A Case of Bilateral Internal Mammary Arterial Infusion Chemotherapy Using Implantable Port-catheter Systems for Anterior Chest Wall Metastasis of Breast Cancer.

The patient was a 53-year-old woman who presented with a metastatic tumor of the anterior chest wall after chemotherapy for right accessory breast cancer and radiation therapy for right axillary lymphadenopathy. She had already received standard treatment, but the metastatic tumor was uncontrollable and exacerbated. Palliative treatment by arterial infusion chemotherapy with an implantable catheter-port system was planned. We indwelled a port system through the arteries because the bilateral internal mammary arteries presented a dominant blood supply. The metastatic tumor almost disappeared by arterial infusion chemotherapy after 3 months. This method may be effective in selected cases of arterial infusion chemotherapy for breast cancer.

Real-world outcomes of molecular targeted agents for patients with hepatocellular carcinoma over 80 years old.

AIM: There is insufficient evidence regarding the safety and efficacy of molecular targeted agents (MTAs) for elderly patients with hepatocellular carcinoma (HCC), who are likely to be vulnerable to adverse events (AEs) of therapy. The aim of this study was to compare sorafenib and lenvatinib use in elderly patients with HCC from the viewpoint of overall survival (OS) and rate of AE-induced MTA discontinuation. METHODS: This retrospective study included patients with HCC over 80 years old who received first-line molecular targeted therapy (MTT) at four hospitals between June 2009 and September 2019. They were divided into three groups according to the era and type of first-line MTA: E1-Sora (sorafenib, between 2009 and 2016), E2-Sora (sorafenib, between 2017 and 2019), and E2-Len (lenvatinib, between 2017 and 2019). RESULTS: The study included 173 patients (E1-Sora, n = 79; E2-Sora, n = 50; E2-Len, n = 44) with a median age of 81.9 years (range, 80-93 years). Median OS was 15.1 months in the entire cohort (E1-Sora, 12.7 months; E2-Sora, 20.5 months; E2-Len, 10.3 months). The rate of treatment discontinuation due to AEs was high in the entire cohort, especially in E1-Sora and E2-Len (49.4% in E1-Sora, 28.0% in E2-Sora, and 54.6% in E2-Len, p = 0.0753). More E2-Sora patients received subsequent MTT than E2-Len patients (E2-Sora, 50%; E2-Len, 28.6%; p = 0.0111). CONCLUSION: Both sorafenib and lenvatinib were effective and feasible for elderly patients with HCC. In terms of discontinuation due to AEs and subsequent MTT, sorafenib might be more desirable for elderly patients with HCC over 80 years.

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND AND AIMS: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. APPROACH AND RESULTS: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, n = 267; period 2: 2013-2016, n = 352; period 3: 2017-2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. CONCLUSIONS: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

A Pitfall of Wheezing - A Large Mediastinal Mass Presenting as Persistent Wheezing: A Case Report.

Anchoring bias is the tendency to pursue only the most salient feature, which can lead to closed-minded thinking in the early stage of the diagnostic process. Wheezes are one of the most frequent chief complaints and highly likely to become an anchoring bias. We described a patient initially receiving a diagnosis of asthma after presenting with persistent wheezes; however, there was no improvement upon treatment for asthma and eventually, an anterior mediastinal mass was found. The patient's respiratory condition suddenly deteriorated when he was placed in a prone position and eventually extracorporeal membrane oxygenation (ECMO) was introduced. We must recognize the danger of anchoring bias with any symptoms. A wheezing patient with an atypical clinical course should undergo further investigations, given the possibility of other etiologies such as a mediastinal tumor. In addition, we have to pay close attention to the patient's position when a mediastinal tumor is suspected.

Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents.

BACKGROUND: The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs). METHODS: Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared. RESULTS: The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (p = 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months; p = 0.039, and 18.1 months vs 11.3 months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008). CONCLUSIONS: The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients.

Intrahepatic Tumor Burden as a Novel Factor Influencing the Introduction of Second-line Chemotherapy for Hepatocellular Carcinoma.

BACKGROUND/AIM: To examine the factors influencing the introduction of the second-line chemotherapy and discuss the selection of first-line agent for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively studied 154 patients with HCC who received sorafenib therapy. RESULTS: A total of 109 (70.8%) patients, maintained Child-Pugh grade A and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 upon sorafenib discontinuation. Multivariate analysis revealed that the up-to-seven criteria status in the hepatic lesion [p=0.019; odds ratio=OR, 2.685], albumin-bilirubin (ALBI) grade (p=0.002; OR=3.589), and macroscopic vascular invasion (MVI) (p=0.008; OR=2.972) were significant factors at sorafenib initiation that influenced the maintenance of Child-Pugh grade A and ECOG-PS ≤1 upon therapy discontinuation. CONCLUSION: Not only ALBI grade and MVI, but also up-to-seven criteria status in the hepatic lesion influence the introduction of second-line therapy, and could affect the selection of the first-line therapy.

An unusual manifestation of Sjögren syndrome encephalitis.

Sjögren syndrome (SS) is a systemic inflammatory and autoimmune disease characterized by systemic disorders of the exocrine glands, predominantly the salivary and lacrimal glands. Here, we report a 4-year-old boy who presented with the repetition of generalized tonic-clonic seizures for 1-2 min. Initially, he was diagnosed with idiopathic autoimmune encephalitis and was treated with steroids. He was eventually diagnosed with SS based on the examination results, such as inflammatory cell infiltration into the minor salivary glands and positive serum anti-SSA/Ro antibody. Although central nervous system complications are rare in pediatric SS, this condition should be considered in the differential diagnosis when a patient presents with idiopathic autoimmune encephalitis of unknown cause. Furthermore, SS can occur in relatively young children and can present without imaging abnormalities.

Hidden diagnosis behind viral infection: the danger of anchoring bias.

Anchoring bias is one of the most common diagnostic biases that may lead to closed-minded thinking and could result in unnecessary tests, inappropriate patient management and even misdiagnosis. A 4-year-old boy was brought to the emergency department because of shaking chills. On the basis of bilateral swollen preauricular areas, high level of serum amylase and the prevalence of mumps, he initially received a diagnosis of mumps in spite of the shaking chills. However, blood culture turned out to be positive for two different kinds of bacteria. The patient finally received a diagnosis of polymicrobial bacteraemia resulting from suppurative appendicitis. We must consider and rule out bacteraemia in the differential diagnosis for patients who present with shaking chills, even in the presence of symptoms or information consistent with a more common viral infection such as mumps. In addition, intra-abdominal infection should be ruled out in the presence of polymicrobial enterobacteriaceae bacteraemia.

CCN3 secreted by prostaglandin E2 inhibits intimal cushion formation in the rat ductus arteriosus.

The ductus arteriosus (DA), an essential fetal shunt between the pulmonary trunk and the descending aorta, changes its structure during development. Our previous studies have demonstrated that prostaglandin E2 (PGE2)-EP4 signaling promotes intimal cushion formation (ICF) by activating the migration of DA smooth muscle cells via the secretion of hyaluronan. We hypothesized that, in addition to hyaluronan, PGE2 may secrete other proteins that also regulate vascular remodeling in the DA. In order to detect PGE2 stimulation-secreted proteins, we found that CCN3 protein was increased in the culture supernatant in the presence of PGE2 in a dose-dependent manner by nano-flow liquid chromatography coupled with tandem mass spectrometry analysis and enzyme-linked immunosorbent assay. Quantitative RT-PCR analysis revealed that PGE2 stimulation tended to increase the expression levels of CCN3 mRNA in DA smooth muscle cells. Immunohistochemical analysis revealed that CCN3 was highly localized in the entire smooth muscle layers and the endothelium of the DA. Furthermore, exogenous CCN3 inhibited PGE2-induced ICF in the ex vivo DA tissues. These results suggest that CCN3 is a secreted protein of the DA smooth muscle cells induced by PGE2 to suppress ICF of the DA. The present study indicates that CCN3 could be a novel negative regulator of ICF in the DA to fine-tune the PGE2-mediated DA remodeling.

Changes in skin structure of the Zip13-KO mouse by Makomo (Zizania latifolia) feeding.

Ehlers-Danlos syndrome (EDS) is a group of disorders caused by abnormalities in the extracellular matrix (ECM). Transforming growth factor-ß (TGF-ß) plays a crucial role in formation of the ECM by the SMAD (Sma-and Mad-related protein, mothers against decapentaplegic homolog) pathway. It has been reported that loss of function of zinc transporter ZRT/IRT-like protein 13 (ZIP13) is the cause of the spondylocheiro dysplastic form of EDS (SCD-EDS: OMIM 612350). Our previous study suggested that TGF-ß1 has a relationship with the skin pathological condition in the Zip13-Knockout (KO) mouse, which is a model of SCD-EDS. Thus far, effective treatment based on modern medicine for this syndrome has not yet been established. According to an approach of traditional Chinese medicine, the present study investigates the medicinal effects of Makomo (Zizania latifolia) on certain aspects of SCD-EDS, such as skin morphology and plasma TGF-ß1, in Zip13-KO mice. Increases in densities of collagen fibers and fibrils without a significant change in thickness of the dermal layer were observed in the group of mice fed a Makomo-containing diet. No change in the amount of collagen suggests that Makomo feed does not elevate collagen synthesis, but changes the length of glycosaminoglycan chains and decreases the distance between collagen fibrils. In conclusion, the changes of the skin structure suggest that Makomo can increase the mechanical strength of skin.

"Direct MPR": A Useful Tool for Oblique CT Fluoroscopy-Assisted Puncture.

OBJECTIVE: Conventional multiplanar reconstruction (MPR) imaging can be used as a tool for planning oblique puncture procedures, but it takes a few minutes to reconstruct and is not appropriate for real-time CT fluoroscopy-assisted puncture. Recently, new MPR technology has been used that requires only 8 s and makes it possible to obtain a nearly real-time CT fluoroscopy-assisted oblique puncture. We refer to it as "direct MPR." This is the first clinical report of this technique. METHODS: Since February 2016, we have performed real-time, CT-guided oblique punctures with this new technology, "direct MPR," using an angio-CT system. We retrospectively reviewed all of our procedures with this new method between February 2016 and June 2016. RESULTS: We used this technique for 14 cases during the study period. Eight cases were radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC), four were biopsies (lung and adrenal gland), and two were for percutaneous abscess drainage. Six of eight RFA cases were for HCC located immediately below the diaphragm. Both of the drainage cases were abscesses located immediately below the diaphragm. All procedures were successfully completed. The average length of the lesion in the RFA cases was 15.4 ± 3.2 mm. The average length of the lesions in all of the cases was 30.9 ± 31.9 mm. The average craniocaudal angle was 32.5° ± 14.0°. CONCLUSIONS: Direct MPR makes CT-guided oblique puncture for inaccessible targets, especially those located immediately below diaphragm, easier and safer. LEVEL OF EVIDENCE: Case series, Level IV.

A draft genome of the brown alga, Cladosiphon okamuranus, S-strain: a platform for future studies of 'mozuku' biology.

The brown alga, Cladosiphon okamuranus (Okinawa mozuku), is economically one of the most important edible seaweeds, and is cultivated for market primarily in Okinawa, Japan. C. okamuranus constitutes a significant source of fucoidan, which has various physiological and biological activities. To facilitate studies of seaweed biology, we decoded the draft genome of C. okamuranus S-strain. The genome size of C. okamuranus was estimated as ∼140 Mbp, smaller than genomes of two other brown algae, Ectocarpus siliculosus and Saccharina japonica Sequencing with ∼100× coverage yielded an assembly of 541 scaffolds with N50 = 416 kbp. Together with transcriptomic data, we estimated that the C. okamuranus genome contains 13,640 protein-coding genes, approximately 94% of which have been confirmed with corresponding mRNAs. Comparisons with the E. siliculosus genome identified a set of C. okamuranus genes that encode enzymes involved in biosynthetic pathways for sulfated fucans and alginate biosynthesis. In addition, we identified C. okamuranus genes for enzymes involved in phlorotannin biosynthesis. The present decoding of the Cladosiphon okamuranus genome provides a platform for future studies of mozuku biology.

A Rapid and Simple LC-MS Method Using Collagen Marker Peptides for Identification of the Animal Source of Leather.

Identification of the animal source of leather is difficult using traditional methods, including microscopic observation and PCR. In the present study, a LC-MS method was developed for detecting interspecies differences in the amino acid sequence of type I collagen, which is a major component of leather, among six animals (cattle, horse, pig, sheep, goat, and deer). After a dechroming procedure and trypsin digestion, six tryptic peptides of type I collagen were monitored by LC-MS in multiple reaction monitoring mode for the animal source identification using the patterns of the presence or absence of the marker peptides. We analyzed commercial leathers from various production areas using this method, and found some leathers in which the commercial label disagreed with the identified animal source. Our method enabled rapid and simple leather certification and could be applied to other animals whether or not their collagen sequences are available in public databases.

Thromboxane A(2) receptor stimulation promotes closure of the rat ductus arteriosus through enhancing neointima formation.

Ductus arteriosus (DA) closure follows constriction and remodeling of the entire vessel wall. Patent ductus arteriosus occurs when the DA does not close after birth, and this condition is currently treated using cyclooxygenase inhibitors. However, the efficacy of cyclooxygenase inhibitors is often limited. Our previous study demonstrated that low-dose thromboxane A2 receptor (TP) stimulation constricted the DA with minimal adverse effects in rat neonates. However, its effect on DA remodeling remains unknown. In this study, we focused on the impact of the exogenous TP stimulation on the DA remodeling, especially intimal thickening. Using DA explants from rat fetuses at embryonic day 19 as a ex vivo model and primary cultured rat DA smooth muscle cells from embryonic day 21 as a in vitro model, we evaluated the effect of TP stimulation on the DA remodeling. The selective TP agonists U46619 and I-BOP promoted neointima formation in the ex vivo DA explants, and TP stimulation increased DA SMC migration in a dose-dependent manner. Both effects were inhibited by the selective TP antagonist SQ29548 or the siRNA against TP. TP stimulation also increased DA SMC proliferation in the presence of 10% fetal bovine serum. LC/MS/MS analysis revealed that TP stimulation increased secretion of several extracellular matrix proteins that may contribute to an increase in neointima formation. In conclusion, we uncovered that exogenous administration of TP agonist promotes neointima formation through the induction of migration and proliferation of DA SMC, which could contribute to DA closure and also to its vasoconstrictive action.

Impediment to symbiosis establishment between giant clams and Symbiodinium algae due to sterilization of seawater.

To survive the juvenile stage, giant clam juveniles need to establish a symbiotic relationship with the microalgae Symbiodinium occurring in the environment. The percentage of giant clam juveniles succeeding in symbiosis establishment ("symbiosis rate") is often low, which is problematic for seed producers. We investigated how and why symbiosis rates vary, depending on whether giant clam seeds are continuously reared in UV treated or non treated seawater. Results repeatedly demonstrated that symbiosis rates were lower for UV treated seawater than for non treated seawater. Symbiosis rates were also lower for autoclaved seawater and 0.2-µm filtered seawater than for non treated seawater. The decreased symbiosis rates in various sterilized seawater suggest the possibility that some factors helping symbiosis establishment in natural seawater are weakened owing to sterilization. The possible factors include vitality of giant clam seeds, since additional experiments revealed that survival rates of seeds reared alone without Symbiodinium were lower in sterilized seawater than in non treated seawater. In conclusion, UV treatment of seawater was found to lead to decreased symbiosis rates, which is due possibly to some adverse effects common to the various sterilization techniques and relates to the vitality of the giant clam seeds.

Algivore or phototroph? Plakobranchus ocellatus (Gastropoda) continuously acquires kleptoplasts and nutrition from multiple algal species in nature.

The sea slug Plakobranchus ocellatus (Sacoglossa, Gastropoda) retains photosynthetically active chloroplasts from ingested algae (functional kleptoplasts) in the epithelial cells of its digestive gland for up to 10 months. While its feeding behavior has not been observed in natural habitats, two hypotheses have been proposed: 1) adult P. ocellatus uses kleptoplasts to obtain photosynthates and nutritionally behaves as a photoautotroph without replenishing the kleptoplasts; or 2) it behaves as a mixotroph (photoautotroph and herbivorous consumer) and replenishes kleptoplasts continually or periodically. To address the question of which hypothesis is more likely, we examined the source algae for kleptoplasts and temporal changes in kleptoplast composition and nutritional contribution. By characterizing the temporal diversity of P. ocellatus kleptoplasts using rbcL sequences, we found that P. ocellatus harvests kleptoplasts from at least 8 different siphonous green algal species, that kleptoplasts from more than one species are present in each individual sea slug, and that the kleptoplast composition differs temporally. These results suggest that wild P. ocellatus often feed on multiple species of siphonous algae from which they continually obtain fresh chloroplasts. By estimating the trophic position of wild and starved P. ocellatus using the stable nitrogen isotopic composition of amino acids, we showed that despite the abundance of kleptoplasts, their photosynthates do not contribute greatly to the nutrition of wild P. ocellatus, but that kleptoplast photosynthates form a significant source of nutrition for starved sea slugs. The herbivorous nature of wild P. ocellatus is consistent with insights from molecular analyses indicating that kleptoplasts are frequently replenished from ingested algae, leading to the conclusion that natural populations of P. ocellatus do not rely on photosynthesis but mainly on the digestion of ingested algae.

Past daily light cycle recorded in the strontium/calcium ratios of giant clam shells.

The historical record of daily light cycle in tropical and subtropical regions is short. Moreover, it remains difficult to extract this cycle in the past from natural archives such as biogenic marine carbonates. Here we describe the precise analysis of Sr/Ca, Mg/Ca, and Ba/Ca ratios in a cultivated giant clam shell, using a laterally high-resolution secondary ion mass spectrometer with 2 µm resolution. The Sr/Ca ratio exhibits striking diurnal variations, reflecting the daily light cycle. A clear seasonal variation in Sr/Ca is also observed in another longer set of measurements with 50 µm resolution. Light-enhanced calcification and elemental transportation processes, in giant clam and symbiotic algae, may explain these diurnal and annual variations. This opens the possibility to develop the Sr/Ca ratio from a giant clam shell as an effective proxy for parameters of the daily light cycle.

Isolation of new Symbiodinium strains from tridacnid giant clam (Tridacna crocea) and sea slug (Pteraeolidia ianthina) using culture medium containing giant clam tissue homogenate.

Recent molecular biological studies have revealed that some photosymbiotic invertebrates dwelling in coral reefs host several genetically different dinoflagellates, Symbiodinium species, as symbionts. However, little is known about the difference in physiologic characteristics among these symbionts living in a single host, because some Symbiodinium strains are difficult to culture in vitro. To isolate some of these Symbiodinium strains, we have developed an agar culture medium plate containing antibiotics and a giant clam tissue homogenate. Using-this medium we isolated two new Symbiodinium strains from two molluscan hosts, Tridacna crocea and Pteraeolidia ianthina, each of which hosted two different Symbiodinium strains belonging to Symbiodinium C and D, respectively. The tissue homogenate was essential for the growth of Symbiodinium D. Although it was not essential for the growth of Symbiodinium C, it did stimulate the initial growth. For the isolation of some Symbiodinium strains, isolation medium containing host homogenate is effective.