Genomic features of renal cell carcinoma developed during end-stage renal disease and dialysis.

Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study's goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis exposure. In this study, we obtained 33 RCCs, with various histological subtypes, that developed in ESRD patients receiving dialysis and performed whole-genome sequencing and transcriptome analyses. Driver events, copy-number alteration (CNA) analysis and mutational signature profiling were performed using an analysis pipeline that integrated data from germline and somatic SNVs, Indels and structural variants as well as CNAs, while transcriptome data were analyzed for differentially expressed genes and through gene set enrichment analysis. ESRD related clear cell RCCs' driver genes and mutations mirrored those in sporadic ccRCCs. Longer dialysis periods significantly correlated with a rare mutational signature SBS23, whose etiology is unknown, and increased mitochondrial copy number. All acquired cystic disease (ACD)-RCCs, which developed specifically in ESRD patients, showed chromosome 16q amplification. Gene expression analysis suggests similarity between certain ACD-RCCs and papillary RCCs and in TCGA papillary RCCs with chromosome 16 gain identified enrichment for genes related to DNA repair, as well as pathways related to reactive oxygen species, oxidative phosphorylation and targets of Myc. This analysis suggests that ESRD or dialysis could induce types of cellular stress that impact some specific types of genomic damage leading to oncogenesis.

Peripheral Nerve Blocks in the Preoperative Management of Hip Fractures: A Systematic Review and Network Meta-Analysis.

STUDY OBJECTIVE: We conducted a systematic review and network meta-analysis to evaluate the comparative efficacy of peripheral nerve block types for preoperative pain management of hip fractures. METHODS: We searched Cochrane, Central Register of Controlled Trials, MEDLINE, EMBASE, ICTRP, ClinicalTrials.gov, and Google Scholar for randomized clinical trials. We included participants aged more than 16 years with hip fractures who received peripheral nerve blocks or analgesics for preoperative pain management. The primary outcomes were defined as absolute pain score 2 hours after block placement, preoperative consumption of morphine equivalents, and length of hospital stay. We used a random-effects network meta-analysis conceptualized in the Bayesian framework. Confidence of evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We included 63 randomized controlled studies (4,778 participants), of which only a few had a low risk of bias. The femoral nerve block, 3-in-1 block, fascia iliaca compartment block, and pericapsular nerve group block yielded significantly lowered pain scores at 2 hours after block placement compared with those with no block (standardized mean differences [SMD]: -1.1; 95% credible interval [CrI]: -1.7 to -0.48, [confidence of evidence: low]; SMD: -1.8; 95% CrI: -3.0 to -0.55, [low]; SMD: -1.4; 95% CrI: -2.0 to -0.72, [low]; SMD: -2.3; 95% CrI: -3.2 to -1.4, [moderate], respectively). The pericapsular nerve group block, 3-in-1 block, fascia iliaca compartment block, and femoral nerve block resulted in lower pain scores than the no-block group. Additionally, the pericapsular nerve group block yielded a lower pain score than femoral nerve block or fascia iliaca compartment block (SMD: -1.21; 95% CrI: -2.18 to -0.23, [very low]: SMD: -0.92; 95% CrI: -1.70 to -0.16, [low]). However, both the fascia iliaca compartment block and femoral nerve block did not show a reduction in morphine consumption compared with no block. To our knowledge, no studies have compared the pericapsular nerve group block with other methods regarding morphine consumption. Furthermore, no significant difference was observed between peripheral nerve blocks and no block in terms of the length of hospital stay. CONCLUSIONS: Compared with no block, preoperative peripheral nerve blocks for hip fractures appear to reduce pain 2 hours after block placement. Comparing different blocks, pericapsular nerve group block might be superior to fascia iliaca compartment block and femoral nerve block for pain relief, though the confidence evidence was low in most comparisons because of the moderate to high risk of bias in many of the included studies and the high heterogeneity of treatment strategies across studies. Therefore, further high-quality research is needed.

Lack of clinical evidence of antiviral therapy for human monkeypox: A scoping review.

Since May 2022, many human monkeypox cases have been reported from non-endemic countries. This systematic review aimed to evaluate and summarize the existing research on the efficacy and safety of tecovirimat, brincidofovir, and cidofovir for patients with monkeypox. We searched studies that reported the efficacy and adverse events of tecovirimat, brincidofovir, or cidofovir for patients with human monkeypox in several databases including preprint servers. Only five studies were included. The efficacy and adverse events were assessed in only five and four patients, respectively. Regarding tecovirimat, all two patients recovered from monkeypox. One had no adverse event and the other has no description of an adverse event. Regarding brincidofovir, all three patients recovered from monkeypox but all of them had increased alanine transaminase, and one had nausea and abdominal discomfort. There was no study on treatment with cidofovir. Based on past studies and our results, tecovirimat might be the best choice due to ease of administration (oral drug), fewer side effects, and past treatment results for human monkeypox administration. However, very few studies were included in this scoping review. Therefore, further studies are needed to assess their efficacy and safety as possible treatments for human monkeypox.

Neuropsychiatric aspects of long COVID: A comprehensive review.

Although some patients have persistent symptoms or develop new symptoms following coronavirus disease 2019 (COVID-19) infection, neuropsychiatric aspects of long COVID are not well known. This review summarizes and provides an update on the neuropsychiatric dimensions of long COVID. Its neuropsychiatric manifestations commonly include fatigue, cognitive impairment, sleep disorders, depression, anxiety, and post-traumatic stress disorder. There are no specific tests for long COVID, but some characteristic findings such as hypometabolism on positron emission tomography have been reported. The possible mechanisms of long COVID include inflammation, ischemic effects, direct viral invasion, and social and environmental changes. Some patient characteristics and the severity and complications of acute COVID-19 infection may be associated with an increased risk of neuropsychiatric symptoms. Long COVID may resolve spontaneously or persist, depending on the type of neuropsychiatric symptoms. Although established treatments are lacking, various psychological and pharmacological treatments have been attempted. Vaccination against COVID-19 infection plays a key role in the prevention of long coronavirus disease. With differences among the SARS-CoV-2 variants, including the omicron variant, the aspects of long COVID are likely to change in the future. Further studies clarifying the aspects of long COVID to develop effective treatments are warranted.

Developmental organization of neural dynamics supporting auditory perception.

PURPOSE: A prominent view of language acquisition involves learning to ignore irrelevant auditory signals through functional reorganization, enabling more efficient processing of relevant information. Yet, few studies have characterized the neural spatiotemporal dynamics supporting rapid detection and subsequent disregard of irrelevant auditory information, in the developing brain. To address this unknown, the present study modeled the developmental acquisition of cost-efficient neural dynamics for auditory processing, using intracranial electrocorticographic responses measured in individuals receiving standard-of-care treatment for drug-resistant, focal epilepsy. We also provided evidence demonstrating the maturation of an anterior-to-posterior functional division within the superior-temporal gyrus (STG), which is known to exist in the adult STG. METHODS: We studied 32 patients undergoing extraoperative electrocorticography (age range: eight months to 28 years) and analyzed 2,039 intracranial electrode sites outside the seizure onset zone, interictal spike-generating areas, and MRI lesions. Patients were given forward (normal) speech sounds, backward-played speech sounds, and signal-correlated noises during a task-free condition. We then quantified sound processing-related neural costs at given time windows using high-gamma amplitude at 70-110 Hz and animated the group-level high-gamma dynamics on a spatially normalized three-dimensional brain surface. Finally, we determined if age independently contributed to high-gamma dynamics across brain regions and time windows. RESULTS: Group-level analysis of noise-related neural costs in the STG revealed developmental enhancement of early high-gamma augmentation and diminution of delayed augmentation. Analysis of speech-related high-gamma activity demonstrated an anterior-to-posterior functional parcellation in the STG. The left anterior STG showed sustained augmentation throughout stimulus presentation, whereas the left posterior STG showed transient augmentation after stimulus onset. We found a double dissociation between the locations and developmental changes in speech sound-related high-gamma dynamics. Early left anterior STG high-gamma augmentation (i.e., within 200 ms post-stimulus onset) showed developmental enhancement, whereas delayed left posterior STG high-gamma augmentation declined with development. CONCLUSIONS: Our observations support the model that, with age, the human STG refines neural dynamics to rapidly detect and subsequently disregard uninformative acoustic noises. Our study also supports the notion that the anterior-to-posterior functional division within the left STG is gradually strengthened for efficient speech-sound perception after birth.

Barriers to telemedicine among physicians in epilepsy care during the COVID-19 pandemic: A national-level cross-sectional survey in Japan.

OBJECTIVE: This study aimed to investigate the factors affecting the unwillingness of physicians involved in epilepsy care to continue telemedicine during the coronavirus disease 2019 (COVID-19) pandemic in Japan. METHOD: This was a national-level cross-sectional survey initiated by Japan Young Epilepsy Section (YES-Japan) which is a national chapter of The Young Epilepsy Section of the International League Against Epilepsy (ILAE-YES). We asked physicians who conducted telemedicine in patients with epilepsy (PWE) during the COVID-19 pandemic at four clinics and 21 hospitals specializing in epilepsy care in Japan from March 1 to April 30, 2021. The following data were collected: (1) participant profile, (2) characteristics of PWE treated by telemedicine, and (3) contents and environmental factors of telemedicine. Statistically significant variables (p < 0.05) in the univariate analysis were analyzed in a multivariate binary logistic regression model to detect the independently associated factors with the unwillingness to continue telemedicine. RESULT: Among the 115 respondents (response rate: 64%), 89 were included in the final analysis. Of them, 60 (67.4%) were willing to continue telemedicine, and 29 (32.6%) were unwilling. In the univariate binary logistic regression analysis, age (Odds ratio [OR] = 1.84, 95% confidence interval [CI] 1.10-3.09, p = 0.02), psychiatrist (OR = 5.88, 95% CI 2.15-16.08, p = 0.001), hospital (OR = 0.10, 95% CI 0.01-0.94, p = 0.04), the number of COVID-19 risk factors in the participant (OR = 2.88, 95% CI 1.46-5.69, p = 0.002), the number of COVID-19 risk factors in the cohabitants (OR = 2.52, 95% CI 1.05-6.01, p = 0.04), COVID-19 epidemic area (OR = 4.37, 95% CI 1.18-16.20, p = 0.03), consultation time during telemedicine (OR = 2.51, 95% CI 1.32-4.76, p = 0.005), workload due to telemedicine (OR = 4.17, 95% CI 2.11-8.24, p < 0.001) were statistically significant. In the multivariate binary logistic regression analysis, workload due to telemedicine (OR = 4.93, 95% CI 1.96-12.35) was independently associated with the unwillingness to continue telemedicine. CONCLUSION: This national-level cross-sectional survey found that workload due to telemedicine among physicians involved in epilepsy care was independently associated with the unwillingness to continue telemedicine.

Effectiveness of radiation therapy on brain invasion by human papillomavirus-related multiphenotypic sinonasal carcinoma: A case report.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is newly suggested and characterized by HPV-related tumors. HMSC has a relatively good prognosis. No cases of brain invasion have been reported to date. We encountered a case of brain invasion by HMSC, in which we assessed the effectiveness of radiotherapy in comparison with biopsy and autopsy. A 69-year-old man was referred to a hospital three months after intracerebral hemorrhage (ICH). Contrast magnetic resonance imaging revealed a tumor in the ethmoid sinus involving the brain. We performed transnasal biopsy and intensity-modulated radiotherapy for sinonasal and intracranial lesions. Despite radiotherapy, the patient died on day 41 after radiation. Biopsy specimens displayed mixed findings of epithelial and mesenchymal components. The tumor was immunoreactive for p16, and the RNA in situ hybridization for HPV was positive. Finally, we diagnosed the patient as having HMSC. Autopsy of the sinonasal tissue revealed a reduction in the number of tumor cells. There was a marked reduction in the number of tumor cells in the sinonasal tissue compared to that in the invaded brain tissue. The effectiveness of radiotherapy could depend on the histopathological components and location of the lesion, even in the same patient.

Epilepsy and COVID-19: Updated evidence and narrative review.

The coronavirus disease 2019 (COVID-19) outbreak started in Wuhan, China, in late 2019 and rapidly spread globally. Vaccines have recently been developed and are being administered in some countries, but their widespread use is not yet sufficient; the battle against COVID-19 is protracted and people need to adapt to living under the influence of this disease. Epilepsy is a common chronic neurological condition characterized by spontaneous recurrence of unprovoked seizures. Various effects of COVID-19 on epilepsy have been studied in recent months. As clinicians, we need to keep up with daily updates in the evidence regarding interactions between COVID-19 and epilepsy. This review article summarizes the current evidence. Prospective studies on epilepsy and COVID-19 remain lacking. Most articles have comprised case reports, case series, retrospective studies, and recommendations/opinions that do not include data. However, summarizing these articles can identify the demands for research into COVID-19 and epilepsy by clarifying what is known and what remains unclear from current research.

Considering temporality in causal relationship between seizure worsening and psychological stress in patients with epilepsy during the COVID-19 pandemic: A systematic review.

OBJECTIVE: To investigate whether published studies that identified a causal relationship between psychological stress and seizure worsening in patients with epilepsy during the coronavirus disease 2019 (COVID-19) pandemic considered the temporality of Hill's criteria. METHOD: A systematic review approach was used to comprehensively search MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov databases for relevant studies. Studies that reported an association between psychological stress and seizure worsening in patients with epilepsy during the COVID-19 pandemic were included accordingly. The quality of assessments in each study was evaluated and an assessment for considering temporality in the causal relationship between the two events in each study was carried out. RESULTS: Seventeen studies were included in the analysis. Most (14/17) were cross-sectional studies and only four out of these 17 studies (23.5%) considered temporality in the causality. Further, these four studies did not consider temporality in the study design, they only described it as a limitation. CONCLUSION: We found that many articles reported a causal relationship between psychological stress and seizure worsening without considering temporality. As both researchers and readers, we need to consider temporality when interpreting the causal relationship between increased psychological stress and seizure worsening in patients with epilepsy during the COVID-19 pandemic.

Psychological impact of the COVID-19 pandemic for patients with epilepsy: A systematic review and meta-analysis.

OBJECTIVE: To investigate psychological comorbidities in patients with epilepsy during the coronavirus disease 2019 (COVID-19) pandemic. METHOD: A systematic review and meta-analysis approach was used to comprehensively search MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov databases for relevant studies. Studies that reported psychological stress in patients with epilepsy during the COVID-19 pandemic were included. Psychological comorbidities were defined as anxiety, depression, and sleep disturbance. Pooled proportions of psychological comorbidities with 95% confidence intervals (CIs) were assessed using a random-effects model. The quality of assessment for each study, heterogeneity between the studies, and publication bias were also evaluated. RESULTS: A total of 28 studies with 7959 patients/caregivers were included in the meta-analysis. The pooled proportions of anxiety/worry, depression/bad mood, and sleep disturbance were 38.9% (95% CI: 31.3-46.7); I2 = 97%; p < 0.01, 30.9% (95% CI: 23.3-38.9), I2 = 97%; p < 0.01, and 36.5% (95% CI: 28.3-45.1), I2 = 97%, p < 0.01, respectively. CONCLUSION: Although the heterogeneity was high, our results showed a relatively high incidence of psychological comorbidities. Therefore, clinicians need to intervene early in the stress of patients with epilepsy to prevent worsening of stress, which can result in seizure worsening.

Association between telemedicine and incidence of status epilepticus during the COVID-19 pandemic.

OBJECTIVE: We aimed to investigate the association between telemedicine and the incidence of status epilepticus (SE) in patients with epilepsy (PWE) during the coronavirus disease 2019 (COVID-19) pandemic using a large population database in the United States. METHODS: We performed a retrospective analysis of a private, cloud-based healthcare platform (Explorys Inc., Cleveland, Ohio, USA). We compared each of the previously reported risk factors for SE, such as child, male, and refractory epilepsy, using the chi-square test or Fisher's exact test in two groups: PWE with SE or without SE. We determined whether telemedicine could be a risk factor for the incidence of SE using multivariate binary logistic regression analysis incorporating statistically significant variables in the chi-square test or Fisher's exact test (p < 0.05). Statistical significance was set at p < 0.05. RESULTS: We identified 1600 PWE with SE and 61,700 PWE without SE from May 2020 to May 2021. The proportion of children, males, refractory epilepsy, and telemedicine was higher in PWE with SE than in PWE without SE (children: 21.9% vs. 17.7%, p < 0.001; male: 52.5% vs. 48.2%, p = 0.001; refractory epilepsy: 20.6% vs. 8.2%, p < 0.001; telemedicine: 42.5% vs. 23.6%, p < 0.001). The multivariate binary logistic regression model identified four significant variables as follows: child (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.17-1.50), male (OR, 1.19; 95% CI, 1.07-1.31), refractory epilepsy (OR, 2.44; 95% CI, 2.15-2.77), and telemedicine (OR, 2.29; 95% CI, 2.07-2.54). CONCLUSION: Telemedicine might be associated with an increased risk of SE in PWE during the COVID-19 pandemic.

Meta-analysis of EEG findings in patients with COVID-19.

OBJECTIVE: To perform a systematic review and meta-analysis to summarize and quantitatively evaluate the electroencephalogram (EEG) findings in patients with coronavirus disease 2019 (COVID-19). METHODS: The MEDLINE, CENTRAL, and ClinicalTrials.Gov databases were comprehensively assessed and searched for observational studies with EEG findings in patients with COVID-19. Pooled proportions of EEG findings with 95% confidence intervals (CIs) were assessed using a random effects model. The quality of assessment for each study, heterogeneity between the studies, and publication bias were also evaluated. RESULTS: In total, 12 studies with 308 patients were included in the meta-analysis. Abnormal background activity and generalized slowing in the pooled proportions were common findings among the patients with COVID-19 (96.1% [95% CI: 89.4-99.9]; I2 = 60%; p < 0.01 and 92.3% [95% CI: 81.2-99.3]; I2 = 74%; p < 0.01, respectively). The proportion of patients with epileptiform discharges (EDs) was 20.3% ([95% CI: 9.85-32.9]; I2 = 78%; p < 0.01). The proportion of EDs varied between patients with a history of epilepsy or seizures (59.5% [95% CI: 33.9-83.2]; I2 = 0%; p = 0.49) and patients without them (22.4% [95% CI: 10.4-36.4]; I2 = 46%; p = 0.07). The findings of seizures and status epilepticus on EEG were observed in 2.05% ([95% CI: 0.02-6.04]; I2 = 39%; p = 0.08) and 0.80% ([95% CI: 0.00.-3.69]; I2 = 28%; p = 0.17) of the patients, respectively. CONCLUSION: The proportion of abnormal background activity in patients with COVID-19 was high (96.1%). Epileptiform discharges were present in 20.3% of the cases and the proportion varied between people who had a history of epilepsy/seizure and those who did not. However, the proportion of seizures and status epilepticus on EEG was low (2.05% and 0. 80%, respectively).

Long-term satisfaction after extraoperative invasive EEG recording.

This retrospective cohort study investigated 53 patients with drug-resistant focal epilepsy and identified factors predictive of long-term satisfaction of patients and families following extraoperative intracranial EEG (iEEG) recording. The mixed model analysis assessed the utility of intracranial EEG (iEEG) predictor variables, including the seizure-onset zone (SOZ), modulation index (MI), and naming-related high-gamma activity. Modulation index, quantifying the coupling between high-frequency activity at >80 Hz and local slow wave at 3-4 Hz, effectively functions as a surrogate marker of the burden of interictal spike-and-slow-wave discharges. The mixed model specifically incorporated 'subtraction-MI', defined as the subtraction of mean z-score normalized MI across all preserved sites from that across all resected sites. Auditory naming-related high-gamma activity at 70-110 Hz is a biomarker to characterize the underlying language and speech function. The model incorporated 'maximum resected high-gamma', defined as the high-gamma percent change largest among sites included in the resected language-dominant hemispheric region. The model also incorporated the clinical and imaging profiles of given patients. The analysis revealed that complete removal of SOZ (p = 0.003) and younger patient age (p = 0.040) were independently associated with greater satisfaction. Neither 'subtraction-MI' nor 'maximum naming-related high-gamma' showed a significant and independent association with long-term satisfaction in our patient cohort. The observed impact of complete resection of SOZ and early surgery can be considered when counseling candidates for epilepsy surgery.

Risk factors for psychological distress in electroencephalography technicians during the COVID-19 pandemic: A national-level cross-sectional survey in Japan.

OBJECTIVE: To identify the risk factors for psychological distress in electroencephalography (EEG) technicians during the coronavirus disease 2019 (COVID-19) pandemic. METHOD: In this national-level cross-sectional survey initiated by Japan Young Epilepsy Section (YES-Japan), which is a national chapter of The Young Epilepsy Section of the International League Against Epilepsy (ILAE-YES), a questionnaire was administered to 173 technicians engaged in EEG at four clinics specializing in epilepsy care and 20 hospitals accredited as (quasi-) epilepsy centers or epilepsy training facilities in Japan from March 1 to April 30, 2021. We collected data on participants' profiles, information about work, and psychological distress outcome measurements, such as the K-6 and Tokyo Metropolitan Distress Scale for Pandemic (TMDP). Linear regression analysis was used to identify the risk factors for psychological distress. Factors that were significantly associated with psychological distress in the univariate analysis were subjected to multivariate analysis. RESULTS: Among the 142 respondents (response rate: 82%), 128 were included in the final analysis. As many as 35.2% of EEG technicians have been under psychological distress. In multivariate linear regression analysis for K-6, female sex, examination for patients (suspected) with COVID-19, and change in salary or bonus were independent associated factors for psychological distress. Contrastingly, in multivariate linear regression analysis for TMDP, female sex, presence of cohabitants who had to be separated from the respondent due to this pandemic, and change in salary or bonus were independent associated factors for psychological distress. CONCLUSION: We successfully identified the risk factors associated with psychological distress in EEG technicians during the COVID-19 pandemic. Our results may help in understanding the psychological stress in EEG technicians during the COVID-19 pandemic and improving the work environment, which is necessary to maintain the mental health of EEG technicians.

Comprehensive pathological assessment of histological subtypes, molecular subtypes based on immunohistochemistry, and tumor-associated immune cell status in muscle-invasive bladder cancer.

Molecular assessments of muscle-invasive bladder cancer (MIBC) have yielded several molecular categorizations associated with basal and luminal subtypes or tumor-associated immune cell status (TAICs). However, the histological relationships among histological subtypes, molecular subtypes, and TAICs and their clinical implications remain unclear. Thus, we aimed to evaluate the histological associations among these factors and their clinicopathological outcomes. We retrospectively analyzed 106 patients with MIBC who underwent radical cystectomy. The histological subtypes and TAICs were evaluated with hematoxylin and eosin staining, while the basal and luminal molecular subtypes were determined by immunohistochemical expression of cytokeratin (CK) 5/6, CK14, CK20, GATA3 and uroplakin II. Urothelial carcinoma with squamous differentiation and the sarcomatoid variant were highly associated with the basal subtype (P < 0.001 and P = 0.04, respectively). Additionally, high TAICs were significantly correlated with the basal subtype (P < 0.001). Although there was no significant difference in the cancer-specific survival (CSS) rate between molecular subtypes (P = 0.295), TAICs significantly discriminated CSS rates (P < 0.001). Furthermore, the combination of molecular subtypes and TAICs significantly stratified cancer-specific mortality rates. In conclusion, a comprehensive pathological evaluation of histological subtypes, molecular subtypes, and TAICs is feasible and can influence the oncological outcome.

Paneth-like cells in renal cell carcinomas and in cysts associated with acquired cystic kidney disease: Clinicopathologic analysis, comparative study and description of precursor lesions.

Paneth-like cells (PLCs) are different from Paneth cells (PCs) and contain Paneth-like granules, which have been reported in non-neoplastic conditions and in neoplasms of various organs. PLCs have been reported in clear cell renal cell carcinoma (CCRCC), but not in non-CCRCC, including acquired cystic disease-associated renal cell carcinoma (ACD-RCC). We analyzed clinicopathological features of 24 acquired cystic disease-associated renal cell carcinoma (ACD-RCC) with PLCs (ACD-RCCP+) and compared with those of 23 ACD-RCCs without PLCs (ACD-RCCP-). Approximately half of ACD-RCCs had PLCs and that almost all kidneys harboring ACD-RCC had cysts with PLCs. The fact that many ACD-RCCs and the cysts had PLCs is further evidence that the cyst with vacuoles and complex architecture might be a precursor lesion for ACD-RCC. The presence of PLCs may provide additional morphologic clue for distinguishing ACD-RCC from PRCC in challenging differential diagnostic workup in acquired cystic disease of the kidney setting.

Review of TFEB-amplified renal cell carcinoma with focus on clinical and pathobiological aspects.

The disease entity of TFEB-amplified renal cell carcinoma (RCC) has been recently established. In this article, we review such cases. Clinically, the age of patients ranged from 28 to 83 years with a mean age of 62.8 years. The size of the tumor ranged from 1.9 to 19.5 cm with a mean size of 8.7 cm. The tumor demonstrated a variety of architectural patterns such as solid, alveolar, papillary, pseudopapillary, nested or tubular. The International Society of Urological Pathology (ISUP) grade usually corresponds to grade 3 or 4. Cytomorphology shows eosinophilic, clear, amphophilic or even oncocytic cytoplasm. Necrosis can be frequently observed. Neoplastic cells with TFEB-amplified RCC show diffuse or patchy positivity for TFEB. Fluorescence in situ hybridization frequently show the amplification of more than 10 or 20 copies of the TFEB gene. Most TFEB-amplified RCCs behave in an aggressive fashion. Metastasis frequently occurs. In conclusion, this tumor seems to be characterized by occurrence in older patients, frequent necrosis, papillary/pseudopapillary growth pattern, high-grade nuclear grade, TFEB gene amplification, and aggressive clinical behavior. In order to clarify whether this tumor is a distinct entity from previously described renal tumors or not, a further examination in a large scale study will be required in the future.

ALK rearranged renal cell carcinoma (ALK-RCC): a multi-institutional study of twelve cases with identification of novel partner genes CLIP1, KIF5B and KIAA1217.

ALK rearranged renal cell carcinoma (ALK-RCC) has recently been included in 2016 WHO classification as a provisional entity. In this study, we describe 12 ALK-RCCs from 8 institutions, with detailed clinical, pathological, immunohistochemical (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) analyses. Patients' age ranged from 25 to 68 years (mean, 46.3 years). Seven patients were females and five were males (M:F = 1:1.4). Tumor size ranged from 17 to 70 mm (mean 31.5, median 25 mm). The pTNM stage included: pT1a (n = 7), pT1b (n = 1), and pT3a (n = 4). Follow-up was available for 9/12 patients (range: 2 to 153 months; mean 37.6 months); 8 patients were alive without disease and one was alive with distant metastases. The tumors demonstrated heterogeneous, 'difficult to classify' morphology in 10/12 cases, typically showing diverse architectural and cellular morphologies, including papillary, tubular, tubulocystic, solid, sarcomatoid (spindle cell), rhabdoid, signet-ring cell, and intracytoplasmic vacuoles, often set in a mucinous background. Of the remaining two tumors, one showed morphology resembling mucinous tubular and spindle cell renal cell carcinoma (MTSC RCC-like) and one was indistinguishable from metanephric adenoma. One additional case also showed a focal metanephric adenoma-like area, in an otherwise heterogeneous tumor. By IHC, all tumors were diffusely positive for ALK and PAX8. In both cases with metanephric adenoma-like features, WT1 and ALK were coexpressed. ALK rearrangement was identified in 9/11 tumors by FISH. ALK fusion partners were identified by NGS in all 12 cases, including the previously reported: STRN (n = 3), TPM3 (n = 3), EML4 (n = 2), and PLEKHA7 (n = 1), and also three novel fusion partners: CLIP1 (n = 1), KIF5B (n = 1), and KIAA1217 (n = 1). ALK-RCC represents a genetically distinct entity showing a heterogeneous histomorphology, expanded herein to include unreported metanephric adenoma-like and MTSC RCC-like variants. We advocate a routine ALK IHC screening for "unclassifiable RCCs" with heterogeneous features.

Difficulty in differential diagnosis for renal cancer with microscopic papillary architecture: overlapped pathological features among papillary renal cell carcinoma (RCC), mutinous tubular and spindle cell carcinoma, and unclassified RCC. Lessons from a Japanese multicenter study.

OBJECTIVES: In our multicenter study evaluating metastatic papillary renal cell carcinoma (PRCC), 29% of tumors diagnosed as PRCC in collaborative institutes were finally diagnosed as other RCCs under central review. In those tumors, mucinous tubular and spindle cell carcinoma (MTSCC) was the leading histology, followed by unclassified RCC (ucRCC). We focused on those patients with MTSCC or ucRCC. METHODS: We reviewed the processes for the pathological diagnoses of nine tumors and reviewed their clinical features. RESULTS: All of the MTSCCs and ucRCCs were positive for AMACR, which is frequently positive in PRCC. Mucin was demonstrated in 80% of the MTSCCs, and its presence is important for their diagnoses. One MTSCC was diagnosed as a mucin-poor variant. The presence of spindle cells with low-grade nuclei was suggestive of MTSCC, but the diagnosis of high-grade MTSCC was difficult. Four tumors were diagnosed as ucRCC by histological and immunohistochemical findings. Three of the four tumors were suspicious of ucRCC in the initial review due to atypical findings as PRCC. Sunitinib and interferon-α were effective for one MTSCC patient who survived for >5 years. Two MTSCC patients who were Memorial Sloan-Kettering Cancer Center poor risk had unfavorable prognoses. One patient with mucin-poor MTSCC had an indolent clinical course. Two of four ucRCC patients showed durable stable disease with targeted agents (TAs) and survived >3 years. CONCLUSION: Some MTSCC metastases progressed very slowly and poor-risk tumors progressed rapidly. Systemic therapies including TAs showed some efficacies. Some patients who have metastatic ucRCC with microscopic papillary architecture can benefit from TAs.

Significance of tumor microenvironment in acquiring resistance to vascular endothelial growth factor-tyrosine kinase inhibitor and recent advance of systemic treatment of clear cell renal cell carcinoma.

The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.