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Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.

Background: Although the combination of conventional endoscopy (CE) and endoscopic ultrasonography (EUS) is useful for predicting the depth of early gastric cancer (EGC), the diagnostic value of EUS for submucosal (SM) invasive cancer has not been fully investigated. Methods: We conducted a multicenter prospective study from May 2017 to January 2021 to evaluate the validity of a diagnostic strategy combining CE and EUS and to clarify the additional value of EUS for EGC suspected of SM invasion. In each case, the diagnosis was first made using CE, followed by EUS, and finally confirmed using a combination algorithm. Results: A total of 180 patients with EGC were enrolled from 10 institutions, of which 175 were analyzed. The histopathological depths were M, SM1, SM2, and ≥ MP in 72, 16, 64, and 23 lesions, respectively. Treatment included 92 endoscopic submucosal dissection cases and 83 surgical cases. The overall diagnostic accuracy classified by M-SM1 or SM2-MP was 58.3% for CE, 75.7% for EUS, and 78.9% for the combination of CE and EUS; the latter two were significantly higher than that of CE alone (P< 0.001). The CE, EUS, and combination accuracy rates in 108 differentiated-type lesions were 51.9%, 77.4%, and 79.6%, respectively; the latter two were significantly higher than CE alone (P< 0.001). A significant additive effect of EUS was observed in CE-SM2 low-confidence lesions but not in CE-M-SM1 lesions or in CE-SM2 high-confidence lesions. Among the nine CE findings, irregular surface, submucosal tumor-like elevation, and non-extension signs were significant independent markers of pSM2-MP. Poorly delineated EUS lesions were misdiagnosed. Conclusions: EUS provides additional value for differentiated-type and CE-SM2 low-confidence EGCs in diagnosing invasion depth.

Exome DNA sequencing of blood samples from a Li-Fraumeni family with a TP53germline mutation (codon 236 deletion) and multiple nervous system tumors revealed additional germline mutations. Missense mutations in the MSH4DNA repair gene (c.2480T>A; p.I827N) were detected in three patients with gliomas (two anaplastic astrocytomas, two glioblastomas). Two family members without a TP53germline mutation who developed peripheral schwannomas also carried the MSH4germline mutation, and in addition, a germline mutation of the LATS1gene (c.286C>T; p.R96W). LATS1 is a downstream mediator of the NF2, but has not previously been found to be related to schwannomas. We therefore screened the entire coding sequence of the LATS1gene in 65 sporadic schwannomas, 12 neurofibroma/schwannoma hybrid tumors, and 4 cases of schwannomatosis. We only found a single base deletion at codon 827 (exon 5) in a spinal schwannoma, leading to a stop at codon 835 (c.2480delG; p.*R827Kfs*8). Mutational loss of LATS1 function may thus play a role in some inherited schwannomas, but only exceptionally in sporadic schwannomas. This is the first study reporting a germline MSH4mutation. Since it was present in all patients, it may have contributed to the subsequent acquisition of TP53and LATS1germline mutations.

The authors propose the use of a pinching gesture for relating the applications running on discrete mobile devices. The gesture is realized by swiping the touch-screen of two annexed mobile devices as if pinching them together. The authors believe that this user interface can create new user experiences of multiple-screen usages, especially by designing the applications’ content to react instantly to the connection and disconnection triggered by the gesture, and to make it happen even while applications are running in each device. The authors expect this interface to fulfill a great potential in inspiring application designers to conceive various ideas especially suited for visually fascinating contents that take advantage of the dynamic reconfigurable multi-display feature. To demonstrate that potential, the authors produced some sample applications. Herein, the authors explain the idea and details of the interface mechanism, and explain the design of sample applications.

Crystal structures of perovskite-type lanthanum cobaltites, La0.4Ba0.6CoO3−δand La0.6Sr0.4CoO3−δ, have been studied by in situ neutron powder diffractometry from 27 to 1258 °C. La0.4Ba0.6CoO3−δhas a cubic Pm3̅mstructure in the whole temperature range, while La0.6Sr0.4CoO3−δexhibits a phase transition from hexagonal (R3̅c) to cubic (Pm3̅m) symmetry between 400 and 600 °C. Geometric information on oxygen diffusion is essential to understand the facile electrode reaction of perovskite-type cobaltites, but previous approaches have been limited to computational predictions. Here we provide long-awaited experimental evidence for a curved three-dimensional oxygen diffusion path in an ABO3mixed ionic-electronic conductor, La0.4Ba0.6CoO3−δ. The oxide ions diffuse in the ⟨100⟩ direction near the stable position, while the path is along ⟨110⟩ around the middle point of the path. The connected path was not visualized in La0.6Sr0.4CoO3−δbut in La0.4Ba0.6CoO3−δ, which indicates the higher oxygen diffusivity in La0.4Ba0.6CoO3−δ. The oxygen defect concentration, bottleneck size for oxygen diffusion, and oxygen atomic displacement parameter of La0.4Ba0.6CoO3−δare higher than those of La0.6Sr0.4CoO3−δ, which are responsible for the higher oxygen diffusivity in La0.4Ba0.6CoO3−δ.

Follicle-stimulating hormone (FSH) plays important roles in spermatogenesis. However, the biologic activity of FSH can vary in different vertebrate classes, and the definitive function of FSH has not been established. In this study, we investigated the functions of FSH on spermatogenesis using an in vitro culture system for Japanese eel testis. The eel Fsh receptor was expressed in testis tissue during the whole process of spermatogenesis, mainly by Leydig cells that produce steroid hormones and by Sertoli cells surrounding type A spermatogonia and early type B spermatogonia. In an in vitro organ culture, recombinant eel Fsh (r-eFsh) induced complete spermatogenesis from the proliferation of spermatogonia to spermiogenesis during 36 days of culture; also, spermatozoa were observed in the testicular fragments. Spermatogenesis induced by r-eFsh was inhibited by trilostane, a specific inhibitor of 3beta-hydroxysteroid dehydrogenase. However, trilostane did not inhibit spermatogenesis induced by 11-ketotestosterone. These results clearly show that the main function of FSH in eel is to induce spermatogenesis via stimulating androgen production.

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A 66-year-old woman was transferred to our hospital for emergency treatment of a ruptured abdominal aortic aneurysm (AAA) and impending rupture of a descending thoracic aortic aneurysm (TAA) caused by a Stanford type-B dissection. She had severe coronary artery disease and a highly calcified aorta, and had been taking long-term steroids for rheumatoid arthritis. Endovascular repair of the TAA failed because the femoral artery was too small, so we performed simultaneous repair of the TAA and the AAA. A temporary axillofemoral bypass was constructed and the AAA was replaced with a bifurcated prosthetic graft. A thoracic stent graft was delivered successfully through a chimney graft of the abdominal graft. About 4 months later, the TAA extended proximally, causing hemoptysis, which was stopped by placing a new stent graft proximal to the previous one. This case report shows that a combination of open and endovascular repair is useful for treating a TAA with an AAA, especially in a small or frail patient.

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Abstract: Nine patients with an aortic graft infection presented after undergoing aortic grafting. Seven of 9 patients underwent an initial aortic reconstruction in our hospital. The incidence of aortic graft infection was 1.5% (7/456). There were 6 cases of paraprosthetic infection and 3 cases of aortointestinal fistulas. The treatments consisted of a complete graft excision and an axillofemoral bypass in 6 patients, a complete graft excision alone, a partial graft excision and a femorofemoral bypass, and the preservation of the graft with omental wrapping and irrigation in 1 each. Broad-spectrum antibiotics were intravenously administered to all patients and were then replaced by selective antibiotics for the responsible organisms. All surviving patients received antibiotics orally for 3–6 months. The early postoperative mortality rate was 11.1%. Aortoduodenal fistula occurred in 1 patient with graft excision alone. Graft thrombosis occurred in 2 patients with an axillofemoral bypass. No late graft infection or stump blowout occurred in any patient. We believe that a complete excision of the infected graft as well as the maintenance of distal tissue perfusion is necessary. However, based on the condition of the patient, the appearance of the operating field, and the difficulty of a repeat operation, we would like to stress the importance of selecting the best and safest treatment plan for each case.

In this work, we examined the functions of the female hormone “estrogen” on spermatogenesis of the Japanese eel (Anguilla japonica).Estradiol-17β (E2), a natural estrogen in vertebrates, was present in the serum and its receptor was expressed in the testis during the whole process of spermatogenesis. Spermatogonial stem cell renewal was promoted by E2implantation but was suppressed by tamoxifen (an antagonist of estrogen). In vitro,10 pg/ml of E2was sufficient to induce spermatogonial stem cell division in cultured testicular tissue, therefore confirming the in vivoobservations. These results clearly show that estrogen is an indispensable “male hormone” in the early spermatogenetic cycle.

We conducted a midterm follow-up of 150 claudicants who underwent surgical reconstruction by assessing cumulative patency, survival, and palliation (graft patency in live patients) rates. Eighty-nine claudicants (group I) underwent direct (in situ) proximal revascularization, 33 (group II) had indirect (ex situ) proximal revascularization, while 28 (group III) had distal revascularization. The secondary patency rates at 3 years were 97.5% in group I, 97.0% in group II, and 75.0% in group III, respectively. Only one patient with limb graft thrombosis required below-knee amputation. There were 3 perioperative deaths (2 in group I and 1 in group II). The survival rates at 3 years were 86.0% in group I, 69.5% in group II, and 95.8% in group III, respectively. The palliation rates at 3 years were 84.8% in group I, 70.0% in group II, and 77.9% in group III, respectively. These findings indicate the midterm benefits of supra- and infrainguinal arterial reconstructions, and also suggest that the preoperative assessment of risks in individual patients, the selection of the appropriate operative procedure and graft material, and intensive postoperative follow-up and management of any associated disease are all important aspects in the treatment of claudicants.

A manufacturing system which integrates a machining center with a multi-axis force sensor and realtime controller. CAD system and data-base was developed to realize high precision and high efficiency autonomously. To realize highly efficient machining while maintaining a stable cutting state, both a real-time adaptive control function and learning capability were implemented. Learning behavior was obtained by storing the actual state of the system in the form of an experimentally-determined stability lobe diagram. Efficient machining conditions, including the detailed tool path, were dynamically realized by regenerating the tool path periodically. Experimental results showed the effectiveness of the system.

The dynamic viscoelasticity of polymeric composites consisting of silicone gel and polymethacrylic acid cobalt(II) salt (PMACo) particles was studied in d.c. electric fields. It was measured by applying sinusoidally varying shear strain or compressive strain to the composites. It was found that the electric fields enhanced the storage and loss moduli of the composites, and changed the loss tangent (electroviscoelastic effect). The amount of the electroviscoelastic effect was influenced by the content of absorbed water in the PMACo particle, the fraction of PMACo particles, and the intensity of the electric field. It also depended on the amplitude and frequency of the applied strain. The increments of the compressive moduli due to the electroviscoelastic effect were much larger than those of the shear moduli.

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Arterial insufficiency of the foot was examined by radioisotope study with intravenous administration of thallium-201. We observed the immediate distri bution during postocclusive reactive hyperemia and the redistribution in the foot after a 3 hours interval. Seventy-seven feet were examined: 18 normal feet, 24 feet with claudication, 31 feet with rest pain or ischemic ulcers, 4 feet with diabetic ulcers. The distribution index (D.I.), which defined the ratio of uptake counts of the immediate distribution to those of the redistribution, was of use to evaluate quantitively the degree of ischemia. Using these parameters to assess the therapeutic effects, 23 feet with ischemic ulcers were examined before and after treatment.: 5 feet with arterial reconstruction, 4 feet with lumbar sympa thectomy, 14 feet undergoing medical treatment. The effect index (E.I.) was defined as the ratio of the D.I. after treatment to before treatment. When the E.I. value was more than 1.0, 18 of 20 ischemic ulcers were improved and two were unchanged whereas all four ulcers with the E.I. value less than 1.0 became worse. The D.I. is a reliable indicator to estimate the degree of ischemia and the E.I. is of use to predict therapeutic effect particularly following lumbar sympa thectomy or medical treatment, which are frequently difficult to be evaluated by other noninvasive diagnostic methods.

Abstract: Vibrio vulnificus, a recently described strain of the halophilicVibrio species, was isolated from the blood of a 73-year-old man, who developed rapidly progressive wound infection and fatal septicemia. Twenty-one patients withVibrio vulnificus infection have been reported in the Japanese literature.Vibrio vulnificus most frequently causes primary septicemia and necrotising cellulitis after the eating of raw fish or shellfish or after exposure to seawater. The infection is characterized by its occurring during the warm months of the year, in patients with underlying diseases, especially liver diseases, and the mortality rate is surprisingly high. Clinicians should therefore consider the possibility ofVibrio vulnificus infection in the differential diagnosis of severe wound infections. Early surgical intervention and intensive antibiotic therapy are recommended for preventing the progress of the septicemia.

The pharmacokinetics and depressor effect of a nonsulfhydryl angiotensin-converting enzyme inhibitor, delapril, was assessed by administering a single dose of 30 mg to nine patients with mild to moderate essential hypertension. Orally administered delapril is a prodrug and must be deesterified to its active metabolites, delapril diacid and 5-hydroxy delapril diacid. The pharmacokinetic parameters for delapril, delapril diacid, and 5-hydroxy delapril diacid were, respectively: t½0.30, 1.21, and 1.40 hours; Cmax489, 635, and 229 ng/ml; AUC 572, 1859, and 948 ng · hr/ml. Delapril produced significant decreases in systolic blood pressure and angiotensin-converting enzyme activity 24 hours after dosing. There were no significant changes in the endogeneous creatinine clearance after the drug. Thus delapril may represent a useful antihypertensive agent for control of blood pressure in patients with essential hypertension.Clinical Pharmacology and Therapeutics (1987) 41, 74–79; doi:10.1038/clpt.1987.12

Abstract: The natural history of intermittent claudication (IC) was surveyed in 59 limbs of 44 patients. The mean follow-up period was 3 years (1 to 8.3 years). During the follow-up period, 72.0 per cent of the limbs with a solitary arterial lesion improved or remained unchanged. However, detailed analysis showed that 53.3 per cent of limbs with iliac artery stenosis and 50.0 per cent of those with femoropopliteal artery stenosis worsened, whereas only 18.7 per cent of limbs with iliac artery occlusion and no limbs with femoropopliteal artery occlusion had worsening of symptoms. Of limbs with multiple arterial lesions, 62.5 per cent worsened. Although the natural history of IC is relatively favorable, IC due to a solitary arterial stenosis tends to worsen, whereas IC due to a solitary arterial occlusion will, in more than 80 per cent of cases, improve or remain unchanged. In cases of arterial stenosis, therefore, more careful follow-up, including control of risk factors, is mandatory.

Abstract: Replantation of a completely severed finger, hand or arm is now performed with wide success. We now report an extremely rare complication of this replantation, an arterio-venous (A-V) shunt formation. Pathogenesis of the new A-V fistual formation is discussed.

• A traumatic aneurysm of the abdominal aorta resulting in acute peripheral thrombosis is rare. A 29-year-old man suffered a sudden occlusion of the terminal abdominal aorta and bilateral iliac arteries. An infrarenal abdominal aortic aneurysm was found, along with destruction of lumbar vertebrae and an aberrant renal artery. The pathogenesis of this false aneurysm was thought to be traumatic rather than inflammatory because the patient's history and laboratory findings showed no signs of inflammatory reactions. He had been in an automobile accident five years previously, resulting in lumbar vertebral injury. Arterial reconstruction and intraoperative perfusion of the aberrant renal artery were performed successfully. To our knowledge, our case is the seventh one reported in the English literature of a traumatic aneurysm of the abdominal aorta successfully repaired by surgery.(Arch Surg 1983;118:1337-1339)

Abstract: We investigated the XLRS1 gene in Japanese patients with retinoschisis (RS). All exons of the XLRS1 gene were sequenced in 14 males, including a pair of monozygotic twins, from 11 individual families with RS and five of their mothers who are asymptomatic but diagnosed as carriers. Six kinds of missense mutations and a nonsense mutation, including six novel mutations, were detected in all 14 patients and carriers. Mutations in the XLRS1 gene are also responsible for RS in non-Caucasian patients. Most Japanese RS cases are caused by an XLRS1 gene defect. A novel mutation, Glu72Lys, was found in four families, suggesting a common mutation in the Japanese population. Clinical features of RS patients with both the Glu72Lys and Pro193Leu mutations indicate that a genotype–phenotype correlation is not recognized in RS.

A massively parallel Fourier-spectrometer array that takes advantage of the voltage-controlled birefringence of a liquid-crystal cell is proposed. The retardation variation of a nematic liquid-crystal cell controlled by an ac voltage is used for the optical path scanning of a Fourier-spectrometer array. An experiment for correcting the nonlinearity of retardation is demonstrated, and problems related to this massively parallel array are pointed out.

Schwannomas are benign nerve sheath tumors composed of well-differentiated Schwann cells. Other than frequent NF2 (neurofibromatosis type 2) mutations (50%–60%), their molecular pathogenesis is not fully understood. LATS1 and LATS2 are downstream molecules of NF2 and are negative regulators of the yes-associated protein (YAP) oncogene in the Hippo signaling pathway. We assessed mutations of the NF2, LATS1, and LATS2 genes, promoter methylation of LATS1 and LATS2, and expression of YAP and phosphorylated YAP in 82 cases of sporadic schwannomas. Targeted sequencing using the Ion Torrent Proton instrument revealed NF2 mutations in 45 cases (55%), LATS1 mutations in 2 cases (2%), and LATS2 mutations in 1 case (1%) of schwannoma. Methylation-specific polymerase chain reaction showed promoter methylation of LATS1 and LATS2 in 14 cases (17%) and 25 cases (30%), respectively. Overall, 62 cases (76%) had at least 1 alteration in the NF2, LATS1, and/or LATS2 genes. Immunohistochemistry revealed nuclear YAP expression in 18 of 42 cases of schwannoma (43%) and reduced cytoplasmic phosphorylated YAP expression in 15 of 49 cases of schwannoma (31%), all of which had at least 1 alteration in the NF2, LATS1, and/or LATS2 genes. These results suggest that an abnormal Hippo signaling pathway is involved in the pathogenesis of most sporadic schwannomas.

Gemistocytic astrocytoma (World Health Organization grade II) is a rare variant of diffuse astrocytoma that is characterized by the presence of neoplastic gemistocytes and has a significantly less favorable prognosis. Other than frequent TP53 mutations (>80%), little is known about its molecular profile. Here, we show that gemistocytic astrocytomas carry a lower frequency of IDH mutations than fibrillary astrocytomas (74% vs 92%; p = 0.0255) but have profiles similar to those of fibrillary astrocytomas with respect to TERT promoter mutations (5% vs 0%), 1p/19q loss (10% vs 8%), and loss of heterozygosity 10q (10% vs 12%). Exome sequencing in 5 gemistocytic astrocytomas revealed homozygous deletion of genes at 19q13 (i.e. RRAS [related RAS viral oncogene homolog; 2 cases] and ERCC1 [excision repair cross-complementing rodent repair deficiency, complementation group 1; 1 case]). Further screening showed RRAS homozygous deletion in 7 of 42 (17%) gemistocytic astrocytomas and in 3 of 24 (13%) IDH1 mutated secondary glioblastomas. Patients with gemistocytic astrocytoma and secondary glioblastoma with an RRAS deletion tended to have shorter survival rates than those without deletion. Differential polymerase chain reaction and methylation-specific polymerase chain reaction revealed an ERCC1 homozygous deletion or promoter methylation in 10 of 42 (24%) gemistocytic astrocytomas and in 8 of 24 (33%) secondary glioblastomas. Alterations in RRAS and ERCC1 appear to be typical in gemistocytic astrocytomas and secondary glioblastomas, since they were not present in 49 fibrillary astrocytomas or 30 primary glioblastomas.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.