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[This corrects the article DOI: 10.3389/fendo.2024.1392247.].

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Multifocal growth is characteristic of hereditary medullary thyroid cancer (MTC), whereas origin and impact of multifocal growth is enigmatic for sporadic MTC. To address this, 460 RET-negative patients with sporadic MTC, stratified by 1 (93.3 %), 2 (5.7 %) and 3 (1.1 %) thyroid tumor foci, were compared with 219 RET-positive patients with hereditary MTC, stratified by 1 (38.4 %), 2 (45.7 %), 3 (6.4 %), 4 (6.8 %) and ≥5 (2.7 %) thyroid tumor foci. For sporadic MTC, significant associations were identified with bilateral thyroid lobe involvement, microscopic lymphatic invasion, extrathyroid extension, node and distant metastases, number of node metastases, preoperative basal calcitonin level, and decreasing biochemical cure. For hereditary MTC, significant associations were limited to bilateral thyroid lobe involvement, largest thyroid tumor diameter, and preoperative basal calcitonin level. In sporadic MTC, multifocal growth is due to lymphatic invasion with frequent node metastases, whereas in hereditary MTC, it reflects malignant progression from C-cell hyperplasia to cancer.

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In cancer, tumor-related inflammation affects disease progression and survival outcomes. However, the role of systemic inflammation in tumor multifocality in upper tract urothelial carcinoma (UTUC) is not well understood. The aim of the present study was to evaluate the impact of the systemic inflammation response index (SIRI) on tumor multifocality for predicting oncological outcomes in patients with UTUC after radical nephroureterectomy (RNU). For this purpose, data from 645 patients with non-metastatic UTUC who underwent RNU between 2008 and 2020 were retrospectively analyzed. Survival outcomes such as overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) RATES were assessed using the Kaplan-Meier method, and independent prognostic factors were identified through a multivariable Cox proportional hazards regression model. Of the 645 patients with UTUC included in the present study, 163 (25%) had multifocal UTUC. Kaplan-Meier analysis indicated that multifocal UTUC synchronous with a high-level SIRI was significantly associated with poorer outcomes after RNU. Furthermore, the results of the multivariate Cox proportional hazards model analysis demonstrated that multifocal tumor coupled with a high-level SIRI was an independent factor for predicting a shorter survival and disease progression. In conclusion, the results of the present study indicated that an elevated SIRI significantly influenced the survival rate of patients with multifocal UTUC. Specifically, integrating multifocal UTUC with a high-level SIRI emerged as an independent risk factor for poorer OS, CSS and RFS. These findings highlighted the potential role of SIRI in the risk stratification and management of patients with multifocal UTUC.

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Background: Papillary thyroid microcarcinoma (PTMC) is characterized by its favorable prognosis and potential for active surveillance (AS) as a management option. However, the presence of cervical lymph node (LN) metastasis, especially lateral LN metastasis, significantly impacts management and prognosis. Previous studies have focused on post-surgery risk factors for cervical LN metastasis. This study aims to identify predictors of lateral LN metastasis by analyzing pre-operative ultrasonographic findings alongside clinicopathological factors. Methods: A retrospective review of medical records was conducted for patients with PTMC who underwent surgery at Chonnam National University Hwasun Hospital between 2004 and 2013. This is a case-control study that compares patients with lateral LN metastasis (N1b) to age- and sex-matched patients without LN metastasis (N0). Subgroup analysis was performed to evaluate risk factors of skip metastasis. Results: The study included 90 patients with PTMC with lateral LN metastasis (N1b) and 268 age- and sex-matched patients without LN metastasis (N0). The mean age was 49.3 years, and female patients were dominant in both groups. Structural recurrences of 4.4% (4/90) were observed only in the N1b group. The N1b group exhibited a higher frequency of upper lobe tumor location compared to the N0 group (38.9% vs. 16.0%, p < 0.001). There was no significant difference in the locations with the presence of invasion to adjacent organs. A higher proportion of non-parallel shape was observed in the N1b group than the N0 group (80.0% vs. 66.0%, p = 0.013). There were no differences in echogenicity, sonographic feature, margin, and AP diameter of the thyroid gland between the two groups. In multivariate analysis, independent risk factors for lateral LN metastasis included extrathyroidal extension, multiplicity, upper lobe tumor location, and non-parallel shape. Skip metastasis in patients with PTMC was associated with upper lobe tumor location. Conclusion: Detailed ultrasound examinations, evaluating tumor location, number, orientation, and the presence of ETE, are crucial in accurately predicting lateral LN metastasis especially when primary tumor was in the upper lobe to avoid missing skip metastasis. These evaluations can help guide the decision between AS and immediate surgery in patients with PTMC.

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INTRODUCTION: The prognostic value of multifocality in paediatric papillary thyroid carcinoma (PTC) patients remains a subject of debate. This study aimed to explore the clinical significance and prognostic value of multifocality in children and adolescents with PTC. METHODS: This study retrospectively analysed the clinicopathological characteristics and postoperative follow-up data of 338 PTC patients aged ≤ 20 years from May 2012 to July 2022. The clinical and pathological characteristics of 205 patients with unifocal lesions and 133 patients with multifocal lesions were compared. A logistic regression model evaluated the relationship between multifocal lesions and disease recurrence/persistence in children and adolescents with PTC. Based on the median follow-up time of children with multifocal PTC, 114 patients with multifocal PTC older than 20 years were added, and the clinicopathological characteristics were compared between the 133. paediatric/adolescent patients and 114 adult patients with multifocal PTC. RESULTS: Among the paediatric and adolescent patients, over a median follow-up time of 49 months, 133 had multifocal disease and 205 had unifocal disease. Multifocal PTC patients exhibited stronger invasiveness in the form of extrathyroidal extension, tumour diameter, lymph node metastasis, and distant metastasis. Multifocality (OR 2.68; p = 0.017), lateral lymph node metastasis (OR 2.85; p = 0.036), and distant metastasis (OR 4.28; p = 0.010) were identified as independent predictive factors for the recurrence/persistence of disease. Comparing the paediatric/adolescent vs. adult multifocal patients, the former demonstrated greater tumour invasiveness. Lateral lymph node metastasis (OR 6.36; P = 0.012) and distant metastasis (OR 3.70; P = 0.027) were independent predictive factors for recurrence/persistence of disease in multifocal patients, while age was not (OR 0.95; P = 0.455). CONCLUSION: Tumour multifocality independently predicts persistent/recurrent disease in paediatric and adolescent PTC patients.

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Invasive lobular carcinoma of the breast has different mammographic appearances, including spiculated or lobulated masses, architectural distortion, increased breast density, and the possibility of also being occult. Histologically, the morphology is also variable, as several patterns have been described beside the classical one, including the solid, the alveolar, the trabecular, the one with tubular elements, and others. Of 146 ILC cases, 141 were reviewed for mammographic appearance and 136 for histological patterns by two radiologist and two pathologists, respectively; 132 common cases were analyzed for possible associations between mammographic presentation and the histological patterns. Interobserver agreement on the presence or absence of a given mammographic morphology ranged from 45% (increased density) to 95% (occult lesion); the most common radiomorphology was that of a spiculated mass. Interobserver agreement on the presence or absence of a given histological pattern ranged between 79% (solid) and 99% (classical) but was worse when semi-quantification was also included. The mammography-pathology correlation was less than optimal. Multifocality was more commonly detected by histology. The identification of a mammographic mass lesion often coincided with a mass-like lesion on the histological slides and vice versa, but nearly half of the mammographically occult lesions were felt to have masses on histological slides assessed grossly. Histological patterns showed no obvious associations with one or the other mammographic appearance.

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BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) represent 1-2% of pancreatic tumors, with recent guidelines recommending active surveillance for non-functioning PNETs (NF-PNETs) smaller than 2 cm. However, the management of multiple NF-PNETs, as well as the influence of tumor number on prognosis, remains under-researched. METHODS: This retrospective study analyzed NF-PNET patients who underwent pancreatic resection at Severance Hospital between February 1993 and August 2023, comparing the characteristics of patients diagnosed with multifocal tumors and those with unifocal tumors. A subgroup analysis of overall survival (OS) and recurrence-free survival (RFS) was performed based on multifocality employing the Kaplan-Meier method and the log-rank test. RESULTS: Of 187 patients, 169 (90.4%) had unifocal and 18 (9.6%) had multifocal tumors. Multifocal tumors were more likely to be diffusely spread, necessitating more total pancreatectomies (diffuse tumor location: 4.7% in unifocal vs. 38.9% in multifocal cases, p < 0.001; total pancreatectomy: 4.1% in unifocal vs. 33.3% in multifocal cases, p < 0.001). In patients with NF-PNET who underwent the same extent of pancreatic resection, no significant difference in the incidence of complication was observed regardless of multifocality. Moreover, no significant difference in OS was seen between the unifocal and multifocal groups (log-rank test: p = 0.93). However, the multifocal group exhibited a poorer prognosis in terms of RFS compared to the unifocal group (log-rank test: p = 0.004) Hereditary syndrome, tumor grade, size, lymphovascular invasion, and lymph node metastasis were key factors in the recurrence. CONCLUSION: This study's findings suggest that the presence of multiple tumors was associated with poorer recurrence-free survival but did not affect long-term survival following surgery. Given the long-term oncologic outcome and quality of life following surgery, resection of tumors over 2 cm is advisable in patients with multifocal PNETs, while a cautious "wait-and-see" approach for smaller tumors (under 2 cm) can minimize the extent of resection and improve the quality of life. In cases with only small multifocal NF-PNETs (< 2 cm), immediate resection may not be crucial, but the higher recurrence rate than that in solitary NF-PNET necessitates intensified surveillance.

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Background: Active surveillance has been an option for patients with low-risk papillary thyroid carcinoma (PTC). However, whether delayed surgery leads to an increased risk of local tumor metastasis remain unclear. We sought to investigate the impact of observation time on central lymph node metastasis (CLNM) and multifocal disease in patients with low-risk PTC. Methods: Patients who were diagnosed with asymptomatic low-risk PTC, and with a pathological maximum tumor size ≤1.5 cm by were included. The patients were classified into observation group and immediate surgery group, and subgroup analyses were conducted by observation time period. The prevalence of CLNM, lymph node (LN) involved >5, multifocal PTC and bilateral multifocal PTC were considered as outcome variables. The changing trend and risk ratio of prevalence over observation time were evaluated by Mann-Kendall trend test and Logistics regression. Results: Overall, 3,427 and 1,860 patients were classified to the observation group and immediate surgery group, respectively. Trend tests showed that decreasing trends both on the prevalence of CLNM and LN involved >5 over the observation time, but the difference was not statistically significant, and the prevalence of multifocal PTC and bilateral multifocal PTC showed the significant decreasing trends. After adjustment, multivariate analysis showed no statistically significant difference between observed and immediate surgery groups in the four outcome variables. Conclusion: In patients with subclinical asymptomatic low-risk PTC, observation did not result in an increased incidence of local metastatic disease, nor did the increased surgery extent in patients with delayed surgery compared to immediate surgery. These findings can strengthen the confidence in the active surveillance management for both doctors and patients.

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Whereas multifocality typically concerns papillary thyroid carcinoma (PTC) without specification of intrathyroidal metastatic or independent nature of tumor foci, the designation of the latter as Multi-UniFocal (MUF) may be relevant for select cases. A case series involving multifocal thyroid lesions with divergent histopathological morphology and/or molecular profile, with molecular evaluation of multiple individual tumor foci per patient based on a next-generation sequencing approach, was retrospectively reviewed. Twenty-five patient cases with multifocal thyroid lesions suggestive of MUF, with 2-6 (median 3) tumor foci per patient, were described. Tumor lesions comprised diverse histopathology, including PTC, (E)FVPTC, NIFTP, FA, FTC, and oncocytic. Morphologically similar and/or diverse tumor foci harbored different molecular alterations (suggestive of non-shared clonality); with(out) coexistent similar foci harboring identical molecular alterations; or (partly) shared molecular alterations. MUF was associated with chronic lymphocytic thyroiditis in almost half of the cases. The recognition of MUF may justify the independent clinical consideration per individual tumor focus; as separate lesions albeit within a multifocal context. The potential clinical relevance and prognostic value of MUF remain to be further established.

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OBJECTIVE: The association between obesity, metabolic dysregulation, and the aggressive pathological traits of papillary thyroid carcinoma (PTC) continues to be a contentious issue. To date, no investigations have examined the impact of metabolic status on the malignant pathological features of PTC in relation to obesity. METHODS: This research involved 855 adult patients with PTC from Shandong Provincial Hospital, classified into 4 groups based on metabolic and obesity status: metabolically healthy nonobese, metabolically unhealthy nonobese (MUNO), metabolically healthy obese, and metabolically unhealthy obese. We employed logistic regression to investigate the relationship between these metabolic obesity phenotypes and PTC's pathological characteristics. Mediation analysis was also performed to determine metabolic abnormalities' mediating role in the nexus between obesity and these characteristics. RESULTS: Relative to metabolically healthy nonobese individuals, the metabolically unhealthy obese group was significantly associated with an elevated risk of larger tumor sizes and a greater number of tumor foci in PTC. Mediation analysis indicated that obesity directly influences tumor size, whereas its effect on tumor multifocality is mediated through metabolic dysfunctions. Specifically, high-density lipoprotein cholesterol levels were notably associated with tumor multifocality within obese subjects, serving as a mediator in obesity's impact on this trait. CONCLUSION: The concurrent presence of obesity and metabolic dysregulation is often connected to more aggressive pathological features in PTC. The mediation analysis suggests obesity directly affects tumor size and indirectly influences tumor multifocality via low high-density lipoprotein cholesterol levels.

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Background and Aim: Patients with hepatocellular carcinoma (HCC) are managed in various hospital departments, which complicates the assessment of the overall picture. In our large liver transplant institute, we evaluate all HCC patients in a weekly multi-disciplinary liver tumor board, and their data are prospectively collected in an institutional HCC database to evaluate HCC causes, tumor features, treatments, and survival. Materials and Methods: Baseline data for patients (n=1322) were prospectively recorded, including hepatitis status, routine clinical serum parameters, radiological assessment of maximum tumor diameter (MTD), tumor number, presence of macroscopic portal vein thrombosis (PVT), and serum alpha-fetoprotein (AFP) levels. Results: Cirrhosis was found in 81.1% of patients; 58.5% had hepatitis B virus (HBV), 14.9% hepatitis C virus (HCV), 8.9% cryptogenic cirrhosis, and less than 2% had alcoholism. MTD was <5 cm in 61.95% of patients, and 31.9% had PVT. The median overall survival was more than six-fold greater for the 444 liver transplant patients than for those without surgery. Transplanted patients had smaller tumors, whereas larger tumors (MTD >10 cm) were primarily in the no-surgery group. Parallel differences were found for AFP levels (highest in the no-surgery group). PVT was present in similar proportions (25.0% for transplant, 28.0% for no-surgery). The presence of cirrhosis was higher in the transplant group. MTD and levels of serum AFP, gamma-glutamyl transferase (GGT), and blood platelets were prognostic parameters for transplant. Furthermore, AFP and GGT levels were prognostic for transplanted PVT patients. Only albumin was prognostic in the no-surgery patients. Conclusion: Transplanted HCC patients have longer survival, smaller tumors, and more severe liver damage than no-surgery patients. Prognostic subsets were identified within the surgery and the PVT groups.

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PURPOSE: To analyze concordance rates between individual foci of bifocal BC for histological grade, type and intrinsic subtype based on immunohistochemical (IHC) and mRNA-testing using MammaTyper. METHODS: We evaluated histological grade and type as well as intrinsic subtype based on IHC status for estrogen and progesterone receptors, HER2 and the mitotic activity index in 158 individual foci of 79 bifocal BC. A subgroup of 31 cases additionally underwent mRNA-based subtyping using the MammaTyper (MT) test. We calculated concordance rates between individual foci, as well as Cohen's Kappa (K). RESULTS: For 79 bifocal BC, concordance rates between individual foci for grade, histological type, and IHC-based subtype were 69.6% (K=0.53), 92.4% (K=0.81), and 74.7% (K=0.62), respectively. In the MT subgroup of 31 bifocal BC, concordance rates between individual foci for grade, histological type, IHC-based and mRNA-based intrinsic subtype were 87.1% (K=0.78), 90.3% (K=0.73), 87.1% (K=0.82), and 87.1% (K=0.7), respectively. Overall concordance between IHC- and mRNA-based subtype in the MT subgroup was 79% (K=0.7). In 6/79 cases (7.6%), testing of the smaller focus added clinically relevant information either on IHC- or mRNA-level: four cases showed high hormonal receptor expression while the expression in the larger focus was negative or low, warranting additional endocrine treatment; two cases presented with higher proliferative activity in the smaller focus, warranting additional chemotherapy. CONCLUSION: In bifocal BC, intertumoral heterogeneity on the morphological, immunohistochemical and molecular level is common, with discordant intrinsic subtype in up to 25% between individual foci, with about 8% clinically relevant discordances.

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PURPOSE: This study aimed to evaluate the factors associated with bilateral papillary thyroid carcinoma (PTC) and lateral cervical lymph node metastasis (LLNM) in patients with suspicious unilateral PTC. METHODS: This study analyzed patients with suspicious unilateral PTC who were enrolled in a university hospital between 2016 and 2019 in Zhejiang, China. Using logistic regression, the study examined the factors associated with bilateral PTC and LLNM in demographic data, anthropometric measurements, lifestyle factors, medical history, preoperative diagnostic tests, and histopathological factors. RESULTS: A total of 256 patients, with a mean age of 49 years, were enrolled. Bilateral PTC was associated with multifocality (aOR: 5.069, 95% CI: 2.440-10.529, P < 0.001), and contralateral nodule in the upper (aOR: 9.073, 95% CI: 2.111-38.985, P = 0.003) and middle (aOR: 9.926, 95% CI: 2.683-36.717, P < 0.001). LLNM was positively associated with bilateral PTC (aOR, 4.283, 95% CI: 1.378-13.308, p = 0.012), male (aOR, 3.377, 95% CI: 1.205-9.461, P = 0.021), upper location of carcinoma (aOR, 3.311, 95% CI: 1.091-10.053, p = 0.035), and punctate echogenic foci (aOR, 3.309, 95% CI: 1.165-9.394, P = 0.025). Contralateral maximal nodule in the upper (aOR: 0.098, 95% CI: 0.015-0.628, p = 0.014), middle (aOR: 0.114, 95% CI: 0.033-0.522, p < 0.001), and lower (aOR, 0.028, 95% CI: 0.003-0.276, P = 0.002) location were inversely associated with LLNM. CONCLUSION: Upper and middle location of contralateral nodule and tumor multifocality predicted the risk bilateral PTC. Bilateral PTC, male, upper tumor location, punctate echogenic foci and contralateral nodule location in the entire lobes were independent predictors for LLNM.

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There are limited data regarding the significance of multifocality in testicular cancer patients. This study evaluated the relationship between multifocality and clinicopathological features determined at the time of radical orchiectomy. The study involved 280 consecutive patients who underwent radical orchiectomy between 2018 and 2023. Multifocality was defined as a distinct tumor focus characterized by a group of malignant cells > 1 mm, clearly differentiated from the primary tumor mass. Uni- and multivariate logistic regression analyses were employed to investigate the association between multifocality and histopathological parameters along with potential risk factors for clinical stages II + III. Multifocality was identified in 44 (15.7%) patients. Significantly smaller primary tumors were observed in subjects with multifocality (20.0 mm vs. 30.0 mm, p = 0.0001), while those exhibiting monofocality presented a markedly elevated rate of tumors exceeding 4 cm (40.3% vs. 18.2%, p = 0.005). Furthermore, multifocality was associated with a significantly higher rate of primary tumors < 2 cm (52.3% vs. 29.2%, p = 0.003). Univariate logistic regression analysis revealed a substantial decrease in the likelihood of multifocality occurrence in seminoma patients with tumors > 4 cm (OR = 0.38, p = 0.017). Meanwhile, in multivariate logistic regression, multifocality did not emerge as a significant risk factor for clinical stages II + III in either seminoma (p = 0.381) or non-seminoma (p = 0.672) cases. Our study suggests that multifocality holds no substantial prognostic relevance for clinically advanced disease in testicular cancer patients. The findings indicate that multifocality is associated with smaller primary tumors, particularly those measuring less than 2 cm.

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Papillary thyroid microcarcinoma (PTMC) represents 35-40% of all papillary cancers; it is defined as a nodule ≤ 10 mm at the time of histological diagnosis. The clinical significance of PTMC is still controversial, and it may be discovered in two settings: incidental PTMC (iPTMC), in which it is identified postoperatively upon histological examination of thyroid specimens following thyroid surgery for benign disease, and nonincidental PTMC (niPTMC), in which it is diagnosed before surgery. While iPTMC appears to be related to mild behavior and favorable clinical outcomes, niPTMC may exhibit markers of aggressiveness. We retrospectively review our experience, selecting 54 PTMCs: 28 classified as niPTMC (52%) and 26 classified as iPTMC (48%). Patients with niPTMC showed significant differences, such as younger age at diagnosis (p < 0.001); a lower male/female ratio (p < 0.01); a larger mean nodule diameter (p < 0.001); and a higher rate of aggressive pathological findings, such as multifocality, capsular invasion and/or lymphovascular invasion (p = 0.035). Other differences found in the niPTMC subgroup included a higher preoperative serum TSH level, higher hospital morbidity and a greater need for postoperative iodine ablation therapy (p < 0.05), while disease-free long-term survival did not differ between subgroups (p = 0.331) after a mean follow-up (FU) of 87 months, with one nodal recurrence among niPTMCs. The differences between iPTMC and niPTMC were consistent: patients operated on for total thyroidectomy and showing iPTMC can be considered healed after surgery, and follow-up should be designed to properly calibrate hormonal supplementation; conversely, niPTMC may sometimes exhibit aggressive behavior, and so the FU regimen should be closer and aimed at early detection of cancer recurrence.

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(1) Introduction: The impact of multifocality/bilaterality on the prognosis of papillary thyroid carcinoma (PTC) is a matter of debate. In order to clarify this debate, several studies have attempted to identify additional parameters associated with poor prognosis, including total tumor diameter (TTD), in the context of multifocal PTCs. In this context, this study was carried out to investigate the impact of TTD on tumor recurrence and lymph node metastasis (LNM) in PTCs. (2) Materials and Methods: The sample of this single-center retrospective study consisted of 706 patients diagnosed with PTC. TTD was calculated as the sum of the largest diameters of tumor foci in multifocal tumors. The resulting TTDs were grouped into TTDs ≤ 10 mm, TTDs > 10 mm, TTDs ≤ 20 mm, and TTDs > 20 mm, using 10 mm and 20 mm as cutoff values. (3) Results: There was no significant difference between multifocal papillary microcarcinomas (PTMCs) with a TTD of >10 mm and unifocal PTCs with a primary tumor diameter (PTD) of >10 mm except for advanced age and lymphovascular invasion (LVI). In addition, perineural invasion (PNI) and TTD > 10 mm were found to be significant risk factors for LNM, and PNI, TTD > 10 mm, TTD > 20 mm, and bilaterality were found to be significant risk factors for recurrence. LVI, and TTD > 10 mm were found to be independent significant predictors for recurrence, and LVI and extrathyroidal extension (ETE) were found to be independent significant predictors for LNM. (4) Conclusions: Considering TTD > 10 mm in recurrence risk categorization models and adopting a clinical approach that takes into account multifocal PTMCs with TTD > 10 mm along with unifocal PTCs with PTD > 10 mm may be more useful in terms of clinical management of the disease.

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Prostate cancer is unique compared to other major cancers due to the presence of multiple primary malignant foci in the majority of patients at the time of diagnosis. Each malignant focus has distinct somatic mutations and gene expression patterns, which represents a challenge for the development of prognostic tests for localized prostate cancer. Additionally, the molecular heterogeneity of advanced prostate cancer has important implications for management, particularly for patients with metastatic and locally recurrent cancer. Studies have shown that prostate cancers with mutations in DNA damage response genes are more sensitive to drugs inhibiting the poly ADP-ribose polymerase (PARP) enzyme. However, testing for such mutations should consider both spatial and temporal heterogeneity. Here, we summarize studies where multiregional genomics and transcriptomics analyses have been performed for primary prostate cancer. We further discuss the vast interfocal heterogeneity and how prognostic biomarkers and a molecular definition of the index tumor should be developed. The concept of focal treatments in prostate cancer has been evolving as a demand from patients and clinicians and is one example where there is a need for defining an index tumor. Here, biomarkers must have proven value for individual malignant foci. The potential discovery and implementation of biomarkers that are agnostic to heterogeneity are also explored as an alternative to multisample testing. Thus, deciding upon whole-organ treatment, such as radical prostatectomy, should depend on information from biomarkers which are informative for the whole organ.

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Objective: Serum 25-hydroxyvitamin D (25(OH)D) deficiency has been known to be associated with the risk and mortality of several cancers. However, the role of 25(OH)D in papillary thyroid cancer (PTC) remains controversial. This study aimed to investigate the association between 25(OH)D and clinicopathologic features of PTC. Methods: Patients who underwent thyroidectomy were retrospectively reviewed. Serum 25(OH)D levels were measured within a week prior to surgery. The patients were categorized into four quartiles according to season-specific 25(OH)D levels. The association between 25(OH)D levels and clinicopathologic features of PTC was analyzed. Results: A total of 2932 patients were enrolled in the study. The 25(OH)D levels were significantly higher in patients with lymph node metastasis (LNM; P < 0.001), lateral LNM (P < 0.001), and multifocal tumors (P < 0.001). Compared to the first quartile (Q1) of 25(OH)D level, the third quartile (Q3) and the fourth quartile (Q4) showed an unadjusted OR of 1.36 (95% CI: 1.09-1.69; P = 0.006) and 1.76 (95% CI: 1.42-2.19; P < 0.001) for LNM (P for trend < 0.001), respectively. An increased risk of multifocal tumors was strongly associated with high 25(OH)D concentration (P for trend <0.001). Similar results were obtained after adjusting for confounding factors. Conclusion: High 25(OH)D levels are associated with aggressive features of PTC, such as lymph node metastasis and multifocality.