductions due to panitumumab.

The Japanese guidelines for the proper use of granulocyte-colony stimulating factor(G-CSF)have been revised on the basis of the current international guidelines and latest evidence. The guidelines for primary and secondary prophylactic administration of G-CSF are clearly defined in the revised version. Primary prophylactic administration is recommended as per the incidence of febrile neutropenia(FN): it is highly recommended for patients with an FN rate>20%, but selectively recommended for patients with an FN rate<20%. Secondary prophylactic administration is recommended only for patients who should be maintained on a constant dose of G-CSF for curative purposes. The revised version aims to improve, not limit, the clinical use of G-CSF based on both patient- and evidence-oriented decisions in clinical practice.

Guidelines for proper use of the G-CSF(2001 edition)by the Japan Society of Clinical Oncology have been revised the first time in 12 years. The differences between the first edition and the new one are as follows: The new guidelines(2013 edition) adopted the clinical question format, and used the level of evidence and recommendation grades, along with the Handbook of Clinical Guidelines of Minds(2007 edition). There are relatively few evidence-based randomized controlled trials(RCTs) that can inform G-CSF use in Japan at present. Thus, we had to select the evidence from RCTs conducted in Europe and the USA when setting the recommendation level. Guidelines from Europe and the USA were also referred to; however, because the incidence of febrile neutropenia(FN)is presumed to differ between Japan and the USA/Europe, the clinical trials conducted in Japan were investigated as much as possible. New chapters on topics such as biosimilars, pegfilgrastim(domestic non-release), and the dosage and method of G-CSF administration(medical insurance in Japan)were added. The chemotherapy regimen-specific incidence of FN in Japan for primary prophylactic G-CSF administration and G-CSF use in hematological malignancy were described in detail. Nurses, pharmacists, and medical doctors participated in guideline steering committee, because the new guidelines are directed at a wide range of health care workers.

Erythema multiforme (EM) is a known side effect of sorafenib therapy in cancer patients; at onset, the causative medication should be permanently discontinued. Here we report two cases of hepatocellular carcinoma (HCC) that developed sorafenib-induced EM. In both cases, retreatment with sorafenib combined with steroid therapy achieved effective tumor control without EM recurrence. The first patient was a 72-year-old woman who showed a dramatic response to sorafenib retreatment, with complete remission after 8 months of therapy. There was no rash recurrence after the steroid dose was gradually tapered and stopped. The second patient was a 69-year-old man who responded to sorafenib and exhibited stable disease, with no recurrence of the rash after the steroid dose was tapered. However, mild hand-foot syndrome persisted throughout sorafenib therapy. Although sorafenib should be discontinued if EM occurs, if there is no suitable alternative treatment, retreatment may be considered with steroid cover in patients with unresectable HCC.

A 67-year-old woman with acute Philadelphia-chromosome-positive mixed phenotype leukemia developed bilateral periorbital ecthyma gangrenousum (EG) subsequent to periorbital edema while undergoing combined imatinib mesylate (imatinib) chemotherapy. Although initial periorbital edema was considered an imatinib side effect, the lesion deteriorated rapidly with high fever in the neutropenic phase, and the woman died of septic shock. Cultures from blood and exudative fluid grew Pseudomonas aeruginosa, after which EG was diagnosed. EG is a well-recognized emergent cutaneous infection most commonly associated with Pseudomonas aeruginosa bactremia. Because some patients present with EG a few days prior to developing life-threatening septicemia, it is important that EG be diagnosed correctly. Imatinib side effects such as edema are usually tolerable, and imatinib is widely used to treat Philadelphia-chromosome-positive leukemia, particularly in those with acute lymphoblastic leukemia, and neutropenic patients undergoing imatinib therapy are expected to increase in number. Delay in initiating appropriate therapy is correlated with poor outcome, so drug side effects and EG must be carefully differentiated when skin edema with surrounding erythema is noted in neutropenic patients undergoing imatinib therapy.

We prospectively investigated the safety and efficacy of sunitinib using a modified regimen (2 weeks on/1 week off) in 24 patients (22 males, 2 females ; age range 39-86 years, median 64 years) with metastatic renal cell carcinoma (RCC). During the observation period (3-62 weeks, median 21 weeks), thrombocytopenia was seen in 13 (54.2%), leukopenia in 11 (45.8%), hand-foot syndrome in 5 (20.8%), hypertension in 4 (16.7%), and hypothyroidism in 3 (12.5%) patients, while grade 3 or higher adverse events were found in 4 (16.7%), 1 (4.2%), 1 (4.2%), 2 (8.3%), and 0 patients, respectively. Of the 21 patients evaluable for response, 5 (23. 8%) showed partial response, 8 (38.1%) stable disease, and 8 (38.1%) progressive disease. This new modified regimen may lead to a reduction in adverse events for treatment of patients with metastatic RCC as a substitute for the standard dosing regimen of sunitinib.

A 53-year-old man initially presented with costalgia and was diagnosed with MM, based on the pathological findings. IgE monoclonal protein was detected by Serum protein electrophoresis (SPEP) and, surprisingly, IgE was elevated to 7,950,000 IU/ml. Monitoring the disease response during treatment, we employed quantification of serum M protein at SPEP, because IgE levels were found to be inaccurate and erratic. The patient was treated with CyBorD. He found injection site reactions to be very burdensome, due to extreme skin changes. The diameter of the hyperpigmentation area was 8 cm. To reduce the severity of this reaction, we used an air sandwich technique, and succeeded in ameliorating the skin changes.