Detailed Analysis of Three Major Breast Reconstructions Using BREAST-Q Responses From 1001 Patients.

BACKGROUND: Patient-reported outcomes have become as important as mortality and morbidity in the postoperative evaluation of breast reconstruction surgery. The BREAST-Q is one of the most widely used patient-reported outcomes for breast reconstruction. OBJECTIVES: A comparative analysis of the scores on each of the BREAST-Q modules could help analyze different reconstruction methods. However, few studies have utilized BREAST-Q for this purpose. The aim of this study was therefore to compare breast reconstruction methods in terms of BREAST-Q module ratings. METHODS: The authors retrospectively reviewed the data of 1001 patients who had been followed for more than 1 year after breast reconstruction. The 6 BREAST-Q modules were rated on a scale of 0 to 100 and statistically analyzed by multiple regression. In addition, Fisher's exact test was performed after dividing the responses to each question into high- and low-rating groups. RESULTS: Microvascular abdominal flap reconstruction scored significantly better than implant-based reconstruction on all modules, except psychosocial and sexual well-being. In terms of satisfaction with the breast, latissimus dorsi flap reconstruction was superior to implant-based reconstruction. However, in terms of the reconstruction method, there were no differences in patients' willingness to make the same choice again or whether they regretted having surgery. CONCLUSIONS: The results highlight the superiority of autologous breast reconstruction. Reconstruction methods should only be performed after a thorough explanation of their characteristics to achieve results that meet patient expectations. The findings are useful for facilitating patient decision-making in breast reconstruction.

Tertiary Autologous Breast Reconstruction After Implant-Based Reconstruction: Safety and Patient-Related Outcomes.

Silicone breast implants are popularly used for breast reconstruction. As more patients receive long-term silicone breast implants, the number of replacement operations will also increase, and some patients prefer to change from silicone breast implantation to tertiary autologous reconstruction. We evaluated the safety of tertiary reconstruction and assessed patient views regarding the two reconstruction methods. We retrospectively analyzed patient backgrounds, surgical characteristics, and silicone breast implantation retention periods until tertiary reconstruction. We designed an original questionnaire to assess patient opinion regarding silicone breast implantation and tertiary reconstruction. Twenty-three patients (24 breasts) with decisive factors of patient-initiated elective surgery (n = 16), contralateral breast cancer occurrence (n = 5), or late-onset infection (n = 2) underwent tertiary reconstruction. The median time from silicone breast implantation to tertiary reconstruction was significantly shorter in patients with metachronous cancer (47 months) than that in those undergoing elective surgery (92 months). Complications included partial flap loss (n = 1), seroma (n = 6), hematoma (n = 5), and infection (n = 1). Total necrosis did not occur. Twenty-one patients responded to the questionnaire. The satisfaction score was significantly higher for abdominal flaps than for silicone breast implants. When presented with the option to select the initial reconstruction method again, 13 of 21 respondents chose silicone breast implantation. Tertiary reconstruction is beneficial because it reduces clinical symptoms and cosmetic complaints and is recommended as a bilateral reconstruction method, especially for patients with metachronous breast cancer. However, silicone breast implants, which are minimally invasive and associated with shorter hospital stays, were simultaneously found to be sufficiently attractive to patients.

The Effects of Vonoprazan Fumarate on the Tacrolimus Blood Concentration in Liver Transplant Recipients.

BACKGROUND/AIM: The proton pump inhibitors were reported to affect the blood concentration of tacrolimus. Vonoprazan fumarate is a new acid suppressant with potent acid inhibitory effects. There have been no reports concerning the effect of vonoprazan on the tacrolimus blood concentration in liver transplant (LT) recipients. PATIENTS AND METHODS: Eighteen living donor liver transplantation (LDLT) recipients who switched from proton pump inhibitors (PPIs) to vonoprazan between 2016 to 2018 were enrolled in this retrospective study. We investigated blood levels of tacrolimus, and liver and renal function before and after the change from PPIs to vonoprazan. RESULTS: The median C 0 /D of tacrolimus before conversion, 3 months after conversion, and 6 months after conversion were 2.33, 1.53, and 1.89, respectively, and there was no significant difference. Conversion from another PPI to vonoprazan was not associated with a worsening liver function. The estimated glomerular filtration rate was significantly worse after conversion. CONCLUSION: Vonoprazan can be safely administered to LT recipients receiving tacrolimus during the stable period.

Safety evaluation of immediate breast reconstruction for locally advanced breast cancer in Japanese patients.

BACKGROUND: While breast reconstruction often improves the quality of life of patients with locally advanced breast cancer, there is still no consensus on its safety. This retrospective report aimed to verify the safety of immediate breast reconstruction for locally advanced breast cancer. METHODS: We retrospectively analyzed 500 breast cancer surgeries performed between January 2005 and December 2019 at our hospital, including 120 immediate breast reconstructions. The following five items were analyzed: the patients' choice of reconstruction method, rate of chemotherapy and radiotherapy, surgical margin positivity rate, complications associated with surgery, overall survival rate, and breast cancer-free survival rate. RESULTS: Sixty-three of the 120 patients underwent autologous breast reconstruction. Of those who underwent reconstruction surgery, 95.8% received chemotherapy and 78.3% underwent post-mastectomy radiation therapy. Reconstruction failed in 8 cases with tissue expander and in 1 case with free TRAM flap. Breast reconstruction surgery was not a factor in delaying adjuvant therapy, but complications requiring intervention tended to increase the duration of adjuvant therapy. There was no statistically significant difference in the rate of surgical margin positivity, overall survival rate, or breast cancer-free survival rate. CONCLUSIONS: Although complications associated with reconstructive surgery occurred, appropriate intervention prevented delays in breast cancer treatment, and the complications did not negatively affect the overall or breast cancer-free survival rates. Our study found no evidence to avoid primary breast reconstruction in patients with locally advanced breast cancer.

Reconstitution of mammalian mitochondrial translation system capable of correct initiation and long polypeptide synthesis from leaderless mRNA.

Mammalian mitochondria have their own dedicated protein synthesis system, which produces 13 essential subunits of the oxidative phosphorylation complexes. We have reconstituted an in vitro translation system from mammalian mitochondria, utilizing purified recombinant mitochondrial translation factors, 55S ribosomes from pig liver mitochondria, and a tRNA mixture from either Escherichia coli or yeast. The system is capable of translating leaderless mRNAs encoding model proteins (DHFR and nanoLuciferase) or some mtDNA-encoded proteins. We show that a leaderless mRNA, encoding nanoLuciferase, is faithfully initiated without the need for any auxiliary factors other than IF-2mt and IF-3mt. We found that the ribosome-dependent GTPase activities of both the translocase EF-G1mt and the recycling factor EF-G2mt are insensitive to fusidic acid (FA), the translation inhibitor that targets bacterial EF-G homologs, and consequently the system is resistant to FA. Moreover, we demonstrate that a polyproline sequence in the protein causes 55S mitochondrial ribosome stalling, yielding ribosome nascent chain complexes. Analyses of the effects of the Mg concentration on the polyproline-mediated ribosome stalling suggested the unique regulation of peptide elongation by the mitoribosome. This system will be useful for analyzing the mechanism of translation initiation, and the interactions between the nascent peptide chain and the mitochondrial ribosome.

Toe Keloids Treated with Core Excision, Postoperative Radiotherapy, and Steroid Plaster.

Although keloids are common on the joints, precordial areas, and abdomen, toe keloids are rare. The limited literature to date also suggests that they can be difficult to treat. We experienced the case of a 21-year-old woman with toe keloids on the first, second, and third toes that arose after ingrown-nail operations at another hospital. The second toe keloid was resected but recurred. Since subsequent conservative treatments were ineffective, the patient was referred to our hospital. The first visit revealed three large keloids: in particular, the keloid on the second toe had engulfed the entire circumference of the toe. Surgery with the core-excision method and postoperative radiotherapy were performed. After the sutures were removed, the scars were treated for 24 hours/day with steroid plaster until the induration disappeared. One and a half years after the operation, recurrence was not observed and the appearance of the toes had improved greatly. Thus, combination therapy composed of core excision, radiotherapy, and steroid plaster therapy is highly effective for toe keloids.

The Immunosuppressant Fingolimod (FTY720) for the Treatment of Mechanical Force-Induced Abnormal Scars.

AIM: Abnormal scars such as hypertrophic scars (HSs) and keloids are excessively growing scars that exhibit chronic inflammation and capillary vasculogenesis. The lipid mediator sphingosine-1-phosphate (S1P) is important in inflammatory cell recruitment and angiogenesis. Fingolimod (FTY720) is an analog of S1P and thus functionally antagonizes S1P receptors and inhibits the enzyme that produces S1P. We examined the effects of topical FTY720 injections on mechanical force-induced HS progression. METHODS: Mechanical force-induced HSs were generated in C57BL6/J mice by suturing a dorsal incision and applying a stretching device on Days 6, 8, 10, and 12. On Days 8, 10, and 12, intracutaneous FTY720 (10 µM) or control vehicle injections were performed. On Day 14, scar tissues and blood were procured and subjected to histology and flow cytometry. RESULTS: Flow cytometry showed that FTY720 decreased the frequencies of macrophages with M2 predominance in the scars but had no effect on total, CD4+, or CD8a+ T cell frequencies. FTY720 also decreased the vascular endothelial cell frequencies in the scar along with the microvessels, as determined by immunohistochemistry. Compared to the vehicles, FTY720 treatment significantly reduced the gross scar area and the cross-sectional scar area on histology. On the other hand, FTY720 tended to reduce white blood cells and significantly reduced the lymphocyte frequencies in the blood. CONCLUSION: Topical FTY720 induces M2 predominance and impairs angiogenesis. Therefore, its local immunosuppressive mechanisms differ from those of conventional immunosuppressive agents. Topical FTY720 can be a novel therapeutic option for abnormal scars that are difficult to control with corticosteroids. Its lymphocytopenic effects may be limited by careful optimization of the treatment regimen.

The influence of light sources on sunitinib measurements with photoisomerization.

Sunitinib is an orally administered tyrosine kinase inhibitor. Therapeutic drug monitoring is an important component of the follow-up of patients because of high interpatient variability in the pharmacokinetics of sunitinib and large variabilities in its efficacy and toxicity. The aim of the present study was to examine the light stability of sunitinib and confirm the effects of light exposure on sunitinib measurements by LC-MS/MS. Sunitinib and its active metabolite, SU12662, convert Z isomers to E isomers with exposure to light. The Z-E photoisomerization ratio reached a plateau at 35% for both E isomers in methanol within 15 min of normal light exposure (700 lx). However, the Z isomer of the sunitinib and SU12662 peak area ratios in plasma decreased by 10% within 15 min. These results suggest that sunitinib samples need to be handled without light exposure in all sample preparation steps. Alternatively, it should be measured sunitinib and SU12662 after the sample has reached photoisomerical equilibrium. These results suggest that the sunitinib therapeutic range changes depending on light conditions during sample handling in sunitinib and SU12662 measurements.

Efficacy and safety of sunitinib alternate day regimen in patients with metastatic renal cell carcinoma in Japan: Comparison with standard 4/2 schedule.

AIM: Sunitinib is a standard agent for metastatic renal cell carcinoma (mRCC). The standard schedule, 4 weeks-on followed by 2 weeks-off (4/2 schedule), often does not maintain an adequate dosage because of the severe adverse events (AEs). We compared the efficacy and safety of an alternative every other day (q.a.d.) dosing with that of the 4/2 schedule in mRCC patients. METHODS: Of the 55 Japanese patients, 32 and 23 were administered 4/2 (standard group) and q.a.d. schedules (50 or 37.5 mg, every other day; experimental groups), respectively. The AEs, anticancer effects, and trough plasma concentrations of sunitinib were compared between them. RESULTS: The most common AE in the standard group was thrombocytopenia (43.2%), but it was observed in only two patients in the experimental group (8.7%). Although leukopenia and hand-foot syndrome were both detected in six patients (18.8%) in the standard group, no patients had these AEs in the experimental group. The incidence of dose interruption in the experimental group (21.7%) was significantly lower than that in the standard group was (59.4%, P = 0.005). Time to progression (TTP) and overall survival (OS) of the experimental group were better than those of the standard group (P < 0.001 and P = 0.002, respectively). Mean plasma levels in the experimental group (64.83 ng/mL) were significantly lower than those in the standard group (135.82 ng/mL, P < 0.001) were. CONCLUSION: Sunitinib administered q.a.d. was safe and effective for mRCC patients. We speculate that the persistent optimal drug plasma concentrations contributed to these effects.

Evaluation of Antiemetic Therapy for Hepatic Transcatheter Arterial Infusion Chemotherapy with Cisplatin.

Antiemetic prophylaxis with aprepitant, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist and dexamethasone is recommended for patients receiving intravenous cisplatin chemotherapy. Whether the same antiemetic regime is superior for hepatic transcatheter arterial infusion chemotherapy with cisplatin (CDDP-TAI) is unknown. We conducted a retrospective study of antiemetic prophylaxis protection against chemotherapy-induced nausea and vomiting (CINV) in CDDP-TAI at Nagasaki University Hospital. The rate of complete response (CR) to antiemetics in the acute (<24 h) and delayed phases (24-120 h) was measured. Twenty-four patients were treated with a 5-HT3 receptor antagonist (granisetron or azasetron) and dexamethasone on the day of chemotherapy (day 1 only). There was a significant difference between the CR rates in the acute and delayed phases, 91.6, and 69.7%, respectively. Combination of a 5-HT3 antagonist and dexamethasone on day 1 is effective against acute CINV, but not delayed CINV during CDDP-TAI. These results may help guide the management of nausea and vomiting during CDDP-TAI to achieve better tolerance and compliance for fewer interventions and increased favorable therapeutic outcomes.

HMRF1L is a human mitochondrial translation release factor involved in the decoding of the termination codons UAA and UAG.

While all essential mammalian mitochondrial factors involved in the initiation and elongation phases of translation have been cloned and well characterized, little is known about the factors involved in the termination process. In the present work, we report the functional analysis of human mitochondrial translation release factors (RF). Here, we show that HMRF1, which had been previously denoted as a human mitochondrial RF, was inactive in in vitro translation system, although it is a mitochondrial protein. Instead, we identified another human mitochondrial RF candidate, HMRF1L, and demonstrated that HMRF1L is indeed a mitochondrial protein that functions specifically as an RF for the decoding of mitochondrial UAA and UAG termination codons in vitro. The identification of the functional mitochondrial RF brings us much closer to a detailed understanding of the translational termination process in mammalian mitochondria as well as to the unraveling of the molecular mechanism of diseases caused by the dys-regulation of translational termination in human mitochondria.

Histopathologic evaluation of the internal limiting membrane surgically excised from eyes with diabetic maculopathy.

PURPOSE: To histopathologically evaluate the internal limiting membrane (ILM) in diabetic eyes with macular edema as compared to nondiabetic controls. METHODS: The authors ultrastructurally and immunohistochemically studied ILM specimens that were intentionally peeled from five eyes with diabetic maculopathy, comprising four with diffuse diabetic macular edema and one with macular hole accompanying diabetic retinopathy (DM group), and five with nondiabetic idiopathic macular hole (MH group). They compared ultrastructural and immunohistochemical findings between the two groups. RESULTS: A larger amount of cellular elements was observed on the vitreous side of the ILM in the DM group. The thickness of the ILM in the DM group was significantly increased (mean 4.8 +/- 1.6 microm) compared with that in the MH group (1.8 +/- 0.6 microm) (P < 0.0001). Immunoreactions for heparan sulfate proteoglycan in the ILM were more abundant in the DM group than in the MH group. CONCLUSION: The ILM thickening and cell abundance on the vitreous surface might contribute to the course and the pathogenesis of diabetic maculopathy.

Application of the PKCYP test to predict caffeine clearance mediated by CYP1A2 in a rat acute liver injury model.

We previously established a method for assessing in vivo drug-metabolizing capacity by pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP test), in which an apparent liver-to-blood free concentration gradient in vivo (qg) is introduced (Matsunaga et al., Jpn. J. Hosp. Pharm., 26: 492-504 (2000)). This method was applied to estimate the amount of CYP2C11 in rats treated with carbon tetrachloride (CCl(4)-treated rats). In this study, we estimated the amount of CYP1A2 in CCl(4)-treated rats by using acetanilide and caffeine as a probe and a model drug, respectively. In CCl(4)-treated rats, the total body clearance (CL(tot)) of acetanilide and caffeine was about one-fifth and one-eighth of that in control rats, respectively. In CCl(4)-treated rats, the amount of CYP1A2 was predicted as 0.60+/-0.06 nmol/kg from the clearance of acetanilide mediated by CYP1A2. Moreover, the clearance of caffeine mediated by CYP1A2 in CCl(4)-treated rats was estimated as 0.47+/-0.05 mL/min/kg by using the predicted amount of CYP1A2. The observed value was 0.44+/-0.03 mL/min/kg, and the predicted value was within the 95% confidence interval of the observed value. In conclusion, we have demonstrated that the PKCYP test can also be applied for estimating the amount of CYP1A2 in CCl(4)-treated rats.

Advanced glycation end products (AGE) and the receptor for AGE are present in gastrointestinal tract of familial amyloidotic polyneuropathy patients but do not induce NF-kappaB activation.

Familial amyloidotic polyneuropathy (FAP), Portuguese type, is a hereditary amyloidosis caused by mutated transthyretin (ATTR) in which an exchange of valine for methionine at position 30 has taken place (ATTR Val30Met). Gastrointestinal complications, such as nausea, diarrhoea and malabsorption, have a significant impact on survival since the cause of death in the majority of cases is a consequence of extreme malnutrition due to dysmotility of the gastrointestinal tract. Recently, a role of the receptor for advanced glycation end products (RAGE) has been implicated in amyloid toxicity. Transthyretin (TTR) amyloid fibrils have been shown to have affinity for RAGE and subsequently induce NF-kappaB activation and apoptosis. Since gastrointestinal dysfunction plays an important role in FAP, we wanted to investigate if amyloid toxicity in the gastrointestinal tract is related to RAGE, NF-kappaB activation and apoptosis. Gastrointestinal tract autopsy samples were studied for the distribution of amyloid, RAGE, advanced glycation end products (AGE) and NF-kappaB. Furthermore, we examined the immunoreactivity of an apoptotic marker to investigate if an apoptotic pathway contributes to amyloid toxicity. The distribution of RAGE and AGE strongly correlated to that of amyloid deposits. Sequential immunofluorescence staining revealed a clear relationship between TTR, AGE and RAGE. No correlation between NF-kappaB, apoptotic marker and amyloid deposits was found. We conclude that RAGE-AGE or RAGE-TTR interaction might play important roles for gastrointestinal dysfunction and amyloid toxicity, although not through NF-kappaB activation and apoptosis.

Polarized glucose transporters and mRNA expression properties in newly developed rat syncytiotrophoblast cell lines, TR-TBTs.

In this study, we have established new syncytiotrophoblast cell lines (TR-TBTs) from the recently developed transgenic rat harboring temperature-sensitive simian virus 40 large T-antigen gene (Tg-rat). Four conditionally immortalized syncytiotrophoblast cell lines (TR-TBT 18d-1 approximately 4) were obtained from pregnant Tg-rats at gestational day 18. These cell lines had a syncytium-like morphology, could be prepared as monolayers, expressed cytokeratins and rat syncytiotrophoblast markers, and exhibited apical or basal GLUT1 localizations and apical GLUT3 localizations. TR-TBTs express large T-antigen and grow well at 33 degrees C with a doubling time of about 30 h. TR-TBTs have processes for the uptake of dehydroepiandrosteron-3-sulfate (DHEAS) and these are predominantly located on the basal side, and this is the first report of an in vitro model of blood placental barrier (BPB) able to incorporate DHEAS. Therefore, TR-TBTs are an appropriate in vitro model for investigating carrier-mediated transport functions at the BPB. Moreover, TR-TBTs express betaine/GABA transporter (GAT-2/BGT-1), concentrative nucleoside transporter 2 (CNT2), equilibrative nucleoside transporter 1 (ENT1), and ENT2 and the expression of these transporters has been reported in blood-brain barrier (BBB). Thus, the expression patterns of nucleoside and neurotransmitter transporters examined are quite similar in both the BPB and BBB.

A novel localized amyloidosis associated with lactoferrin in the cornea.

We report a novel localized amyloidosis associated with lactoferrin. To elucidate the precursor protein of corneal amyloidosis associated with trichiasis, we analyzed amyloid deposits from three patients by histopathology and biochemistry. Amyloid deposits showed immunoreactivity, confirmed by electron microscopy, for only anti-human lactoferrin antibody. Electrophoresis of amyloid fibrils revealed lactoferrin with and without sugar chains; N-terminal sequence analysis revealed full-length lactoferrin and a truncated tripeptide of N-terminal amino acids, Gly-Arg-Arg. Carboxymethylated wild-type lactoferrin formed amyloid fibrils in vitro. Lactoferrin gene analysis in the three patients revealed a Glu561Asp mutation in all of the patients and a compound heterozygote of Ala11Thr and Glu561Asp mutations in one patient. A heterozygotic Glu561Asp mutation appeared in 44.8% of healthy Japanese volunteers, suggesting that the mutation may not be an essential mutation for amyloid formation (p = 0.104). Results thus suggest that lactoferrin is this precursor protein.

Simultaneous assessment of the in vivo amount of CYP1A2 and CYP3A2 by the PKCYP-test using theophylline in rats.

Recently, we developed a method for assessing in vivo drug metabolism capacity by pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test), in which an apparent liver-to-blood free concentration gradient in vivo (qg) is introduced. The qg value can be alternatively defined as the ratio of the in vivo-in vitro clearance by a single CYP isoform. In this study, we examined the application of the PKCYP-test to drugs metabolized by multiple CYP isoforms in a rat model with fluctuating CYP1A2 levels using theophylline as a model drug. In control rats, the estimated qg values for each CYP1A2 and CYP3A2 based on the in vivo hepatic intrinsic clearance, in vitro Michaelis constant (K(m)) and maximal rate of metabolism (V(max)) values for liver slices agreed well. Moreover, the qg value for CYP1A2 determined by the K(m) and V(max) values for recombinant CYP1A2 was compatible with that based on liver slices. These qg values also agreed with that of rats pretreated with 3-methylcholanthrene. The time-course of theophylline concentrations in serum simulated by a physiologically-based pharmacokinetic model incorporating the hepatic clearance determined by the PKCYP-test agreed with the observed values. These results demonstrate that the qg value in the PKCYP-test is applicable to drugs metabolized by multiple CYP isoforms.