Mechanism of action of adapalene for treating EGFR-TKI-induced skin disorder.

BACKGROUND: Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder. METHODS: To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1ß. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR. RESULTS: Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene. CONCLUSION: We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.

Diagnostic yield and the number of tumor cells of ultrathin bronchoscopy for peripheral lung lesions: A comparison with thin bronchoscopy.

Ultrathin bronchoscopy has been reported to have a higher diagnostic yield than thin bronchoscopy for small peripheral lung lesions in transbronchial biopsy under radial endobronchial ultrasonography (EBUS). However, data comparing the number of tumor cells in non-small cell lung cancer (NSCLC) are limited. We retrospectively compared the number of NSCLC tumor cells in peripheral lung lesions obtained using an ultrathin bronchoscope and a thin bronchoscope with radial EBUS between April 2020 and October 2021. In all patients, we used virtual bronchoscopic navigation (VBN) software, and guide sheaths were used in thin bronchoscopy cases. A total of 175 patients were enrolled in this study. Ultrathin bronchoscopy cases (n = 69) had lesions with a smaller diameter that are more peripherally located compared to thin bronchoscopy cases (n = 106) (median, 25.0 vs. 26.5 mm, mean bronchial generations accessed by bronchoscopy; 4.4±1.2 vs. 3.8±1.0, respectively; p<0.010). There were no significant differences in the overall diagnostic yield (ultrathin vs. thin bronchoscopy cases, 68.1% vs. 72.6%, p = 0.610) or diagnostic yield in only lung cancer cases (78.6% vs. 78.5%, p = 1.000). In histologically NSCLC cases (n = 102), the maximum number of tumor cells per slide as the primary endpoint was similar (average, 307.6±246.7 vs. 328.7±314.9, p = 0.710). The success rate of the Oncomine™ analysis did not differ significantly (80.0% vs. 55.6%, p = 0.247). The yield of NSCLC tumor cells was not different between the samples obtained by the ultrathin bronchoscope and those obtained by the thin bronchoscope.

Information provision and retrieval by registered salespersons from consumers during over-the-counter drug sales - a questionnaire survey.

BACKGROUND: In Japan, non-pharmacists who are accredited as registered salespersons can sell over-the-counter (OTC) drugs, and they play a very important role in supporting proper OTC drug use by consumers. The purpose of this study was to evaluate information provided to and information collected from consumers, and cooperation with pharmacists during OTC drug sales by registered salespersons, and to clarify their related concerns and behaviors. METHODS: A cross-sectional questionnaire-based survey of 385 registered salespersons working at 56 drugstores throughout Japan was conducted. Based on the questionnaire survey, the frequency of information provision/collection in various categories was determined for the registered salespersons. The relation between concerns of registered salespersons relating to OTC drug sales and the frequency of information provision/collection was examined. The frequency of consultation of registered salespersons with a pharmacist was calculated for registered salespersons with/without in-store pharmacists. The χ-square test or Fisher's exact test was performed to assess the significance of differences. RESULTS: Two hundred and seven registered salespersons (53.7%) responded completely. A greater number of OTC drug purchasers per day was associated with a greater frequency of information provision about "side effects" and information collection about "favorite items" (alcohol, tobacco, health foods, etc.) (p < 0.05). One hundred and thirty-nine (67.2%) participants had concerns about "interactions between OTC drugs and prescription drugs", and these concerns were related to the frequency of information provision/collection (p < 0.05). Regarding the frequency of consultation with a pharmacist, 35 of 46 participants (76.1%) working with pharmacists answered "always" or "usually", whereas only 19 of 161 participants (11.8%) working without full-time pharmacists answered "always" or "usually". More than half of the registered salespersons thought that cooperation with a pharmacist was necessary when they were "asked about concomitant use with prescription drugs" or "told that side effects happened." CONCLUSIONS: The results of this study show that experienced registered salespersons selling OTC drugs are more likely to collect information from consumers and to provide information to consumers. It appears to be important for registered salespersons to cooperate with pharmacists in order to provide and collect appropriate information about concomitant medications.

Yield of tumor samples with a large guide-sheath in endobronchial ultrasound transbronchial biopsy for non-small cell lung cancer: A prospective study.

BACKGROUND: Adequate tumor tissue is required to make the best treatment choice for non-small cell lung cancer (NSCLC). Transbronchial biopsy (TBB) by endobronchial ultrasonography with a guide sheath (EBUS-GS) is useful to diagnose peripheral lung lesions. The data of tumor cell numbers obtained by two different sizes of GSs is limited. We conducted this study to investigate the utility of a large GS kit to obtain many tumor cells in patients with NSCLC. METHODS: Patients with a peripheral lung lesion and suspected of NSCLC were prospectively enrolled. They underwent TBB with a 5.9-mm diameter bronchoscope with a large GS. When the lesion was invisible in EBUS, we changed to a thinner bronchoscope and TBB was performed with a small GS. We compared the tumor cell number prospectively obtained with a large GS (prospective large GS group) and those previously obtained with a small GS (small GS cohort). The primary endpoint was the tumor cell number per sample, and we assessed characteristics of lesions that could be obtained by TBB with large GS. RESULTS: Biopsy with large GS was performed in 55 of 87 patients (63.2%), and 37 were diagnosed with NSCLC based on histological samples. The number of tumor cells per sample was not different between two groups (658±553 vs. 532±526, estimated difference between two groups with 95% confidence interval (CI); 125 (-125-376), p = 0.32). The sample size of the large GS group was significantly larger than that of the small GS cohort (1.75 mm2 vs. 0.83 mm2, estimated difference with 95% CI; 0.92 (0.60-1.23) mm2, p = 0.00000019). The lesion involving a third or less bronchus generation was predictive factors using large GS. CONCLUSIONS: The sample size obtained with large GS was significantly larger compared to that obtained with small GS, but there was no significant difference in tumor cell number. The 5.9-mm diameter bronchoscope with large GS can be used for lesions involving a third or less bronchus generation.

Utility of an adverse drug event database based on the narrative accounts of patients with breast cancer.

Patient narratives of adverse drug events (ADEs) often differ from the symptoms listed on the package inserts of pharmaceutical products using common ADE terminology and could be a source of great comfort to patients with the same disease. To explore this idea, we analyzed written narratives obtained from 48 patients with breast cancer using the NPO Corporation Database of Individual Patients' Experiences, Japan (DIPEx-Japan). Our analysis aimed to determine the utility of an "Adverse Drug Event Database" for use in clinical settings as a novel source of disease information in patients' own words. An analysis of transcripts from 29 patients, in which they recounted their treatment drugs and the time of onset and duration of ADEs in great detail, revealed several discrepancies between the language they used to describe various side effects and the standard ADE terminology on package inserts. We conclude that the language used to describe ADEs on package inserts is insufficient for helping patients as they struggle to recognize, internalize, and overcome ADEs, and argue the need for available, detailed information in the words of real patients about the nature of the ADEs predicted, as well as their clinical course and duration. Such information would be invaluable in supplementing the standardized language used on package inserts. Databases of patients' narrative accounts of ADEs are needed as information sources that can be reliably disseminated among patients.

The process of surplus medicine accumulation by elderly Japanese patients with chronic disease: A qualitative study.

The Japanese government actively urges pharmacists to support efforts to reduce surplus medicines. However, these activities currently serve only to dispose of surplus medicines; no measures are being taken to fundamentally prevent the accumulation of surplus medicines from the outset. A deep understanding of patients' views about storing medicines at home and how they might be accumulating surplus medicines would contribute to the prevention of surplus accumulation. This study aimed to characterize the process by which elderly chronic disease patients in Japan accumulate surplus medicines. Semi-structured interviews were conducted with 18 elderly patients, and the interview data were analyzed using a modified grounded theory approach (M-GTA) to present the process by which surplus medicines were accumulated at patients' homes. The results suggest that elderly patients with chronic diseases often wish to avoid unnecessary medications because of anxiety about medicines, and that these patients seek to maximize medicine suppression. In this context, patients use their own judgment to decide whether to use medicines as needed. Additionally, when patients accumulate surplus medicines, they hesitate to throw them away because they feel that to do so is mottainai (wasteful), or because they accumulate surplus medicines as emergency household medicines. These findings reveal when and how surplus medicine accumulation occurs and the points at which pharmacists can easily intervene to promote a close relationship with patients.

Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

OBJECTIVE: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. METHODS: We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. RESULTS: The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. CONCLUSIONS: This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells.

S100A11, a small Ca2+ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

Medications associated with falls in older people: systematic review of publications from a recent 5-year period.

PURPOSE: Falls are an important public health problem in older people. Medication use is considered a risk factor for falls. This study systematically reviewed recent studies to determine the medications that might be associated with the risk of falling in older people. METHODS: We conducted a systematic review of prospective and retrospective studies identified through the MEDLINE and CINAHL databases that quantitatively assessed the contribution of medications to falls risk in participants ≥60 years old published in English between May 2008 and April 2013. RESULTS: The search identified 1,895 articles; 36 articles met the inclusion criteria. Of the 19 studies that investigated the effect of polypharmacy on the risk of falling, six studies reported that the risk of falling increased with polypharmacy. Data on the use of antihypertensive medications including calcium channel blockers, beta-blockers, and angiotensin system blocking medications were collected in 14 studies, with mixed results. Twenty-nine studies reported an association between the risk of falls and psychotropic medications including sedatives and hypnotics, antidepressants, and benzodiazepines. CONCLUSIONS: The use of sedatives and hypnotics and antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors appears to be related with an increased risk of falls. It is not clear if the use of antihypertensive medications is associated with the risk of falls in older people.

A Study on Drug Interaction between Warfarin and Capecitabine with Special Reference to the Co-Administered Term or the Discontinuation Term of Capecitabine.

We used the prothrombin time international normalized ratio(PT-INR)to investigate the change in degree and term of warfarin following co-administration and after discontinuation of capecitabine. In this study, approximately 3 years of medical records of 7 patients receiving co-administration therapy of warfarin and capecitabine were obtained from 4 hospitals. We observed daily increases in PT-INR values up to peak PT-INR levels following co-administration of warfarin and capecitabine. Interestingly, the peak PT-INR values of 4 of the patients remained remarkably high despite discontinuation of capecitabine. The peak PT-INR values for concomitant warfarin and capecitabine were attained after an average of 31.3 days of usage. When compared with the average PT-INR values attained before co-administration, the PT-INR values following co-administration significantly increased by 3 times (p<0.05). After discontinuation of capecitabine for an average of 15.1 days, i. e., for approximately 14 days, the PT-INR values returned to the PT-INR values attained prior to co-administration. These results suggest that capecitabine has influence on the anticoagulant effect of warfarin during not only the co-administered term but also the discontinuation term, and that this influence occasionally continues after discontinuation of capecitabine. These findings also suggest that a period of approximately 14 days after discontinuation is necessary for the interaction of capecitabine to dissipate and the PT-INR values to return the levels attained before receiving concomitant warfarin and capecitabine.

First case report of suspected onset of convulsive seizures due to co-administration of valproic acid and tebipenem.

OBJECTIVE: A patient presented with convulsive seizures when sodium valproate (VPA) and tebipenem pivoxil (Orapenem) were co-administered accidentally. The seizures were suspected to be caused by a reduced concentration of VPA in the blood. CASE SUMMARY: A 6-year-old boy (weight: 16 kg, at the start of treatment) began sodium valproate (valproate syrup 5%) treatment for epilepsy in February 2012. At a dose of 350 mg/day, he experienced no convulsive seizures and maintained stable symptoms for the past 9 months. In December, he was prescribed 160 mg/day tebipenem pivoxil by an otolaryngologist for inflammation of the tympanic membrane. He experienced convulsive seizures the day after beginning co-administration. The concentration of VPA in his blood at this time was 30.0 µg/mL, which was lower than the optimal blood concentration. DISCUSSION: Marked reduction of VPA concentration in the blood due to co-administration of VPA and injectable carbapenem antibiotics has been well-documented; however, this is the first report of such an interaction with tebipenem, which is an orally-administered carbapenem antibiotic. Although the mechanism of drug interaction between VPA and carbapenem antibiotics is not fully understood, it is thought that VPA blood concentrations decrease due to production of valproic acid glucuronic acid conjugates (VPA-Gluc) being promoted directly or indirectly by carbapenem antibiotics. When we assessed the patient according to the DIPS system, we calculated a score of +4 (possibility of interaction). CONCLUSIONS: The results suggest that co-administration of oral carbapenem antibiotics and VPA should be avoided.

[Problems of collaboration between community and hospital pharmacists for cancer chemotherapy and proposed corrective measures: KJ method based identification and planning workshop].

We conducted a workshop that aimed to address the problems of collaboration between community and hospital pharmacists to provide safe outpatient chemotherapy and promote continuous collaboration. Thirty-nine pharmacists in Gunma were enrolled in the workshop and divided into five groups. Each group comprised similar number of community and hospital pharmacists in the neighboring area. Participants in these groups discussed using the KJ method and identified the following important and urgent problems; "lack of collaboration between hospitals and pharmacies" and "lack of exchanging patients' information, including regimen". To improve collaboration, the participants recommended a workshop or a study group and setting up a hotline, and to exchange patients' information, they proposed to utilize a medicine notebook and reconfirm how to use these notebook. Furthermore, usage of cloud storage as a means to exchange patients' information was discussed. Post-workshop questionnaire revealed that 97% participants acknowledged an increased awareness toward collaboration, and 90% participants were motivated to take more aggressive action for promoting collaboration; whereas, only 53% participants believed that they could summarize the problems and corrective measures in promoting collaboration. The workshop seemed to be productive in identifying the problems of collaboration and improving the awareness and motivation toward collaboration. However, it served only as a "trigger", and therefore it is important for valuable "results" to continuously collaborate face-to-face between community and hospital pharmacists.

Sequential interaction of phenytoin and phenobarbital with fluorouracil.

OBJECTIVE: We report a case of sequential interaction of phenytoin (PHT) and phenobarbital (PB) with fluorouracil (5-FU). CASE REPORT: A male patient aged 60 under treatment with PHT and PB in which serum concentrations of PHT (32.8 µg/ml) and PB (26.7 µg/ml) increased ~ 2-fold after the start of postoperative adjuvant therapy with calcium levofolinate (l-LV) and fluorouracil (5-FU). When the drug interactions of this case evaluated using the Drug Interaction Probability Scale, was assessed as "probable". DISCUSSION: In this case, 5-FU increased PHT, which in turn may have increased the PB concentration, suggesting that when fluoropyrimidine antitumor agents are administered to patients receiving PHT in combination with other drugs, some measures should be taken in consideration of secondary effects of antitumor agents on other drugs that may possibly interact with PHT, including frequent monitoring of blood drug concentration.

[Single-stage procedure for multiple dissected aortic aneurysms with coagulopathy in an elderly patient].

An 86-year-old man was admitted for abdominal pain. Dissected descending thoracic aortic aneurysm and infrarenal abdominal aortic aneurysm were observed under computed tomographic (CT) scan. Hematologic studies revealed low platelet count and an increase in fibrin degradation products (FDP), and disseminated intravascular coagulation( DIC) associated with dissecting aortic aneurysm was highly suspected. Platelet transfusion was performed and gabexate mesilate was administered, however, no improvement of DIC could be obtained. An increase in aortic diameter was observed under CT scan and surgery was performed. The infrarenal aneurysm was replaced with a bifurcated prosthetic graft under open repair. Simultaneously, an endovascular stent-graft was delivered from the left limb of the abdominal graft and implanted into the descending thoracic aorta. The postoperative recovery was uneventful but platelet count did not improve in this case.

Example of evoked potential monitoring for a neurogenic tumor positioned high in the mediastinum.

Excision of a neurogenic tumor of the brachial plexus positioned high in the mediastinal space could potentially result in a functional disorder of the arm. We report on a case in which we performed evoked potential monitoring on a tumor located high in the mediastinum. We found large potential changes in the median and ulnar nerve areas and had a concern that the excision might injure the brachial plexus. We did a biopsy and intraoperative rapid histological diagnosis, which promptly revealed that the tumor was not malignant. Thus, we decided not to excise the tumor because the procedure could possibly injure nerves in the arm.

Brachial-ankle pulse wave velocity is an independent predictor of incident hypertension in Japanese normotensive male subjects.

OBJECTIVES: Cardiovascular morbidity and mortality are closely associated with hypertension, however, predictors of incident hypertension have not been fully established. We have conducted a study aimed at evaluating whether brachial-ankle pulse wave velocity (baPWV) is a predictor of incident hypertension. METHODS: The relation between baPWV, a noninvasive index of aortic stiffness, and incident hypertension was evaluated in a cohort of 2278 Japanese normotensive male subjects with a follow-up of 3 years. RESULTS: Of the 2278 study participants, 151 (6.6%) had incident hypertension during the follow-up. After adjustment for variables, including age, gender, body mass index (BMI), smoking habit, alcohol consumption, diabetes mellitus, hyperlipidemia, family history of hypertension, heart rate, systolic blood pressure, low-density lipoprotein cholesterol, triglyceride, and fasting plasma glucose, multiple logistic regression analysis revealed that baPWV was a significant and independent predictor of incident hypertension with an adjusted odds ratio 1.45 (95% confidence interval 1.17-1.79, P < 0.01). In addition, baPWV values >1380 cm/s indicated a high risk for incident hypertension. CONCLUSIONS: Among the Japanese normotensive male subjects participating in this study, BaPWV was a significant and independent predictor of incident hypertension. This result suggests that BaPWV could be a useful screening method to identify normotensive individuals who should be targeted for interventions aimed at preventing the incident hypertension.

Inhibitory effects of herbal extracts on breast cancer resistance protein (BCRP) and structure-inhibitory potency relationship of isoflavonoids.

The inhibition of intestinal breast cancer resistance protein (BCRP), which restricts the absorption of xenobiotics, may increase the systemic availability of its substrates. The aim of this study was to evaluate the inhibitory effects of herbal extracts and their constituents on BCRP-mediated transport. The inhibitory effects of 9 herbal extracts and 23 isoflavonoids, including soybean-derived isoflavones, on BCRP-mediated methotrexate (MTX) transport were evaluated using BCRP-expressing membrane vesicles. The structure-inhibitory potency relationship was investigated by multiple factor analysis. Extracts of soybean, Gymnema sylvestre, black cohosh and passion flower and rutin strongly inhibited BCRP-mediated transport of MTX at 1 mg/ml, while inhibition by chlorella, milk thistle and Siberian ginseng extracts was weak. Among the 23 isoflavonoids examined, all of which inhibited BCRP-mediated transport, coumestrol showed the most potent inhibition (IC(50)=63 nM). The inhibitory potencies of 6 isoflavonoid glucosides were 10- to 100-fold lower than those of the corresponding aglycones. The addition of a 5-hydroxyl or 6-methoxyl moiety tended to potentiate the inhibition. The inhibitory potency of daidzein was decreased 100-fold by 7-glucuronidation, but was virtually unaffected by 4'-sulfation. Thus, some herbal and dietary supplements and isoflavonoids may increase the systemic availability of BCRP substrates when concomitantly given orally.

Saturable binding of finasteride to steroid 5alpha-reductase as determinant of nonlinear pharmacokinetics.

Finasteride, a steroid 5alpha-reductase (5alphaR) inhibitor, is used to treat benign prostatic hyperplasia and androgenetic alopecia. We aimed to develop a pharmacokinetic/pharmacodynamic model to explain its nonlinear pharmacokinetics and describe the serum concentration profile of dihydrotestosterone (DHT) after finasteride administration. We developed a pharmacokinetic model incorporating a compartment that represents the binding of finasteride to 5alphaR. We fitted this model to the time-concentration profiles of finasteride after repeated administration of finasteride 0.2 and 1 mg/day. We constructed a pharmacodynamic model considering the inhibition of 5alphaR type I and type II (5alphaR1 and 5alphaR2). This model was fitted to the time profiles of serum DHT. The developed pharmacokinetic model well described nonlinear increase in AUC after repeated administration of finasteride. The association and dissociation rate constants were estimated to be 0.0293/nmol/hr and 0.0185/hr, respectively. Pharmacodynamic model analysis suggested that the 5alphaR1 inhibition is dose-dependent in the dose range from 0.2 to 100 mg, while the 5alphaR2 inhibition is almost saturated in the same dose range. Finasteride's saturable binding to 5alphaR2 is the likely cause of its nonlinear pharmacokinetics. The developed pharmacokinetic/pharmacodynamic model should allow prediction of plasma concentration profiles of finasteride and DHT.

[Prevention of wound complications after salvage total laryngectomy following chemoradiotherapy with a pectoralis major muscle interposition flap].

There is an increased risk of wound complications in patients undergoing salvage laryngectomy following chemoradiotherapy. To reduce the rate of wound complications after a salvage total laryngectomy, a fresh tissue reinforcement of the pharyngeal suture line (pharyngeal interposition graft) has been reported to be useful. In the present study, wound complications after a salvage total laryngectomy with a pectoralis major muscle flap as a pharyngeal interposition graft were analyzed. Four patients with recurrent laryngeal cancer (three with supraglottic, and one with glottic cancer) after chemoradiotherapy underwent salvage total laryngectomy using a pectoralis major muscle interposition flap. Minor wound complications were observed in three of the four patients, with an infection around the tracheostoma, a minor subcutaneous abscess, and a superficial skin necrosis in one patient each. These complications were managed with local wound care. No patients had major wound complications such as pharyngocutaneous fistulas. There were no necroses or wound complications of the pectoralis major muscle flap. This study has suggested that the pectoralis major muscle flap as a pharyngeal interposition graft is safe and useful for prevention of wound complications in salvage total laryngectomy following chemoradiotherapy.

Increased anticoagulant activity of warfarin used in combination with doxifluridine.

PURPOSE: The purpose of this article is to report the first case of markedly increased anticoagulant activity of warfarin when used in combination with doxifluridine, given as a replacement for capecitabine. METHODS: International normalized ratio (INR) of a 73-year-old female patient receiving warfarin was increased after starting chemotherapy using oral fluoropyrimidines (capecitabine or doxifluridine). Since the concomitant use of warfarin and the oral fluoropyrimidines was unavoidable in this case, the warfarin dosage was adjusted to keep INR within goal range (1.7-2.7). To evaluate the effects of the oral fluoropyrimidines on the anticoagulant activity of warfarin, the INR/Dose (warfarin dose in mg/day) was used. RESULTS: To keep INR within goal range, the maintenance dosage of warfarin was reduced during the treatment with doxifluridine as well as capecitabine. It was finally reduced from 5 mg daily in the absence of oral fluoropyrimidines to 1.5 mg daily during the concomitant use of doxifluridine (600 mg daily). In contrast, the higher INR/Dose (1.03-1.66) was continued during the concomitant use of warfarin and doxifluridine compared with the INR/Dose before the start of chemotherapy (about 0.5). These results clearly indicate that the anticoagulant activity of warfarin was markedly increased by the concomitant use of doxifluridine as well as capecitabine. CONCLUSIONS: It is important that physicians closely monitor anticoagulant activity in patients concomitantly receiving doxifluridine and warfarin, and appropriately adjust the dose of warfarin.