N6-methyladenosine (m6A) is an endogenous A3 adenosine receptor ligand.

About 150 post-transcriptional RNA modifications have been identified in all kingdoms of life. During RNA catabolism, most modified nucleosides are resistant to degradation and are released into the extracellular space. In this study, we explored the physiological role of these extracellular modified nucleosides and found that N6-methyladenosine (m6A), widely recognized as an epigenetic mark in RNA, acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. We used structural modeling to define the amino acids required for specific binding of m6A to the human A3 receptor. We also demonstrated that m6A was dynamically released in response to cytotoxic stimuli and facilitated type I allergy in vivo. Our findings implicate m6A as a signaling molecule capable of activating G protein-coupled receptors (GPCRs) and triggering pathophysiological responses, a previously unreported property of RNA modifications.

Active surveillance for adult low-risk papillary thyroid microcarcinoma-a review focused on the 30-year experience of Kuma Hospital.

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.

Deep learning-based video-analysis of instrument motion in microvascular anastomosis training.

PURPOSE: Attaining sufficient microsurgical skills is paramount for neurosurgical trainees. Kinematic analysis of surgical instruments using video offers the potential for an objective assessment of microsurgical proficiency, thereby enhancing surgical training and patient safety. The purposes of this study were to develop a deep-learning-based automated instrument tip-detection algorithm, and to validate its performance in microvascular anastomosis training. METHODS: An automated instrument tip-tracking algorithm was developed and trained using YOLOv2, based on clinical microsurgical videos and microvascular anastomosis practice videos. With this model, we measured motion economy (procedural time and path distance) and motion smoothness (normalized jerk index) during the task of suturing artificial blood vessels for end-to-side anastomosis. These parameters were validated using traditional criteria-based rating scales and were compared across surgeons with varying microsurgical experience (novice, intermediate, and expert). The suturing task was deconstructed into four distinct phases, and parameters within each phase were compared between novice and expert surgeons. RESULTS: The high accuracy of the developed model was indicated by a mean Dice similarity coefficient of 0.87. Deep learning-based parameters (procedural time, path distance, and normalized jerk index) exhibited correlations with traditional criteria-based rating scales and surgeons' years of experience. Experts completed the suturing task faster than novices. The total path distance for the right (dominant) side instrument movement was shorter for experts compared to novices. However, for the left (non-dominant) side, differences between the two groups were observed only in specific phases. The normalized jerk index for both the right and left sides was significantly lower in the expert than in the novice groups, and receiver operating characteristic analysis showed strong discriminative ability. CONCLUSION: The deep learning-based kinematic analytic approach for surgical instruments proves beneficial in assessing performance in microvascular anastomosis. Moreover, this methodology can be adapted for use in clinical settings.

Thyroid-Stimulating Hormone, Age, and Tumor Size are Risk Factors for Progression During Active Surveillance of Low-Risk Papillary Thyroid Microcarcinoma in Adults.

BACKGROUND: Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and is gradually spreading worldwide. We assessed the effect of thyroid-stimulating hormone (TSH) levels on PTMC enlargement in patients on AS. METHODS: We enrolled 2705 patients with cytologically diagnosed PTMC who had undergone AS between January 2005 and July 2019. Patients with Graves disease were excluded. The median AS period was 5.5 years (range 1.0-15.7 years). Tumor enlargement was defined as a size increase ≥3 mm. Chi-square test, Kaplan-Meier method, log-rank test, Cox proportional hazard, and logistic regression were used to compare variables. RESULTS: Ninety-two patients (3.4%) experienced tumor enlargement; the 5-, 10-, and 15-year enlargement rates were 3.0%, 5.5%, and 6.2%, respectively. Young age (<40 years, p < 0.001), large tumor size (≥9 mm, p = 0.017), and high detailed TSH score (≥3, higher than the lower normal limit, p = 0.011) were significant factors relating to tumor enlargement in the multivariate analysis. In a subset of patients aged <40 years, a low detailed TSH score (<3) was an independent factor against tumor enlargement (p = 0.039). Only 22 patients (0.8%) experienced novel lymph node metastasis; the 5-, 10-, and 15-year node metastasis rates were very low, at 0.9%, 1.1%, and 1.1%, respectively. CONCLUSIONS: Young patients with PTMC are more likely to experience tumor growth. Mild TSH suppression to achieve a low normal range may prevent carcinoma enlargement; however, prospective studies are needed to draw more reliable conclusions.

Outcomes of immediate surgery for low-risk papillary thyroid microcarcinoma in patients with or without risky features at surgery.

Active surveillance (AS) is an accepted management option for patients with low-risk papillary thyroid microcarcinoma (PTMC), although some patients undergo immediate surgery (IS). At surgery, patients may have risky features such as adhesion or invasion to the adjacent organs. The surgical outcomes of this subset of patients are unknown. Here, we investigated the surgical and oncological outcomes of these patients in comparison with others. Between 2005 and 2019, 4,635 patients were diagnosed with low-risk PTMC at our institute. Of these, 1,739 patients underwent IS. In total, 114 patients had risky features at surgery (risky feature group), while the remaining 1,625 did not (no-risky feature group). The median follow-up periods in the risky and no-risky feature groups were 8.5 and 7.6 years, respectively. The risky feature group had higher incidences of tracheal invasion (8.8%), recurrent laryngeal nerve invasion (RLN) (7.9%), and permanent vocal cord paralysis postoperatively (10.0%) and higher frequency of pathological lateral lymph node metastasis (6.1%) than the no-risky feature group (0%, 0%, and 0.2%, and 0%, respectively [p < 0.01]). However, unexpectedly, the former had a lower incidence of high Ki-67 labeling index (1.1%) and lower locoregional recurrence rate (0%) than the latter (8.3% and 0.7, respectively [p < 0.01], not calculable). None of the groups developed distant metastasis or died of the disease. The risky feature group required resection of the trachea and/or the RLN more often than the no-risky feature group. However, unexpectedly, the tumor growth activity in the risky feature group was low, and their oncological outcome was excellent.

Active surveillance is an excellent management technique for identifying patients with progressive low-risk papillary thyroid microcarcinoma requiring surgical treatment.

Although the outcomes of active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) are generally excellent, some patients undergo conversion surgery for various reasons, including disease progression. We studied the outcomes of PTMC patients who underwent AS, who underwent conversion surgery after AS, and who underwent immediate surgery. Between 2005 and 2019, 4,635 patients were diagnosed with low-risk cT1aN0M0 PTMC at Kuma Hospital: 2,896 opted for AS (AS group) and 1,739 underwent immediate surgery (Surgery group). In the AS group, 242 patients underwent conversion surgery (Conversion group): 72 owing to disease progression (Conversion-prog group) and 170 for other reasons (Conversion-non-prog group). Of the 1,739 patients in the Surgery group, 1,625 had no high-risk features (Surgery-low-risk group). Locoregional recurrence (LRR) occurred in 9, 1, 1, and 0 patient in the Surgery-low-risk group, the Conversion-prog group, the AS group, and the Conversion-non-prog group, respectively. The LRR rate of the AS group was significantly lower than that of the Surgery-low-risk group (0.1% vs. 0.7% at 10 years, p = 0.006). Additionally, the LRR rate of the Conversion group (0.6% at 10 years, p = 0.741) and that of the Conversion-prog group (3.3% at 10 years, p = 0.103) did not significantly differ from the LRR of the Surgery-low-risk group. As the postoperative prognosis of patients with progressive PTMC who underwent conversion surgery did not significantly differ from that of patients who underwent immediate surgery, we think that AS may have resulted in efficient identification of the small proportion of patients with progressive PTMC that require surgical treatment.

A case of childhood unilateral relapsing primary angiitis of the central nervous system.

The patient was a 17-year-old girl with transient right-sided weakness and dysesthesia associated with headache and nausea. Head magnetic resonance imaging (MRI) revealed white matter lesions confined to the left hemisphere. Initially, multiple sclerosis was suspected, and methylprednisolone (mPSL) pulse therapy was administered, followed by fingolimod hydrochloride. However, on day 267, the patient again experienced transient hypesthesia. Cranial MRI showed expansion of the highly infiltrated areas of the left hemisphere on fluid-attenuated inversion recovery (FLAIR) and T2 weighted image, accompanied by edema. Multiple contrasting areas were also observed. Susceptibility-weighted imaging demonstrated several streaks and some corkscrew-like appearances with low signals from the white matter to the cortex, suggestive of occluded or dilated collateral vessels. Multiple dotted spots indicating cerebral microbleeds (MBs) were also observed. A brain biopsy revealed lymphocytic, non-granulomatous inflammation in and around the vessels. Vascular occlusion and perivascular MBs were prevalent. The patient was diagnosed with relapsing primary angiitis of the central nervous system (PACNS), and immunosuppressive treatment was initiated, mPSL 1000 mg/day pulse therapy. The patient's clinical symptoms and neuroradiological abnormalities gradually improved. She is now receiving oral prednisolone (6 mg/day) and mycophenolate mofetil (1750 mg/day). This case corresponds to unilateral relapsing, which has recently been reported as a specific clinicopathological subtype of PACNS.

Increased serum cholesterol and long-chain fatty acid levels are associated with the efficacy of nivolumab in patients with non-small cell lung cancer.

BACKGROUND: Lipids have immunomodulatory functions and the potential to affect cancer immunity. METHODS: The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab. RESULTS: When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid. CONCLUSIONS: Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

Clinicopathological features and outcomes of intrathyroidal thymic carcinoma: a single institution study.

Intrathyroidal thymic carcinoma (ITTC) is a rare malignancy of the thyroid. It is thought to originate from ectopic thymic tissue or embryonic thymic rest, in, or adjacent to, the thyroid. We analyzed the backgrounds, clinicopathological features, and prognosis of 20 patients with ITTC, treated at our hospital. Thirteen of the 15 patients (86%) who underwent ultrasonography were diagnosed as malignant, based on imaging findings. 16 of the 17 patients (93%) who underwent cytology, were diagnosed or suspected to be malignant. Locally curative surgery (thyroidectomy and lymph node dissection) was performed for 19 patients. Large tumor size (>4 cm) was positively related to pathological node metastasis (p = 0.0389). Fourteen patients, including nine Ex-positive patients, underwent adjuvant external beam radiotherapy (EBRT) of the neck after surgery. Two patients showed recurrence of thyroid bed after and neither of them underwent adjuvant EBRT after surgery. Two patients who underwent EBRT showed recurrences of the lateral nodes (level V and level II), but they were easily dissected by re-operation. Ten- and 20-year local recurrence-free survival rates were 84.9% and 60.6%, respectively. To date, four patients showed distant recurrence, and 10- and 20-year distant recurrence-free survival rates were 75.0% and 75.0%, respectively. Our findings indicate that 1) the prognosis of ITTC is generally favorable, and 2) large tumor size is significantly related to lymph node metastasis. Two patients showing recurrence of the central region did not undergo EBRT; thus, further comparative studies are desirable to elucidate whether EBRT can prevent significant local recurrence.

Prognostic significance of patient age in papillary thyroid carcinoma with no high-risk features.

Older age is recognized as a predictor of poor prognosis in papillary thyroid carcinoma (PTC) patients. However, young age is associated with disease progression of PTC measuring 1 cm or smaller in patients on active surveillance. In this study, we investigated the relationship between patient age and prognosis of PTC belonging to very low-, low-, and intermediate-risk groups based on the guidelines published by the Japan Association of Endocrine Surgery in 2018. We enrolled 4,870 PTC patients with no high-risk features and assigned each to one of three categories: very low risk (N = 1,161), low risk (N = 1,746), and intermediate risk (N = 1,963). In very low-risk patients, the local recurrence-free survival (RFS) rate of young patients (<55 years) was significantly worse (p = 0.0437) than that of older patients (≥55 years). In low-risk patients, although age did not affect local recurrence, older patients were more likely to show distant recurrence on univariate (p = 0.0005) and multivariate analyses (p = 0.0017). In the intermediate-risk series, the local RFS rate of older patients tended to be poor (p = 0.0538), and older age was significantly associated with distant RFS (univariate, p = 0.0356; multivariate, p = 0.0439) and carcinoma death (univariate, p < 0.0001; multivariate, not done because of no other suitable factors). The prognostic significance of patient age depends on risk classification: younger age significantly predicts local recurrence in very low-risk PTC, while older age predicts worse prognosis in low- and intermediate-risk patients. These findings indicate that young age is related to rapid growth in early-phase PTC.

Prognostic factors for follicular thyroid carcinoma: the importance of vascular invasion.

The World Health Organization (WHO) classifies follicular thyroid carcinoma (FTC) into three categories: minimally invasive (mFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wFTC). This study investigated whether this classification is appropriate. We enrolled 523 patients who underwent initial surgery at Kuma Hospital between 1998 and 2015 and were diagnosed with FTC. Capsular invasion (CI) was classified as none, minimal (microscopic), or wide (macroscopic) invasion. Vascular invasion (VI) was divided according to the number of invasive foci into three degrees: VI(-), VI(1+), and VI(2+). For 507 M0 patients, age ≥55 years (p = 0.004), non-oxyphilic histology (p = 0.043), and male sex (p < 0.001) predicted poor distant recurrence-free survival (DR-FS) on univariate analysis; however, tumor size >4 cm and wide CI did not. The DR-FS rates significantly decreased from VI(-) to VI(2+) in a step-by-step fashion, including VI(-) vs. VI(1+) (p = 0.011) and VI(1+) vs. VI(2+) (p = 0.014). Multivariate analysis revealed that older age (p = 0.0004), non-oxyphilic histology (p = 0.041), male sex (p = 0.0052), VI(1+) (p = 0.017), and VI(2+) (p < 0.001) independently predicted distant recurrence. The DR-FS rates did not significantly differ among mFTC, wFTC/VI(-), and eaFTC/VI(1+). The DR-FS rate of eaFTC/VI(2+) was worse than that of eaFTC/VI(1+) (p = 0.042), but did not differ from that of wFTC/VI(1+/2+). Our findings suggest that subclassifying eaFTC according to the degree of VI and restricting wFTC to VI-positive cases would be better in the WHO classification. Revising the definition for wide CI is recommended.

Clinical outcomes of follicular tumor of uncertain malignant potential of the thyroid: real-world data.

Thyroid tumors arising from follicular cells can generally be divided into malignant and benign tumors. However, some cases are difficult to clearly diagnose whether they are benign or malignant. Therefore, in the most recent version of World Health Organization (WHO) classification, some borderline lesions such as follicular tumor of uncertain malignant potential (FT-UMP), well-differentiated tumor of uncertain malignant potential (WDT-UMP), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were proposed. In this study, we investigated the clinical aspects, including the prognosis, of FT-UMP patients. We investigated the clinical features of 339 patients with FT-UMP. On ultrasound, 68% of the tumors were diagnosed as intermediate, and only 5% of those tumors were diagnosed as malignant. On cytology, 40% of the tumors were diagnosed as follicular neoplasm, and only 1% of these were suspected to be or diagnosed as malignancy. The diagnosis was based on questionable capsular invasion for 332 patients, questionable vascular invasion for 2 patients, and both for 5 patients. Eighty-six percent of the tumors showed low cell proliferation activity. To date, five patients (1%) have shown distant recurrence during postoperative follow-up and underwent various treatments such as radioactive iodine therapy, orthopedic surgery, and denosumab injection. None of these patients have died due to thyroid carcinoma. Our findings suggest that FT-UMP is generally an indolent disease, but some patients show distant recurrence. Physicians should carefully follow patients, although it remains unknown how long they should be observed after surgery.

Observational management of papillary microcarcinoma appearing in the remnant thyroid after hemithyroidectomy.

Active surveillance for papillary thyroid microcarcinomas (PTMCs) initiated in Japan is becoming adopted worldwide as a management option. However, it remains unclear how to manage newly appearing PTMCs in the remnant thyroid after hemithyroidectomy. We investigated the outcomes of similar observational management (OM) for PTMCs appearing in the remnant thyroid after hemithyroidectomy for papillary thyroid carcinoma (PTC) and benign thyroid nodules. Eighty-three patients were newly diagnosed with PTMC in the remnant thyroid between January 1998 and March 2017. Of these, 42 patients underwent OM with >3 times ultrasound examinations. Their initial diagnoses were PTC (initially malignant group) in 37 patients and benign nodule (initially benign group) in 5 patients. We calculated the tumor volume doubling rate (TV-DR) during OM for each PTMC. The TV-DR (/year) was <-0.1, -0.1-0.1, 0.1-0.5, and >0.5 in 12, 19, 5, and 6 patients, respectively. The TV-DRs in both groups did not statistically differ, but six patients (16%) in the initially malignant group showed moderate growth (TV-DR >0.5/year). They underwent conversion surgery and none of them had further recurrence. The remaining 36 patients retained OM without disease progression. The TV-DR in the initially malignant group was not significantly associated with patients' backgrounds or their initial clinicopathological features. None of the patients in this study showed distant metastases/recurrences or died of thyroid carcinoma. Although a portion of PTMCs appearing after hemithyroidectomy for thyroid malignancy are moderately progressive, OM may be acceptable as a management option for PTMCs appearing in the remnant thyroid after hemithyroidectomy.

Long-term and short-term outcomes of laparoscopic versus open resection following tube decompression for obstructive colorectal cancer: a single-center retrospective study.

PURPOSE: The benefits of laparoscopic surgery over open surgery are well documented; however, the suitability of laparoscopic surgery for obstructive colorectal cancer is still controversial. The aim of this retrospective study was to compare the clinical benefits of laparoscopic surgery vs. open surgery for obstructive colorectal cancer after tube decompression. METHODS: We analyzed the outcomes of patients who underwent laparoscopic surgery vs. open surgery for curative resection after tube decompression for obstructive colorectal cancer at our hospital between January, 2007 and March, 2018. RESULTS: This study comprised 67 patients: 29 patients who underwent open surgery and 38 patients who underwent laparoscopic surgery. The morbidity within 30 days after surgery was comparable between the groups. The 3-year overall survival rates of the open and laparoscopic groups were 83.3 and 79.4%, respectively (p = 0.6244), and the 3-year disease-free survival rates were 59.3 and 71.2%, respectively (p = 0.3200). Multivariate analysis showed that nodal stage (p = 0.021) was an independent prognostic factor for OS and sex (p = 0.010) and side-ness (p = 0.048) were independent prognostic factors for DFS. CONCLUSION: If adequate decompression is achieved, laparoscopic resection following tube decompression for obstructive colorectal cancer can be a safe alternative to open surgery.

Active Surveillance as First-Line Management of Papillary Microcarcinoma.

Papillary thyroid microcarcinoma (PMC) is defined as papillary thyroid carcinoma ≤10 mm. Active surveillance of PMC without high-risk features, such as clinical node metastasis, distant metastasis, and clinical evidence of significant extrathyroid extension, was initiated in two Japanese hospitals in the mid-1990s. This strategy was incorporated into guidelines in Japan in 2010 and in the United States in 2015. In studies conducted by the two hospitals, most PMCs grew very slowly or did not grow, and none of the patients during active surveillance showed distant metastasis or died of thyroid carcinoma. Furthermore, none of the patients who underwent surgery after progression signs were detected showed significant recurrence. Therefore, we conclude that active surveillance should be the first line in management of low-risk PMC, because it is safer and less costly than immediate surgery. Active surveillance helps in avoiding adverse events of surgery and is an economical strategy.

Allelic Mutations in the Ripening -Inhibitor Locus Generate Extensive Variation in Tomato Ripening.

RIPENING INHIBITOR (RIN) is a transcription factor with transcriptional activator activity that plays a major role in regulating fruit ripening in tomato (Solanum lycopersicum). Recent studies have revealed that (1) RIN is indispensable for full ripening but not for the induction of ripening; and (2) the rin mutation, which produces nonripening fruits that never turn red or soften, is not a null mutation but instead converts the encoded transcriptional activator into a repressor. Here, we have uncovered aspects of RIN function by characterizing a series of allelic mutations within this locus that were produced by CRISPR/Cas9. Fruits of RIN-knockout plants, which are characterized by partial ripening and low levels of lycopene but never turn fully red, showed excess flesh softening compared to the wild type. The knockout mutant fruits also showed accelerated cell wall degradation, suggesting that, contrary to the conventional view, RIN represses over-ripening in addition to facilitating ripening. A C-terminal domain-truncated RIN protein, encoded by another allele of the RIN locus (rinG2), did not activate transcription but formed transcription factor complexes that bound to target genomic regions in a manner similar to that observed for wild-type RIN protein. Fruits expressing this truncated RIN protein exhibited extended shelf life, but unlike rin fruits, they accumulated lycopene and appeared orange. The diverse ripening properties of the RIN allelic mutants suggest that substantial phenotypic variation can be produced by tuning the activity of a transcription factor.

Cost-effectiveness of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients with metastatic colorectal cancer.

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.

Long-term outcomes of cytologically benign thyroid tumors: a retrospective analysis of 3,102 patients at a single institution.

Some thyroid tumors that are cytologically diagnosed as benign may be pathologically diagnosed as malignant. Here, we investigated the long-term outcomes of patients with thyroid tumors with benign cytology, and the factors for malignancy. We retrospectively reviewed the cases of 3,102 patients with thyroid tumors >1 cm cytologically diagnosed as benign at our hospital during a 1-year period from January 2007. The median follow-up duration for all patients was 68.7 (range 0.0-168.7) months. Immediate surgery and delayed surgery were performed in 393 and 148 patients, respectively. Eventually, 541 (17.4%) of the 3,102 patients underwent a thyroidectomy, and 2,561 (82.6%) were observed without surgery. Among the surgically treated patients, the tumors of 525 (97.0%) and 16 (3.0%) were pathologically diagnosed as benign and malignant, respectively. There was no significant difference in age, gender, tumor size, serum thyroglobulin level at surgery, or the tumor volume-doubling rate (TV-DR) between the benign and malignant cases. Only the ultrasonographic findings based on our hospital's classification system were directly and significantly linked to pathological diagnosis (p < 0.01). Among the tumors of the 667 patients who were followed without surgery for >10 years, 89.9% remained unchanged and 7.2% were reduced in size. Ultrasonographic evaluation provides important information for therapeutic decision-making regarding surgery versus observation for cytologically benign tumors.

Diagnosis and management of hyalinizing trabecular tumor of the thyroid: a single-institution experience.

Hyalinizing trabecular tumor (HTT) of the thyroid is a mostly benign disease. Its cytological and pathological diagnosis is often difficult, because HTT cells and papillary thyroid carcinoma (PTC) cells share similar features (e.g., intranuclear cytoplasmic inclusions and nuclear grooves). At our institution, 38 patients were diagnosed as or highly suspected of having HTT without the possibility of PTC, based on cytology: 19 of these patients underwent immediate surgery (surgery group) and the remaining 19 underwent active surveillance without surgery (AS group). The surgery-group patients' tumor sizes were significantly larger (p < 0.0001) than those in the AS group. During AS (median 38 months), only one patient (5%) showed tumor enlargement by ≥3 mm; the AS was continued. Of the 34 patients pathologically diagnosed with HTT, 22 (65%) were cytologically diagnosed or highly suspected as having HTT without the possibility of PTC. Of the nine patients who were suspected to have HTT but PTC was possible and surgery was performed, two (22%) and seven (78%) were pathologically diagnosed as having PTC and HTT, respectively. Five patients were cytologically diagnosed with PTC, but pathologically diagnosed as having HTT. No patients showed HTT recurrence during postoperative follow-up (median 60 months). These findings suggest that (1) active surveillance can be a valid strategy for managing tumors that are cytologically diagnosed as HTT with no possibility of PTC; (2) surgery is recommended for tumors suspected of being HTT but may be PTC, and (3) the prognosis of HTT in both the AS and surgery groups was excellent.

Favorable outcomes of papillary thyroid microcarcinoma concurrent with Graves' disease after radioactive iodine therapy.

Graves' disease (GD) may coexist with papillary thyroid microcarcinoma (PTMC). The main purpose of this study was to evaluate whether treatment with radioactive iodine (RAI) may cause acute exacerbation of PTMC concurrent with GD or not. From the medical records of 10,257 GD patients who underwent RAI therapy between 2000-2017, 12 subjects with concurrent PTMC were retrieved. Further, 49 patients with concurrent GD and PTMC who underwent no RAI administration throughout their clinical course were enrolled as controls. Size of the PTMC nodules was evaluated based on maximal diameter and tumor volume-doubling rate (TV-DR). Among the 12 subjects who underwent RAI therapy (median dose, 13 mCi), 2 showed tumors >10 mm in maximal diameter with slow growth for more than 10 years, while the other 10 showed tumors with maximal diameter ≤10 mm. No subject showed any clinical findings of nodal or distant metastasis during the follow-up periods (0.4-11.5 years) before surgery or during active surveillance. No significant differences were observed in the TV-DR values (median, 0.044/year; range, -0.81-1.40) between the study subjects and controls (median, 0.025/year; range, -0.70-1.29; p = 0.69). When comparing the TV-DR before and after RAI administration in 3 individuals in particular, in whom PTMC were cytologically confirmed before RAI administration and whose prospective follow-up data were available, tumor progression was observed to be stable or decreased after RAI administration. There were no acute exacerbations or unfavorable outcomes of concurrent PTMC and GD after low-dose RAI administration.