BNCT pancreatic cancer treatment strategy with glucose-conjugated boron drug.

Multidisciplinary therapy centered on radical surgery for resectable pancreatic cancer is expected to prolong prognosis, but relies on CA19-9 biomarker levels to determine treatment strategy. Boron neutron capture therapy (BNCT) is a chemoradiotherapy using tumor hyperaccumulator boron drugs and neutron irradiation. The purpose of this study is to investigate novel boron drug agents for BNCT for pancreatic cancer. Bioinformatics was used to evaluate the uptake of current boron amino acid (BPA) drugs for BNCT into pancreatic cancer. The expression of the amino acid transporter LAT1, a BPA uptake transporter, was low in pancreatic cancer and even lower in high CA19-9 pancreatic cancer. In contrast, the glucose transporter was high in high CA19-9 pancreatic cancers and inversely correlated with LAT1 expression. Considering the low EPR effect in pancreatic cancer, we synthesized a small molecule Glucose-BSH, which is boron BSH bound to glucose, and confirmed its specific uptake in pancreatic cancer. uptake of Glucose-BSH was confirmed in an environment compatible with the tumor microenvironment. The therapeutic efficacy and safety of Glucose-BSH by therapeutic neutron irradiation were confirmed with BNCT. We report Glucose-BSH boron drug discovery study of a Precision Medicine BNCT with application to high CA19-9 pancreatic cancer.

[A Case of Intestinal Obstruction Due to an Internal Hernia in the Mesenteric Defect after Laparoscopic Resection of Transverse Colon].

72-year-old man who was diagnosed with transverse colon cancer cT3N1aM0, Stage Ⅲb, and underwent laparoscopic- assisted resection of the transverse colon. Postoperatively, the patient was discharged from the hospital after 24 days due to complications such as paralytic ileus and intra-abdominal abscess caused by prolonged intestinal congestion. On postoperative day 91, the patient developed abdominal pain and vomiting at home, and was rushed to our hospital on the same day. Abdominal CT showed that an internal hernia had formed in the mesenteric defect after resection of the transverse colon, which was suspected to have caused obstruction of the small intestine. After adequate preoperative decompression of the intestinal tract, a laparoscopic surgery was performed on the 9th day. The operative findings were that the jejunum(100- 160 cm from the Treitz ligament)had strayed into the mesenteric defect of the transverse colon, resulting in an internal hernia. After the internal hernia was repaired laparoscopically, the mesenteric defect was closed with a 3-0 V-Loc(non- absorbable). The patient had a good postoperative course and was discharged home 6 days after surgery.

Myosteatosis as a novel predictor of new-onset diabetes mellitus after kidney transplantation.

OBJECTIVES: We evaluate the effect of myosteatosis on new-onset diabetes mellitus after kidney transplantation. METHODS: Consecutive patients who had renal transplant between 2006 and 2021 were reviewed, and 219 patients were finally included. Psoas muscle index was used to evaluate sarcopenia and average total psoas density (calculated by computed tomography before surgery) for myosteatosis. We used Cox proportional regression analyses in investigation of whether skeletal muscle depletion before surgery inclusive of sarcopenia and myosteatosis is a new additional predictor of new-onset diabetes mellitus. RESULTS: Median recipient age and body mass index were 45 years and 21.1 kg/m2 , respectively, and 123 patients (56%) were male. Preoperative impaired glucose tolerance was present in 58 patients (27%) and new-onset diabetes mellitus in 30 patients (14%), with median psoas muscle index of 6 cm2 /m2 and average total psoas density of 41 Hounsfield Unit. In multivariate analysis, significant risk factors were body mass index ≥25 kg/m2 (p < 0.01), impaired glucose tolerance (p < 0.01), and average total psoas density < 41.9 Hounsfield Unit (p = 0.03). New-onset diabetes mellitus had incidence rates of 3.7% without risk factors, 10% with a single risk factor, 33% with two, and 60% with three. Patients with new-onset diabetes mellitus were effectively stratified by the number of risk factors (p < 0.01). CONCLUSIONS: Myosteatosis could be a new risk factor used to predict new-onset diabetes mellitus.

Association of Alpha-Actinin-3 Polymorphism With Sarcopenia in Kidney Transplant Recipients.

BACKGROUND: Sarcopenia is defined as the loss of skeletal muscle mass and function and is associated with increased mortality. Certain genetic polymorphisms represent risk factors used to assess the incidence of sarcopenia; however, few studies have evaluated the association between genetic polymorphisms and sarcopenia after kidney transplantation (KTx). We examined single-nucleotide polymorphisms (SNPs) in the genes involved in sarcopenia after KTx. METHODS: Sixty-five patients who underwent KTx were enrolled in this study. We used the psoas mass index (PMI; the cross-sectional area of the bilateral psoas muscle/height) as a surrogate marker for assessing the extent of sarcopenia. We determined the PMI before KTx and 1 year after KTx, and we identified 5 SNPs in 5 genes associated with sarcopenia in the general population. Finally, the link between the changes in PMI 1 year after KTx and each SNP was examined. RESULTS: The median PMI before KTx and 1 year after KTx was 7.4 (4.6-13.2) and 7.0 (3.6-13.6), respectively. The PMI decreased in 43 patients (66.2%). The alpha-actinin-3 rs1815739 genotype was associated with changes in PMI; the distribution of CT+TT genotypes in the PMI decrease group was significantly higher than that of the CC genotype (odds ratio, 4.23; 95% CI 0.05-0.97; P = 0.025). Moreover, the T allele frequency was significantly higher in the PMI decrease group than in the PMI increase group (odds ratio, 2.34; 95% CI 0.18-0.950; P = 0.025). CONCLUSION: The alpha-actinin-3 rs1815739 genotype may represent a genetic risk factor for sarcopenia after KTx.

Long-Term Clinical Results of Two-Stage Total Ear Reconstruction of Microtia Using Autologous Cell-Engineered Chondrocytes.

BACKGROUND: Microtia repair requires a large volume of reconstruction material.In pediatric patients, the collectable volume of autologous cartilage is limited, and the impact of surgical invasion and donor-site morbidity can be particularly severe. The authors developed a new treatment method using cultured autologous human auricular chondrocytes that provides a sufficiently large volume of reconstruction material. METHODS: Approximately 1 cm2 of auricular cartilage was collected from the affected site. Chondrocytes were isolated and cultured with autologous serum to accelerate cell proliferation. The cells were subcultured and formed a gel-form mass without a scaffold. In our two-stage implantation, the cultured chondrocytes were first injected into the patient's lower abdomen, where the cells grew into a large, newly generated cartilage in 6 months. Thereafter, this cartilage was sculpted into an ear framework and subcutaneously reimplanted into the new ear location. Clinical outcomes were assessed over a long-term follow-up. RESULTS: Eight patients underwent surgery using cultured autologous auricular chondrocytes from 2002 to 2008. The patients' ages ranged from 6 to 10 years. The follow-up period ranged from 11 to 18 years. None of the patients experienced absorption of cultured chondrocytes after the second stage. Complications included one case of absorption and one case of allergic reaction in the first stage. CONCLUSIONS: The authors' patients represent the first successful cases of regenerative surgery for microtia using cultured chondrocytes. No malignant transformation, change in size, deformation, or other abnormalities were observed during the long-term follow-up, demonstrating the safety of cultured cartilage. No major complications occurred. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

[A Case of HER2-Positive Advanced Breast Cancer Who Was Able to Start and Continue Chemotherapy Despite Liver Damage Due to Diffuse Liver Metastasis].

49-year-old woman, who diagnosed advanced breast cancer with, ER-positive, HER2-positive, T4bN1M1, Stage Ⅳ. At the time of initial diagnosis, liver damage equivalent to Child-Pugh classification C due to diffuse liver metastasis was observed, but trastuzumab/pertuzumab(HP)and paclitaxel(PTX)adjusted according to liver function were administered every 3 weeks, resulting in rapid improvement of liver function, PR of the primary tumor(90% reduction), PR of the liver metastases(70% reduction), and improvement of tumor markers. Currently, chemotherapy has been switched to docetaxel (DTX)due to peripheral neuropathy caused by PTX, and treatment is continuing. In the case of HER2-positive breast cancer, good disease control may be achieved with aggressive treatment and intervention under dose adjustment and careful systemic management, even in the setting of liver injury.

Clinical Outcome of Patients with Pelvic and Retroperitoneal Bone and Soft Tissue Sarcoma: A Retrospective Multicenter Study in Japan.

This study aimed to retrospectively analyze the clinical outcomes of patients with pelvic and retroperitoneal bone and soft tissue sarcoma (BSTS). Overall, 187 patients with BSTS in the pelvis and retroperitoneal region treated at 19 specialized sarcoma centers in Japan were included. The prognostic factors related to overall survival (OS), local control (LC), and progression-free survival (PFS) were evaluated. The 3-year OS and LC rates in the 187 patients were 71.7% and 79.1%, respectively. The 3-year PFS in 166 patients without any distant metastases at the time of primary tumor diagnosis was 48.6%. Osteosarcoma showed significantly worse OS and PFS than other sarcomas of the pelvis and retroperitoneum. In the univariate analyses, larger primary tumor size, soft tissue tumor, distant metastasis at the time of primary tumor diagnosis, P2 location, chemotherapy, and osteosarcoma were poor prognostic factors correlated with OS. Larger primary tumor size, higher age, soft tissue tumor, chemotherapy, and osteosarcoma were poor prognostic factors correlated with PFS in patients without any metastasis at the initial presentation. Larger primary tumor size was the only poor prognostic factor correlation with LC. This study has clarified the epidemiology and prognosis of patients with pelvic and retroperitoneal BSTS in Japan.

Proximal-type epithelioid sarcoma in pubic region expressing L-type amino acid transporter 1: A case report.

Proximal-type epithelioid sarcoma is an aggressive malignant soft-tissue neoplasm, a "proximal" variant of epithelioid sarcoma, resistant to multimodal therapy and involved in early tumor-related death. Pertinent treatments are, therefore, continually being explored. A 24-year-old woman with nonmetastatic proximal-type epithelioid sarcoma, originating subcutaneously on the right side of the vulva, underwent surgical resection; the lesion recurred, however, leading to death 3 months after the second surgery. Here described is a case of proximal-type epithelioid sarcoma expressing L-type amino acid transporter 1 (LAT1) that transports essential amino acids and p-borono-L-phenylalanine (BPA)-the chemical compound used in boron neutron capture therapy (BNCT)-and is highly expressed in many malignant tumors. Recently, LAT1 has drawn attention, and relevant treatments have been studied-LAT1 inhibitor and BNCT. LAT1 expression in proximal-type epithelioid sarcoma may lead to cogent treatments for the disease.

Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction.

Influenza viruses are responsible for contagious respiratory illnesses in humans and cause seasonal epidemics and occasional pandemics worldwide. Previously, we identified a quinolinone derivative PA-49, which inhibited the influenza virus RNA-dependent RNA polymerase (RdRp) by targeting PA-PB1 interaction. This paper reports the structure optimization of PA-49, which resulted in the identification of 3-((dibenzylamino)methyl)quinolinone derivatives with more potent anti-influenza virus activity. During the optimization, the hit compound 89, which was more active than PA-49, was identified. Further optimization and scaffold hopping of 89 led to the most potent compounds 100 and a 1,8-naphthyridinone derivative 118, respectively. We conclusively determined that compounds 100 and 118 suppressed the replication of influenza virus and exhibited anti-influenza virus activity against both influenza virus types A and B in the range of 50% effective concentration (EC50) = 0.061-0.226 µM with low toxicity (50% cytotoxic concentration (CC50) >10 µM).

Effect of Borate Cocatalysts toward Activity and Comonomer Incorporation in Ethylene Copolymerization by Half-Titanocene Catalysts in Methylcyclohexane.

Ethylene copolymerizations with 2-methyl-1-pentene, 1-dodecene (DD), vinylcyclohexane (VCH), [Me2Si(C5Me4)(N t Bu)]TiCl2 (1), Cp*TiMe2(O-2,6- i Pr2-4-RC6H2) [R = H (2), SiEt3 (3)]-borate, and [A(H)]+[BAr4]- [Ar = C6F5; A(H)+ = N+(H)Me(n-C18H37)2, N+(H)(CH2CF3)(n-C18H37)2, HO+(n-C14H29)2·O(n-C14H29)2, HO+(n-C16H33)2·O(n-C16H33)2; Ar = C10F7, A(H)+ = HO+(n-C14H29)2·O(n-C14H29)2 (B5), N+(H)(CH2CF3)(n-C18H37)2] catalyst systems conducted in methylcyclohexane (MCH) exhibited better comonomer incorporation than those conducted in toluene (in the presence of methylaluminoxane (MAO) or borate cocatalysts). The activity was affected by the borate cocatalyst and 1,3-B5 catalyst systems in MCH and showed the highest activity in the ethylene copolymerizations with VCH and DD.

Identification of the first highly selective inhibitor of human lactate dehydrogenase B.

Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC50 = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.

BNCT for primary synovial sarcoma.

Synovial sarcoma is a rare tumor requiring new treatment methods. A 46-year-old woman with primary monophasic synovial sarcoma in the left thigh involving the sciatic nerve, declining surgery because of potential dysfunction of the affected limbs, received two courses of BNCT. The tumor thus reduced was completely resected with no subsequent recurrence. The patient is now able to walk unassisted, and no local recurrence has been observed, demonstrating the applicability of BNCT as adjuvant therapy for synovial sarcoma. Further study and analysis with more experience accumulation are needed to confirm the real impact of BNCT efficacy for its application to synovial sarcoma.

Clinical Outcome of the Patients With Brain Metastasis from Soft Tissue Sarcomas.

BACKGROUND/AIM: This study aimed to evaluate the association of clinical characteristics with treatment outcomes to ascertain the appropriate treatment options for soft tissue sarcomas (STS) patients with brain metastasis (BM). PATIENTS AND METHODS: Medical records of STS patients with BM who were treated in our institutions were retrospectively reviewed, and analyzed to identify the factors associated with post-BM survival. RESULTS: Among the 509 STS patients, BM occurred in five patients (0.98%). The median survival after BM was 1.5 months. Histological subtypes of the primary lesions in the five BM patients were: two synovial sarcomas, one myxoid liposarcoma, one alveolar soft part sarcoma, and one rhabdomyosarcoma. Among the five BM patients, the post-BM survival of two patients, who underwent surgery and postoperative radiotherapy, was longer than that of the other patients (p<0.01). CONCLUSION: Combined surgery and postoperative radiotherapy effectively managed symptoms and prolonged survival in STS patients with BM.

Cathepsin B is highly expressed in pancreatic cancer stem-like cells and is associated with patients' surgical outcomes.

Cancer stem-like cells (CSLCs) in solid tumors are resistant to conventional chemotherapy and molecularly targeted therapy, which is thought to contribute to cancer recurrence and metastasis. The present study aimed to identify biomarkers for pancreatic CSLCs (P-CSLCs). Using our previously reported methods, P-CSLC-enriched populations were generated from pancreatic cancer cell lines. The protein expression profiles of these populations were compared with those of parental cells using two-dimensional electrophoresis, tandem mass spectrometry, flow cytometry and immunohistochemistry. Protein expression in surgical specimens was also evaluated for relationships with clinical outcomes. A lysosomal cysteine protease, cathepsin B (CTSB), was significantly upregulated in P-CSLCs compared with that in the parental cells, as shown using western blotting. Flow cytometry analysis also confirmed that CTSB was more highly expressed on the surface of P-CSLCs compared with that on parental cells. Moreover, PCLCs had elevated cellular secretions of CTSB compared with the parental cells. Finally, CTSB expression was evaluated in 69 resected tumor specimens, and high expression was associated with the patients' clinicopathological features and surgical outcomes. The present results suggested that CTSB is a biomarker for poor survival in patients with pancreatic cancer, which is possibly associated with P-CSLCs. This novel biomarker may also have potential as a therapeutic target.

Preclinical study of boron neutron capture therapy for bone metastasis using human breast cancer cell lines.

Bone metastasis has a major impact on the quality of life that general therapy cannot control. We established a bone metastasis model with a human breast cancer cell line and investigated the therapeutic effect of boron neutron capture therapy (BNCT). BNCT suppressed tumor growth in cases of intramedullary small tumors without damaging normal tissues, providing preliminary evidence that it is a potentially new therapeutic option for controlling tumor growth from bone metastasis. Further research is warranted for its clinical application.

Influence of the particle size of gadolinium-loaded chitosan nanoparticles on their tumor-killing effect in neutron capture therapy in vitro.

Neutron capture therapy using 157Gd (Gd-NCT) is currently under development as a cancer radiotherapy. Melanoma cells were treated with gadolinium-loaded chitosan nanoparticles (Gd-nanoCPs) for Gd-NCT. Smaller Gd-nanoCPs had higher Gd content and better cellular association of Gd and thereby made the tumor-killing effect more efficient in comparison to larger Gd-nanoCPs. This indicates that Gd-nanoCP size reduction is an efficient method for improving the cellular affinity of Gd-nanoCPs and for enhancing the tumor-killing effect of Gd-NCT.

Boron neutron capture therapy for clear cell sarcoma.

Clear cell sarcoma of tendons and aponeuroses (CCS) is a rare, malignant tumor arising in lower extremities with no effective treatment other than wide surgical resection. Here described is a case of primary CCS in the peroneal tendon of the right foot of a 54-year-old woman enrolled to undergo BNCT. The tumor mass post-BNCT disappeared totally without damage to other normal tissue, demonstrating, for the first time, the potential efficacy of BNCT in complete local control of CCS.

Prognostic influence of the treatment approach for pulmonary metastasis in patients with soft tissue sarcoma.

Soft tissue sarcomas (STSs) are rare heterogeneous malignancies of mesenchymal origin. Pulmonary metastases develop in approximately 50% of the patients with high-grade STS, being the major cause of mortality in patients with metastatic STS. Pulmonary metastasectomy has been reported to contribute to long-term survival; however, an appropriate treatment has not been established. We aimed to identify factors associated with post-metastasis survival in STS patients with pulmonary metastasis and determine the appropriate treatment for each patient. We retrospectively reviewed the records of metastatic STS patients treated between 2000 and 2017 and analyzed the clinico-pathologic variables to identify factors associated with the survival. The median survival after pulmonary metastasis was 20.6 months, and the 1-, 3-, and 5-year survival rates were 68.6%, 36.0%, and 25.1%, respectively. The survival was significantly greater in patients who underwent pulmonary metastasectomy than in those without surgery (38.9 months vs. 10.5 months; p < 0.0001). Among those who did not undergo surgery, the survival was significantly greater in patients who received chemotherapy than in those without chemotherapy (19.1 months vs. 6.3 months, p = 0.037). Multivariate analysis identified pulmonary metastasectomy as the most important prognostic factor for post-metastasis survival (Hazard ratio 5.623; 95% Confidence Interval 2.733-11.572; p < 0.0001). In conclusion, pulmonary metastasectomy was the most important prognostic factor for post-metastasis survival in patients with metastatic STS. In addition, chemotherapy could prolong survival in patients who were not eligible for pulmonary resection. Although we should carefully weigh the risks and benefits, appropriate treatment for pulmonary metastases could contribute to long-time survival.

A Novel Orally Available Delta-5 Desaturase Inhibitor Prevents Atherosclerotic Lesions Accompanied by Changes in Fatty Acid Composition and Eicosanoid Production in ApoE Knockout Mice.

Delta-5 desaturase (D5D), encoded by fatty acid desaturase 1 (Fads1), is the rate-limiting enzyme for the conversion from dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA) in the ω-6 polyunsaturated fatty acid pathway. Several AA-derived eicosanoids (e.g., prostaglandins, thromboxanes, and leukotrienes) and DGLA-derived eicosanoids are reported to promote and/or prevent atherosclerosis progression through, at least in part, its proinflammatory or anti-inflammatory effects. To elucidate the effects of D5D inhibition by a D5D inhibitor on atherosclerosis, we generated a potent, orally available and selective D5D inhibitor, 2-(2,2,3,3,3-Pentafluoropropoxy)-3-[4-(2,2,2-trifluoroethoxy) phenyl]-5,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-4,6-dione, compound-326, and examined its effects on Western-diet fed ApoE knockout (KO) mice. Oral administration of compound-326 (3-10 mg/kg per day for 15 weeks) significantly inhibited the progression of atherosclerotic lesions in the aorta without affecting plasma total cholesterol and triglyceride levels. Compound-326 significantly decreased AA levels, while it increased DGLA levels in the liver and the blood accompanied by decreases in AA-derived eicosanoid production and increases in DGLA-derived eicosanoid production from the blood cells. We conclude that compound-326 prevents the progression of atherosclerosis in Western-diet fed ApoE KO mice by modulating a profile of eicosanoid production, suggesting that D5D inhibitors can be a novel remedy for preventing atherosclerosis and subsequent cardiovascular events. SIGNIFICANCE STATEMENT: This study shows a D5D-specific and orally available potent inhibitor provided the first evidence to support the concept that D5D inhibitors will be a novel remedy for preventing the progression of atherosclerosis.

Predicting the survival of patients with bone metastases treated with radiation therapy: a validation study of the Katagiri scoring system.

BACKGROUND: The selection of radiation therapy dose fractionation schedules for bone metastases is often based on the estimation of life expectancy. Therefore, accurate prognosis prediction is an important issue. It is reported that the Katagiri scoring system can be used to predict the survival of patients with bone metastases. We aimed to assess prognostic factors and validate the Katagiri scoring system in patients who were treated with radiation therapy for bone metastases. MATERIALS/METHODS: We retrospectively reviewed data of all patients who were treated with radiation therapy for bone metastases between 2004 and 2013. Age, sex, Karnofsky performance status (KPS), Eastern Cooperative Oncology Group performance status (ECOG PS), primary site (lesions and characteristics), visceral metastases, laboratory data, previous chemotherapy, and multiple bone metastases were analyzed for associations with overall survival (OS). Katagiri scores were calculated for each patient and were used to compare OS. RESULTS: Out of the 616 patients included in this analysis, 574 had died and 42 remained alive. The median follow-up time for survivors was 42 months. Univariate analysis revealed that age (P = 0.604) and multiple bone metastases (P = 0.691) were not significantly associated with OS. Multivariate analysis revealed that sex, ECOG PS, KPS, primary characteristics, visceral metastases, laboratory data, and previous chemotherapy were significantly associated with OS. The survival rates at 3, 6, 12, and 24 months, categorized by Katagiri score, were as follows: score 0-3, 94.4, 77.8, and 61.1%, respectively; score 4-6, 67.7, 48.7, and 31.2%, respectively; and score 7-10, 39.1, 22.1, and 9.0%, respectively (P < 0.001). CONCLUSION: Sex, ECOG PS, KPS, primary characteristics, visceral metastases, laboratory data, and previous chemotherapy were significant predictors of survival in patients with bone metastases. The Katagiri scoring system was significantly correlated with OS and can help us select the optimal dose-fractionation.