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Abstract Background Atraumatic localized convexity subarachnoid hemorrhage (cSAH) is an uncommon form of nonaneurysmal subarachnoid hemorrhage characterized by bleeding limited to the cerebral convexities. Ipsilateral cSAH can result from a variety of causes, such as internal carotid artery stenosis, obstruction, and dissection, although concomitant contralateral cSAH is exceptionally rare. In this case, the initial findings of cSAH led us to discovering contralateral internal carotid artery dissection (ICAD) and an elongated styloid process (ESP). ESP is recognized as a risk factor for ICAD, which is a hallmark of Eagle syndrome. This sequence of findings led to the diagnosis of Eagle syndrome, illustrating a complex and intriguing interplay between cerebrovascular conditions and anatomical variations. Case presentation A 47-year-old Japanese woman experienced acute onset of headache radiating to her neck, reaching its zenith approximately two hours after onset. Given the intractable nature of the headache and its persistence for three days, she presented to the emergency department. Neurological examination revealed no abnormalities, and the coagulation screening parameters were within normal ranges. Brain computed tomography (CT) revealed right parietal cSAH, while CT angiography (CTA) revealed ICAD and an ESP measuring 30.1 mm on the left side, positioned only 1.4 mm from the dissected artery. The unusual occurrence of contralateral cSAH prompted extensive and repeated imaging reviews that excluded reversible cerebral vasoconstriction syndrome (RCVS), leading to a diagnosis of left ICAD secondary to Eagle syndrome. The patient underwent conservative management, and the dissected ICA spontaneously resolved. The patient has remained recurrence-free for two and a half years. Conclusions Managing cSAH requires diligent investigation for ICAD, extending beyond its identification to explore underlying causes. Recognizing Eagle syndrome, though rare, as a potential etiology of ICAD necessitates the importance of evaluating ESPs. The method for preventing recurrent cervical artery dissection due to Eagle syndrome is controversial; however, conservative management is a viable option.

Papillary and follicular thyroid carcinomas (PTC and FTC) are prominent malignancies that originate from thyroid follicular cells. PTC is usually diagnosed via preoperative cytology, and large tumor size, clinical node metastasis, and distant metastasis constitute preoperative prognostic factors. Gross extrathyroidal and extranodal tumor extensions have a significant prognostic impact, are evaluated intraoperatively, and are useful for determining the extent of surgery. Aggressive variants, such as tall cell and hobnail variants, a high Ki-67 labeling index (LI), and somatic gene mutations are prognostic factors in postoperative pathological and molecular examinations. In contrast, FTC is generally diagnosed based on postoperative pathology. Large tumor size and M factors have prognostic value; however, the findings of pathological examinations are very important. FTCs are classified as minimally invasive, encapsulated angioinvasive, and widely invasive FTCs. Widely invasive FTC with vascular invasion (VI) and encapsulated angioinvasive FTCs with extensive VI have a poor prognosis, whereas widely invasive FTC without VI has an excellent prognosis, which is similar to that of minimally invasive FTC. This indicates that VI is a considerably more important prognostic marker than capsular invasion. For postoperative follow-up, dynamic markers such as the thyroglobulin-doubling rate (DR), metastatic tumor volume-DR, and change in the neutrophil-to-lymphocyte ratio are important and are useful for evaluating the effectiveness of treatments, such as radioactive iodine therapy and molecular targeted therapy, for recurrent lesions. For clinicians, it is important to accurately evaluate prognostic markers of PTC and FTC in the pre-, intra-operative, and post-operative phases.

Arterial spin-labeling magnetic resonance imaging (ASL-MRI) is widely used for evaluating collateral development in patients with acute ischemic stroke (AIS). This study aimed to characterize the findings of multiphase ASL-MRI between embolic and atherosclerotic large vessel occlusion (LVO) to aid in the differential diagnosis. Among 982 patients with AIS, 44 who were diagnosed with acute, symptomatic, and unilateral occlusion of the horizontal segment of the middle cerebral artery (MCA) were selected and categorized into embolic stroke (ES) and atherosclerosis (AT) groups. Using ASL-MRI (postlabeling delay [PLD] of 1.5, 2.0, and 2.5 s) at admission, the ipsilateral to contralateral ratio (ICR) of the signal intensity and its time-course increasing rate (from PLD 1.5 to 2.0 and 2.5, ΔICR) were measured and compared between the two groups. The mean ICR was significantly higher in the AT group than in the ES group (AT vs. ES: 0.49 vs. 0.27 for ICR1.5, 0.73 vs. 0.32 for ICR2.0, and 0.92 vs. 0.37 for ICR2.5). The ΔICR of PLD 1.5-2.0 (ΔICR2.0) and 2.5 (ΔICR2.5) were also significantly higher in the AT group than in the ES group (AT vs. ES: 50.9% vs. 26.3% for ΔICR2.0, and 92.6% vs. 42.9% for ΔICR2.5). Receiver operating characteristic curves showed moderate-to-strong discriminative abilities of each ASL-MRI parameter in predicting MCA occlusion etiology. In conclusion, multiphase ASL-MRI parameters may aid in differentiating intracranial LVO etiology during the acute phase. Thus, it is applicable to AIS management.

Generating CRISPR/Cas9-mediated mutants in tomato (Solanum lycopersicum L.) involves screening shoots regenerated from cultured cells transformed with a T-DNA harboring sequences encoding Cas9 and single guide RNAs (sgRNAs). Production of transformants can be inconsistent and obtaining transformants in large numbers may be difficult, resulting in a limited variety of mutations. Here, I report a method for generating various types of mutations from one transgenic plant harboring the CRISPR/Cas9 system. In this method, a wild-type plant was crossed with a T0 biallelic mutant expressing two sgRNAs targeting the RIPENING INHIBITOR (RIN) gene, and the resulting F1 seedlings were classified using a kanamycin resistance marker on the T-DNA. Genotyping of the RIN locus revealed that kanamycin-sensitive F1 seedlings, which carried no T-DNA, always harbored the wild-type allele and a mutant allele from the transgenic parent. Kanamycin-resistant F1 seedlings, which do carry the T-DNA, harbored a variety of novel mutant alleles, but not the wild-type allele, suggesting that it was mutated during crossing. The novel mutations included one-base insertions or short deletions at each target site, or large deletions across the two target sites. This method was also successfully applied to produce mutations in Geranylgeranyl pyrophosphate synthase 2 (GGPS2). Because this method involves crossing rather than transformation, it can be readily scaled up to produce numerous novel mutations, even in plant species or cultivars for which transformation is inefficient. Therefore, when initial transgene experiments fail to induce the desired mutation, this method provides additional opportunities for generating mutants.

Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC), which was initiated at Kuma Hospital (Kobe, Japan) in 1993 and Cancer Institute Hospital (Tokyo) in 1995, is now gradually being adopted worldwide, and several prospective studies have described the favorable outcomes of PTMC patients who underwent AS. The most important factor predicting PTMC growth is young age, and PTMC enlargement in young patients may be affected by high serum levels of thyroid-stimulating hormone. This review notes that one patient showed lung metastasis after conversion surgery (CS) following AS, but there are no reports of patients dying of thyroid carcinoma during or after AS. Some PTMCs enlarge or show newly appeared metastatic nodes requiring CS, and findings on the postoperative prognosis and incidence of significant surgical complications (e.g., permanent vocal cord paralysis, hypoparathyroidism) do not differ significantly between patients who underwent CS after AS and those who underwent immediate surgery (IS). IS has been associated with significantly higher incidences of these complications compared to AS as the initial management. Several studies have examined the quality of life (QoL) of patients who underwent AS versus IS, and reported discrepant findings regarding various psychological conditions (including anxiety). Medical costs for AS and IS vary regionally, and in Japan, the 10-year total cost of IS was 4.1 times greater than that of AS in 2017. Taken together, the existing findings demonstrate that AS can be appropriate for the initial management of patients with PTMC.

Abstract The thyroid gland's neurovascular relationship is commonly portrayed as the recurrent laryngeal nerve (RLN) coursing posteriorly to the thyroid gland. We report a rare case with the RLN running anteriorly to a thyroid tumor. A 56-year-old Japanese woman underwent a thyroidectomy for a benign thyroid tumor. Preoperatively, computed tomography confirmed that part of the tumor had extended into the mediastinum and was descending posteriorly up to the brachiocephalic artery. Intraoperatively, when the sternothyroid muscle was incised to expose the thyroid gland, a cord (nerve)-like structure was observed directly anterior to the thyroid tumor. Although the course of this cord-like structure was clearly different from the "traditional" course of the right RLN, the possibility that the structure was the RLN could not be excluded. The structure was traced back in order to preserve it; we saw that it entered the larynx at the lower margin of the cricothyroid muscle and approximately at the level of the cricothyroid junction through the back of the normal thyroid tissue. With intraoperative neuromonitoring, the structure was identified as the RLN. As a result, the course of the RLN run anterior to the tumor but then posterior to the 'normal thyroid' i.e. into it normal anatomical position. Had we assumed that the RLN was behind the thyroid tumor, we would have damaged the RLN. It would not be possible to diagnose this abnormal running course of the RLN reliably before surgery, but extra care should be taken in similar cases, that is, when a large thyroid tumor is descending posteriorly up to the brachiocephalic artery on the right side.

Abstract Background Postoperative cholangitis is a complication of biliary reconstruction during hepatobiliary pancreatic surgery. Most cases are associated with anastomotic stenosis, but there are also cases of cholangitis without stenosis, and treatment can be difficult, especially in patients with recurrent symptoms. In this report, we describe a case of repeated nonobstructive cholangitis in a patient after total pancreatectomy, in which a good outcome was obtained after performing tract conversion surgery. Case presentation The patient was a 75-year-old man. He underwent total pancreatectomy for stage IIA cancer of the pancreatic body, hepaticojejunostomy via the posterior colonic route, gastrojejunostomy and Braun anastomosis via the anterior colonic route using the Billroth II method. The patient had a good postoperative course and was receiving adjuvant chemotherapy on an outpatient basis, but he developed his first episode of cholangitis 4 months after surgery. Although conservative treatment with antimicrobial agents was successful, the patient continued to have recurrent biliary cholangitis and was repeatedly admitted and discharged from the hospital. Since stenosis at the anastomosis was suspected, endoscopic observation of the anastomosis was performed using small bowel endoscopy for close examination, but no apparent stenosis was observed. Small bowel imaging indicated a possible influx of contrast medium into the bile duct, and reflux due to food residue was suspected as the cause of cholangitis. Since conservative treatment alone did not suppress the flare-up of symptoms, the decision was made to perform tract conversion surgery for curative purposes. The afferent loop was cut midstream, and jejunojejunostomy was performed downstream. The postoperative course was good, and the patient was discharged on the 10th day after surgery. He is currently an outpatient and has been free of cholangitis symptoms for 4 years without cancer recurrence. Conclusions Although the diagnosis of nonobstructive retrograde cholangitis can be difficult, surgical treatment should be considered in patients with recurrent symptoms and refractory treatment.

Objective: This study aimed to elucidate disproportionately low serum thyroglobulin (Tg) values in Tg antibody (TgAb)-positive patients with structural recurrence of papillary thyroid carcinoma (PTC) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Design: A retrospective study was performed on 176 patients in whom Tg and TgAb levels were measured between 2016 and 2021. Several comprehensive analyses of Tg-LC-MS/ MS with an electrochemiluminescence immunoassay for Tg (Tg-ECLIA) were conducted using serum samples. Methods: TgAb-positive patients who underwent total thyroidectomy with multiple lung metastases due to PTC were evaluated using Tg-LC-MS/MS and Tg-ECLIA. Tg expression in lymph node metastases and metastatic lesions was evaluated by immunohistochemistry and Tg levels of aspiration washouts were also evaluated. Two in vitro assays were performed to elucidate TgAb interference. Results: Tg concentrations of negative TgAb in both assays were similar (R2 = 0.99; n = 52). Patients with structural recurrence showed higher Tg values with Tg-LC-MS/MS than with Tg-ECLIA. The undetectable proportion was significantly lower wi th Tg-LC-MS/MS (31.6%, 6/19) than with Tg-ECLIA (68.4%, 13/19; P = 0.023). The spike-recovery rate and Tg concentrations determined by the serum mixture text (n = 29) were significantly reduced to 75.0% (118.3–88.7%) and 81.3% (107.0–87.0%), respectively, w ith TgAb using Tg-ECLIA (both P < 0.001) confirming assay interference but not using Tg-LC-MS/ MS (91.8–92.3%, P = 0.77 and 98.4–100.8%, P = 0.18, respectively). Conclusions: TgAb had no effect on the Tg-LC-MS/MS assay but yielded 19–25% l ower values in Tg-ECLIA. Tg-LC-MS/MS is preferable for monitoring serum Tg levels in TgAb-positive patients, although those with structural recurrence often had disproportionally low Tg values.

Abstract Background The major sites of distant metastases of papillary thyroid carcinoma (PTC) are the lung and bone; metastasis to the liver is rare. Although the postoperative serum thyroglobulin (Tg) level after total thyroidectomy is a good prognostic indicator for PTC when anti-thyroglobulin antibody (TgAb) is negative, the presence of TgAb interferes with the Tg assay, making serum Tg levels unreliable. Here we report a case of liver metastasis of PTC that presented with elevated serum levels of carbohydrate antigen 19-9 (CA19-9), which is usually a serum marker of pancreatic and gastrointestinal neoplasias. Case presentation A 69-year-old man was diagnosed with PTC and underwent total thyroidectomy 16 years ago. The patient’s serum Tg levels increased progressively during follow-up and his serum TgAb was negative. Positron emission tomography (PET) and computed tomography (CT) revealed metastases of the lung, cervical spine, mediastinum and liver. The liver lesion was a solitary tumor measuring 4.0 cm in the greatest dimension. His serum CA19-9 level was very high (326 U/mL), and intrahepatic cholangiocarcinoma was suspected from the results of various examinations including gastrointestinal endoscopic imaging and CT. Laparoscopic partial liver resection for segment 4 was performed. The histopathological diagnosis was a metastatic liver tumor from PTC. The immunohistological examination revealed that the liver tumor was positive for CA19-9 and Tg. The primary PTC, recovered from paraffin-embedded specimen, was also positive for CA19-9. After the surgery, his serum CA19-9 level as well as serum Tg level markedly decreased. Conclusions We presented the first reported case of liver metastasis of a PTC presenting with elevated serum levels of CA19-9 after total thyroidectomy. This case suggests that the serum CA19-9 levels may serve as a surrogate marker for PTC in place of the serum Tg level in patients with positive serum TgAb if the PTC and/or the metastatic lesions are positive for CA19-9 staining.

We reported here four cases presenting with disturbance of consciousness over long periods of time and hyperammonemia. Two patients were on maintenance hemodialysis. Contrast-enhanced computed tomography (CT) of abdomen and balloon-occluded retrograde contrast venography revealed existence of a non-cirrhotic portosystemic shunt. Conservative treatment such as intravenous branched-chain amino acid administration and oral lactulose administration had only a modest effect in all patients. Improvements in symptoms were observed following the occlusion of the shunt path in three patients. Measurements of ammonia values would be the most important test for screening, but changes in Fischer’s ratio or indocyanine green (ICG) test values were also correlated with clinical symptoms. Neurologists should keep in mind the possibility of non-cirrhotic portosystemic shunts when they encounter patients with disturbance of consciousness. They should also remember that occlusion of the shunt pathway is an effective treatment.

Background Posterior reversible encephalopathy syndrome (PRES) is a disease characterised by reversible subcortical vasogenic oedema, neurological symptoms and abnormal findings on head imaging. It is recognised as one of the most prominent organ disorders in hypertensive emergencies but is rarely associated with thrombotic microangiopathy (TMA).Case presentation A woman in her 40s with untreated hypertension had occasional headaches in the past 4 months. The headaches worsened during the 3 weeks prior to admission. On the day of admission, the patient presented with severe headache accompanied by frequent vomiting. MRI of the head revealed oedematous changes in the brainstem, including the subcortical, cerebellum and pons. Fundus examination revealed hypertensive retinopathy with papilloedema. Blood tests indicated thrombocytopenia, renal dysfunction and haemolytic anaemia, and a blood smear confirmed fragmented erythrocytes. Coombs’ test, and tests for ADAMTS13 activity and infectious and autoimmune diseases were negative. The patient was diagnosed with PRES, secondary to malignant hypertension (MH) and associated with TMA. Antihypertensive therapy promptly improved the clinical symptoms, blood pressure, and the abnormal MRI and blood test findings. The patient was discharged from the hospital 20 days after admission.Conclusions We report a rare case of PRES that was associated with TMA and triggered by MH. Antihypertensive therapy was effective in alleviating the associated adverse clinical symptoms. Differentiation of underlying diseases is essential for early intervention, since treatment depends on factors causing TMA.

Abstract Background TAS-102 plus bevacizumab is an anticipated combination regimen for patients who have metastatic colorectal cancer. However, evidence supporting its use for this indication is limited. We compared the cost-effectiveness of TAS-102 plus bevacizumab combination therapy with TAS-102 monotherapy for patients with chemorefractory metastatic colorectal cancer. Method Markov decision modeling using treatment costs, disease-free survival, and overall survival was performed to examine the cost-effectiveness of TAS-102 plus bevacizumab combination therapy and TAS-102 monotherapy. The Japanese health care payer’s perspective was adopted. The outcomes were modeled on the basis of published literature. The incremental cost-effectiveness ratio (ICER) between the two treatment regimens was the primary outcome. Sensitivity analysis was performed and the effect of uncertainty on the model parameters were investigated. Results TAS-102 plus bevacizumab had an ICER of $21,534 per quality-adjusted life-year (QALY) gained compared with TAS-102 monotherapy. Sensitivity analysis demonstrated that TAS-102 monotherapy was more cost-effective than TAS-102 and bevacizumab combination therapy at a willingness-to-pay of under $50,000 per QALY gained. Conclusions TAS-102 and bevacizumab combination therapy is a cost-effective option for patients who have metastatic colorectal cancer in the Japanese health care system.

Objectives: Few studies have compared management and outcomes of bridge to surgery (BTS) for obstructive colonic cancer according to the location of the tumor. Additional information is needed about this procedure's characteristics and short-term and long-term outcomes. We aimed to compare patient and tumor characteristics, and outcomes of BTS for obstructive right-sided versus left-sided colonic cancers. Methods: This was a retrospective, single center, cohort study. The study cohort comprised 149 patients, including 48 with right-sided and 101 with left-sided obstructive colonic cancers, who were treated with BTS between January 2007 and December 2017. Data on medical history, investigations, treatments, and prognosis were collected from an electronic database of a single hospital. The primary end points were overall (OS) and disease-free (DFS) survival and short-term surgical outcomes. Results: Significantly more patients with right-sided cancers had postoperative complications (29.2% vs. 14.9%, p = 0.039). Additionally, postoperative chemotherapy was administered to a marginally significantly greater proportion of patients with left-sided cancers (29.2% vs 45.5%, p = 0.057). The long-term outcomes were comparable between the two groups (the 5-year OS rates were 67.6% and 80.9% [p = 0.117] and the 5-year DFS rates were 62.2% and 58.6% [p = 0.671]). Multivariate analyses using all studied variables showed that lymphovascular invasion, advanced T stage, and adjuvant chemotherapy were independent poor prognostic factors. Conclusions: The long-term outcome was not different between the right- and left-sided groups. In a BTS setting, postoperative complications may reduce the compliance of adjuvant chemotherapy in right-sided cancers and affect long-term outcomes.

Abstract Background Our previous kinetic analyses of changes in the tumor volume (TV) of papillary thyroid microcarcinomas during active surveillance revealed that the tumors’ growth varied over time from rather rapid growth to shrinkage and that the hypothetical TV-doubling rates (DRs) before the patients’ presentation were much larger than their observed TV-DRs, indicating that rapid growth phases preceded their presentation. Whether this phenomenon also occurs in medullary thyroid carcinoma (MTC) was unknown. Methods We retrospectively analyzed the cases of 46 MTC patients (18 hereditary, 28 sporadic; 9–80 years old at surgery, median 53.5 years; 19 males and 27 females) with elevated postoperative calcitonin (Ct) measured with the electrochemiluminescence immunoassay suggesting persistent disease. We calculated each patient’s Ct-DR and his/her hypothetical TV-DR, using the tumor size and age at surgery. Results Ct-DRs (/year) after surgery were > 0.5, 0.1–0.5, − 0.1–0.1, and 1, 0.5–1.0, 0.1–0.5 and

A 77-year-old man was initially diagnosed with idiopathic pulmonary fibrosis (IPF) and treated with anti-fibrotic nintedanib. Despite undergoing anti-fibrotic treatment for one year, his condition remained unstable. The patient was admitted to our hospital for exertional dyspnea. We performed an exposure assessment, including 2-week antigen avoidance and an environmental inhalation challenge, and successfully re-diagnosed him with fibrotic hypersensitivity pneumonitis (HP), known as chronic farmer's lung. Adding oral glucocorticoids to the nintedanib treatment improved his condition. Although antigen avoidance and environmental inhalation challenge tests are not standardized, they may be useful for diagnosing fibrotic HP when properly applied.

BackgroundWe previously reported that a high tumor burden is a prognostic factor based on an analysis of 26 patients with radioactive iodine-refractory differentiated thyroid cancer (RR-DTC) who were treated with lenvatinib. However, the optimal tumor burden for starting lenvatinib still remains to be defined. The aim of this retrospective study was to further explore in the same patient cohort the optimal timing for the start of lenvatinib by focusing on the pre- and post-treatment tumor burden.MethodsThe 26 patients were treated with lenvatinib from 2012 to 2017. We explored the optimal timing for the start of lenvatinib by comparing the characteristics of long-term responders who were defined as patients with progression-free survival ≥ 30 months and non-long-term responders.ResultsLong-term responders had a smaller post-treatment tumor burden at maximum shrinkage than non-long-term responders. Further, post-treatment tumor burden had a strong linear correlation with baseline tumor burden. We created an estimation formula for baseline tumor burden related to prognosis, using these regression lines. Patients with a sum of diameters of target lesions < 60 mm or maximum tumor diameter < 34 mm at baseline were estimated to have significantly better survival outcomes.ConclusionsWe found a strong linear correlation between pre- and post-treatment tumor burden. Our results suggested a cut-off value for baseline tumor burden for long-term prognosis among patients treated with lenvatinib.

RNA polymerase III (POLR3)-related leukodystrophy is an autosomal recessive form of leukodystrophy caused by homozygous or compound heterozygous mutations of the RNA polymerase III subunit genes, including subunit A (POLR3A). With respect to the manifestation triad, hypomyelination, hypodontia, and hypogonadotropic hypogonadism, it is also known as 4H leukodystrophy. Here, we report a 41-year-old woman of POLR3-related leukodystrophy by carrying compound heterozygous pathogenic variants of c.2554A>G (p.M852V) and c.2668G>T (p.V890F) in the POLR3A gene. She was amenorrheic and became a wheelchair user from the age of 15 years and suffered from multiple episodes of pathologic fractures, starting with a subtrochanteric fracture of the right femur after a tonic seizure at age 30 years. Head magnetic resonance imaging demonstrated hypomyelination and atrophies of the cerebellum, brainstem, and corpus callosum. Laboratory examination revealed a marked decrease of gonadotropins and estrogen, low bone density, and high bone resorption markers. Administration of anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody restored bone resorption markers to a normal level and prevented further pathological bone fractures. Our case emphasizes that osteoporosis should be recognized as a potential but serious complication in POLR3-related leukodystrophy. It may be feasible to prevent pathologic fractures by intensive osteoporosis therapy after endocrinological examinations and evaluation of bone metabolism.

The tomato (Solanum lycopersicum) ripening inhibitor (rin) mutation completely represses fruit ripening, as rin fruits fail to express ripening-associated genes and remain green and firm. Moreover, heterozygous rin fruits (rin/+) ripen normally but have extended shelf life, an important consideration for this perishable fruit crop; therefore, heterozygous rin has been widely used to breed varieties that produce red tomatoes with improved shelf life. We previously used CRISPR/Cas9 to produce novel alleles at the rin locus. The wild-type allele RIN encodes a MADS-box transcription factor and the novel allele, named as rinG2, generates an early stop codon, resulting in C-terminal truncation of the transcription factor. Like rin fruits, rinG2 fruits exhibit extended shelf life, but unlike rin fruits, which remain yellow-green even after long-term storage, rinG2 fruits turn orange due to ripening-associated carotenoid production. Here, to explore the potential of the rinG2 mutation for breeding, we characterized the effects of rinG2 in the heterozygous state (rinG2/+) compared to the effects of rin/+. The softening of rinG2/+ fruits was delayed compared to the wild type but to a lesser degree than rin/+ fruits. Lycopene and β-carotene levels in rinG2/+ fruits were similar to those of the wild type, whereas rin/+ fruits accumulated half the amount of β-carotene compared to the wild type. The rinG2/+ fruits produced lower levels of ethylene than wild-type and rin/+ fruits. Expression analysis revealed that in rinG2/+ fruits, the rinG2 mutation (like rin) partially inhibited the expression of ripening-associated genes. The small differences in the inhibitory effects of rinG2 vs. rin coincided with small differences in phenotypes, such as ethylene production, softening, and carotenoid accumulation. Therefore, rinG2 represents a promising genetic resource for developing tomato cultivars with extended shelf life.

Introduction. Young patients with papillary thyroid carcinoma (PTC) generally have excellent prognoses despite their often-advanced disease status. The reasons for this excellent prognosis are poorly understood. Objective. To investigate the natural history of PTC in young patients, we compared the observed tumor volume-doubling rate (TV-DR) with the hypothetical tumor volume-doubling rate (hTV-DR) before presentation in young PTC patients. DR is an inverse of the doubling time and indicates the number of doublings that occur in a unit of time. A negative value indicates the number of times the volume is reduced by half per unit time. Methods. We enrolled 20 patients with the following characteristics: age ≤19 years, diagnosed with PTC according to the cytology results between 2013 and 2018 and followed-up with periodical ultrasound examinations for ≥3 months before surgery for various reasons. Seventeen patients later underwent surgery confirming the diagnosis. We calculated TV-DRs using serial measurements of tumor diameters after presentation and hTV-DRs using tumor diameters and patients’ age at presentation, assuming that a single cancer cell was present at the patient’s birth and that the tumor grew at a constant rate. These values indicate the lowest growth rates necessary for a single cancer cell to achieve the full tumor size at presentation. Results. Thirteen patients had positive TV-DRs (/year) ranging from 0.09 to 1.89, indicating tumor growth, and the remaining seven patients had negative values (−0.08 to −1.21), indicating regression. The median TV-DR was 0.29. The hTV-DRs (1.48–2.66, median 1.71) were significantly larger than the TV-DRs (p

Standard therapy for radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is multi-targeted kinase inhibitors (m-TKIs), represented by sorafenib and lenvatinib. One of the main target molecules of m-TKIs is vascular endothelial growth factor receptor (VEGF-R). m-TKIs are known to cause adverse reactions such as hypertension and proteinuria as a class effect. In particular, proteinuria is thought to result from vascular endothelial damage and podocytopathy in glomeruli, and the development of thrombotic microangiopathy (TMA) has been reported for VEGF inhibitors. We encountered a patient with RAI-refractory (RR) papillary thyroid carcinoma (PTC) who developed proteinuria and renal dysfunction due to lenvatinib. Renal biopsy demonstrated that these changes were caused by TMA. To our knowledge, this is the first reported case of TMA due to lenvatinib in a Japanese patient with RR-PTC. A 70-year-old woman developed proteinuria, renal impairment and hypertension while receiving lenvatinib for RR-PTC. Her proteinuria and renal damage continued to worsen despite dose reductions and dose interruptions. Renal biopsy was consistent with the chronic type of TMA. These findings indicate that TMA is a possible cause of proteinuria due to lenvatinib, as has been reported for the VEGF inhibitors.

Abstract Purpose For the differential diagnosis of medullary thyroid carcinoma (MTC) on thyroid nodules, ultrasound-guided fine-needle aspiration cytology is a useful and safe procedure, but its diagnostic accuracy is not high enough. As an ancillary method to accurately diagnose MTC, the calcitonin in fine-needle aspirate washout fluid (FNA-Ct) is used. However, no data are available about cut-off values of FNA-Ct using the currently available electrochemiluminescence immunoassay (ECLIA). Methods We investigated 180 thyroid nodules in 141 patients. After smearing, the syringe and needle used for the FNA were rinsed with normal saline (0.5 mL). The calcitonin in the washout was measured by ECLIA. Results The FNA-Ct in the non-MTC nodules of MTC patients, non-MTC nodules of non-MTC patients, and MTC nodules were 10.6–2100 pg/mL (median 24.6 pg/mL),

Abstract Background Because the survival rate for patients experiencing late complications after pancreaticoduodenectomy (PD) is increasing, late complications should receive as much attention as early complications do. Methods Between April 2007 and August 2016, 133 patients underwent PD at our institution. We analyzed their cases to determine the predictors of late cholangitis after PD. Results Of the 133 patients, 28 (21.1%) were diagnosed with postoperative cholangitis. A multivariate analysis showed that abnormal postoperative values of alkaline phosphatase were independently associated with postoperative cholangitis (odds ratio, 3.81; 95% confidence interval, 1.519–9.553; P = 0.004). The optimal cut-off value for postoperative alkaline phosphatase calculated from the receiver operating characteristic curve was 410 IU/L (sensitivity, 76.2%; specificity, 67.9%; area under the curve, 0.73). A univariate analysis to identify risk factors showed that pneumobilia was significantly related to a postoperative alkaline phosphatase value ≥ 410 IU/L (P = 0.041). Conclusion This study suggests that an alkaline phosphatase level ≥ 410 IU/L is a predictor of late postoperative cholangitis. In addition, pneumobilia is also related to the postoperative alkaline phosphatase level. Therefore, alkaline phosphatase levels should be carefully monitored in patients with postoperative pneumobilia in the late postoperative course.

Background We aimed to clarify associations between prior anticoagulation and short‐ or long‐term clinical outcomes in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Methods and Results A total of 1189 ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation who were hospitalized within 7 days after onset were analyzed. Of these, 813 patients (68.4%) received no prior anticoagulation, 310 (26.1%) received prior warfarin treatment with an international normalized ratio (INR)

Purpose The purpose of the study is to clarify the prevalence of calcifications within thyroid tumors on ultrasonography as well as the relationship between the calcification and histopathological types. Materials and Methods Calcifications were classified into 6 (or 8) types according to their shape, size, and region. The prevalence of calcifications and types were investigated in new outpatients and patients who underwent thyroid surgery. Results Among 2,902 nodules in 2,678 new outpatients, 747 nodules (26%) had calcifications. The types showed a wide distribution. Among 941 patients with papillary carcinoma (PC), 725 patients (77%) had calcifications, and the types showed a wide distribution. 18 patients with the diffuse sclerosing variant of PC only showed punctate microcalcifications in the parenchyma (100%), 32 patients with the cyst-forming type of PC mostly fragmentary and massive types (100%), and 161 metastatic lymph nodes from PC mostly punctate microcalcifications and fragmentary types (48%). Among 337 patients with follicular carcinoma, 79 patients (23%) had calcifications, and the types were mostly fragmentary, massive, and egg-shell types. Among 41 patients with undifferentiated carcinoma, 33 patients (80%) presented with calcifications, which were mostly the massive and egg-shell types. Among 137 patients with medullary carcinoma, 99 patients (72%) had calcification, and the types showed a wide distribution. None of 173 patients with primary thyroid lymphoma had calcifications (0%). Conclusion Calcifications on ultrasonography can be one of the characteristic findings and a full understanding of the prevalence of calcifications and types will markedly contribute to the ultrasonic diagnosis of thyroid tumors.

Aim. To determine the factors associated with early recurrence in patients with distal cholangiocarcinoma after pancreaticoduodenectomy (PD). Patients and Methods. Sixty-one patients with distal cholangiocarcinoma were enrolled. The clinical data and histopathological findings were collected retrospectively. Results. Patients were divided into two groups as follows: 16 patients (26%) with early recurrence and 45 patients (74%) with late recurrence or no recurrence. In a univariate analysis, lymph node metastases (P=0.0016), lymphatic invasion (P

Background. Children and adolescents with papillary thyroid carcinomas (PTCs) have generally excellent prognoses despite their frequent extended disease. The tumor growth of young patients’ PTCs might show spontaneous slowing postoperatively. We compared young PTC patients’ postoperative thyroglobulin-doubling time (Tg-DT) with their preoperative hypothetical tumor volume-doubling time (hTV-DT). Methods. Fourteen PTC patients aged ≤18 years who underwent total thyroidectomy at Kuma Hospital in 1998–2016 had biochemically persistent disease postoperatively. We calculated their Tg-DTs and estimated their preoperative TV-DTs with the tumor size and the patient’s age at surgery, presuming that a single cancer cell was present at the patient’s birth. Results. Twelve patients had positive Tg-DTs ranging from 2.0 to 147 years, and the remaining two had negative Tg-DTs, indicating slow growth or even regression. The hTV-DTs were 0.3–0.6 years (median 0.5 years), which were significantly shorter than the Tg-DTs (p

BACKGROUND:Thyroid cancer affects over ½ million people in the U.S. and the incidence of thyroid cancer has increased worldwide at a rate higher than any other cancer, while survival has remained largely unchanged. The aim of this research was to develop, calibrate and verify a mathematical disease model to simulate the natural history of papillary thyroid cancer, which will serve as a platform to assess the effectiveness of clinical and cancer control interventions. METHODS:Herein, we modeled the natural pre-clinical course of both benign and malignant thyroid nodules with biologically relevant health states from normal to detected nodule. Using established calibration techniques, optimal parameter sets for tumor growth characteristics, development rate, and detection rate were used to fit Surveillance Epidemiology and End Results (SEER) incidence data and other calibration targets. RESULTS:Model outputs compared to calibration targets demonstrating sufficient calibration fit and model validation are presented including primary targets of SEER incidence data and size distribution at detection of malignancy. Additionally, we show the predicted underlying benign and malignant prevalence of nodules in the population, the probability of detection based on size of nodule, and estimates of growth over time in both benign and malignant nodules. CONCLUSIONS:This comprehensive model provides a dynamic platform employable for future comparative effectiveness research. Future model analyses will test and assess various clinical management strategies to improve patient outcomes related to thyroid cancer and optimize resource utilization for patients with thyroid nodules.

A 64-year-old Japanese woman had a lightly brown-blackish pigmented macule (1.2 cm in diameter) on the left sole of her foot. She received surgical excision following a diagnosis of acral lentiginous melanoma (ALM), which was confirmed histopathologically. One month after the operation, a second melanoma lesion was noticed adjacent to the grafted site. Histopathologically, the two lesions had no continuity, but HMB-45 and cyclin D1 double-positive cells were detected not only on aggregates of atypical melanocytes but also on single cells near the cutting edge of the first lesion. The unique occurrence of a sequential lesion of a primary melanoma might be caused by stimulated subclinical field cells during the wound healing process following the initial operation. This case warrants further investigation to establish the appropriate surgical margin of ALM lesions.

Since papillary thyroid carcinoma (PTC) with tracheal invasion shows a worse prognosis, aggressive surgical treatment including airway resection has been recommended. However, little is known about local recurrence of PTC with minimal tracheal invasion after shaving or laminated resection of the tracheal cartilage. In this study, we investigated the local prognosis of patients who were intra-operatively diagnosed as having minimal tracheal invasion. Methods: Of 6,015 patients who underwent initial surgery for PTC between 1987 and 2004, 127 (2.1%) were intra-operatively suspected of having minimal invasion to the trachea and underwent shaving or laminated resection of the tracheal cartilage. These 127 patients were enrolled in this study. Results: Of 127 patients, 107 were intra-operatively regarded as having received macroscopically curative treatment (curative group), whereas minimal carcinoma remnants were suspected in the remaining 20 patients (suspicious group). To date, six patients (4.6%) (one patient in the curative group and five in the suspicious group) showed local recurrence at the tracheal edge. The local disease-free survival of patients in the curative group was better than that of those in the suspicious group (p = 0.0007), although the cause-specific survival of patients in the two groups did not differ. Cut surfaces of resected carcinoma were also pathologically examined for 119 patients and 58 (48.7%) were diagnosed as carcinoma-positive, but the cut surface status was not related to macroscopic curative treatment. Of six patients showing local recurrence, only one died of lung metastasis of carcinoma. Conclusion: The incidence of local recurrence of PTC with minimal tracheal invasion is low at 4.6%. Although this event might not be immediately life-threatening for patients, to improve local prognosis, local curative treatment should be pursued. In cases that are suspected of persistent carcinoma remnants, further shaving or laminated dissection should be performed, and if the carcinoma remnant cannot be eliminated, tracheal fenestration should be considered, although such high-risk tumours may be likely to recur regardless of surgical radicality.

Anaplastic thyroid carcinoma arises from differentiated carcinoma and has a very aggressive character. In this study, we investigated the prognosis of patients with anaplastic carcinoma based on UICC stage. Patients and Methods: We investigated the prognosis of 75 patients who were diagnosed as having anaplastic carcinoma at Kuma Hospital between 1983 and 2006. Of these patients, 14, 49 and 12 were classified into Stages IVA, IVB, and IVC respectively. Results: Stage IVA patients showed a significantly better prognosis than Stage IVB or IVC patients (p = 0.0017). All patients with Stage IVC died of carcinoma within 1 year regardless of whether locally complete resection was performed. Prognosis of Stage IVB patients who underwent curative surgery did not differ from that of Stage IVA patients, but the prognosis of those who did not undergo surgery or only received palliative surgery was as poor as that of Stage IVC patients. Conclusions: Extensive surgical treatment is recommended for Stage IVA patients and palliative care is appropriate for Stage IVC patients. For Stage IVB patients, surgical treatment as a primary therapy is appropriate only when curative resection of the tumour is expected.

Thyroid carcinoma showing squamous differentiation throughout the entire lesion is diagnosed as squamous cell carcinoma of the thyroid (SCCT) in the WHO classification. This entity is a rare disease and shows a dire prognosis; however, squamous differentiation is more frequently detected in only a portion of papillary thyroid carcinoma. In this paper, we present our experience of 10 patients (8 primary lesions and 2 with recurrence in the lymph nodes) with papillary thyroid carcinoma having an SCC component (PTC-SCC). Only 3 of 8 primary lesions (38%) and none of the 2 recurrent nodes were preoperatively diagnosed as or suspected of having SCC components. All 10 patients underwent locally curative surgery. To date, 3 patients have died of carcinoma, and 2 had distant metastasis at diagnosis or had an undifferentiated carcinoma component. The other 7 are currently alive 5 to 43 months after diagnosis. Systemic adjuvant therapy after the detection of recurrence was effective for 2 patients. It is possible that some PTC-SCC patients without distant metastasis who undergo locally curative surgery can survive for a prolonged period and adjuvant therapies can be effective for local and distant recurrences.

Subcutaneous or intrastrap muscular (SIM) recurrence is rare in papillary thyroid carcinoma (PTC) patients, and its clinical significance remains unclear. We analyzed 29 patients with PTC who showed SIM recurrence in order to elucidate this issue. The incidence of patient age 55 years or older at initial surgery, extrathyroid extension, and clinically detected lymph node metastasis was 83%, 35%, and 46%, respectively. After surgical dissection, 17% of patients showed repeated SIM recurrence. Distant recurrence was detected in 45% of patients and was more likely to occur in patients with high-risk clinicopathological features. In all but one patient in this series, distant recurrence was detected at the same time or after the detection of SIM recurrence. Three patients died of PTC, but none of these patients died of the development of recurrent SIM lesions. These findings suggest that although SIM recurrence is a rare event and is not fatal, it is a predictor of distant recurrence especially in patients with high-risk clinicopathological features. Careful followup is recommended for such patients.

Papillary thyroid carcinoma (PTC) frequently metastasizes to the lymph node in lateral compartment, which can often be detected on preoperative ultrasonography (N1b). However, PTC located in one lobe showing contralateral but not ipsilateral N1b is not common. We analyzed the clinicopathological features and prognosis of 13 patients with PTC limited in one lobe showing contralateral but not ipsilateral N1b. Sizes of the primary lesions ranged from 0.8 cm to 3.0 cm and only 2 tumors showed extrathyroid extension. Metastatic lateral node measured from 0.6 to 3.1 cm. Ten patients showed pathological central node metastasis and 5 had minute PTC lesions in the contralateral lobe. However, 3 patients did not show either of these. None of the patients have developed carcinoma recurrence or died of carcinoma to date. Taken together, PTC located in one lobe with contralateral but not ipsilateral N1b is rare and generally shows an indolent behavior. Although most patients had central node metastasis and/or minute PTC lesions in the contralateral lobe, it is also possible for carcinoma cells to metastasize directly from primary lesions to the contralateral lateral node. Total thyroidectomy with central node dissection and therapeutic MND of the contralateral compartment may be an acceptable surgical design and bilateral MND might not be mandatory.

Background and Aim. Distal cholangiocarcinoma associated with choledocholithiasis has not been reported, and the causal relationship remains to be established. We evaluated diagnosis of distal cholangiocarcinoma diagnosed after the removal of choledocholithiasis. Patients and Methods. We assigned 9 cases of cholangiocarcinoma with choledocholithiasis to Group A. As a control group, 37 patients with cholangiocarcinoma without choledocholithiasis were assigned to Group B. Results. Abdominal pain at admission is the only significant difference between Group A and Group B (P=0.001). All patients in Group A had gall bladder stones, compared with 7 patients (19%) in Group B (P

There are some important prognostic factors for papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). In this paper, clinicopathological features significantly affecting patient prognosis are described based on our data as well as others. Distant metastasis at diagnosis is the most important prognostic factor for both PTC and FTC. Other than that, preoperative and intraoperative findings are important to evaluate the biological behavior of PTC. Extrathyroid extension, large lymph-node metastasis, and extranodal tumor extension that can be evaluated preoperatively or intraoperatively are significant prognostic factors for PTC patients. In contrast, pathological findings are important not only for diagnosis of FTC, but also for the evaluation of its biological character. Grade of invasiveness (minimally or widely invasive) and degree of differentiation (well differentiated or including a poorly differentiated component) greatly affect the prognosis of FTC patients.

Papillary carcinoma is a prominent malignancy originating from follicular cells. This disease generally shows an indolent character, but patients demonstrating certain clinicopathological features have a dire prognosis. At present, Western countries adopted almost routine total thyroidectomy with radioactive iodine (RAI) ablation, while limited thyroidectomy with extensive prophylactic lymph node dissection has traditionally been performed for most patients in Japan. Recently, accurate evaluation of carcinoma stage can be performed on preoperative imaging studies, especially on ultrasonography. It is therefore important to treat papillary carcinoma patients depending on clinicopathological features rather than in a stereotyped fashion. In this paper, appropriate extension of thyroidectomy and lymph node dissection is discussed based on Western and recently published Japanese guidelines and the experience in Kuma Hospital.

Generating CRISPR/Cas9-mediated mutants in tomato (Solanum lycopersicum L.) involves screening shoots regenerated fromcultured cells transformedwith a T-DNA harboring sequences encoding Cas9 and single guide RNAs (sgRNAs). Production of transformants can be inconsistent and obtaining transformants in large numbersmay be difficult, resulting in a limited variety of mutations. Here, I report a method for generating various types of mutations from one transgenic plant harboring the CRISPR/Cas9 system. In this method, a wild-type plant was crossed with a T0 biallelic mutant expressing two sgRNAs targeting the RIPENING INHIBITOR (RIN) gene, and the resulting F1 seedlings were classified using a kanamycin resistancemarker on the T-DNA. Genotyping of the RIN locus revealed that kanamycin-sensitive F1 seedlings, which carried no T-DNA, always harbored the wild-type allele and a mutant allele from the transgenic parent. Kanamycin-resistant F1 seedlings, which do carry the TDNA, harbored a variety of novel mutant alleles, but not the wild-type allele, suggesting that it was mutated during crossing. The novel mutations included one-base insertions or short deletions at each target site, or large deletions across the two target sites. Thismethod was also successfully applied to producemutations in Geranylgeranyl pyrophosphate synthase 2 (GGPS2). Because thismethod involves crossing rather than transformation, it can be readily scaled up to produce numerous novel mutations, even in plant species or cultivars for which transformation is inefficient. Therefore, when initial transgene experiments fail to induce the desired mutation, this method provides additional opportunities for generating mutants. [ABSTRACT FROM AUTHOR]