Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism12. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning7, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered that PIKFYVE is overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulate de novo lipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, by upregulating genes such as FASN and ACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.

Replication study identified EFEMP1 association with varicose vein predisposition among Indians.

BACKGROUND: Varicose vein is a chronic condition that affects the lower extremities of the human body. Several factors have been implicated in the development of this disease, viz age, gender, weight, height and prolonged standing. Recently, genome-wide studies have identified genetic biomarkers that are associated with varicose veins in different ethnic groups. Such genetic studies are lacking in South Asians specifically in Indians where the prevalence of varicose veins is high, and it is important to replicate these variants in the stated population. The study aimed to replicate the association of genetic variants associated with varicose veins in this target population, which were found to be associated with the other ethnic groups. METHODOLOGY: The studied cohort is of the Indian population comprising unrelated 104 varicose veins cases and 448 non-varicose vein controls. The samples were genotyped using the Illumina Global Screening Array. Using the genomic data from UK BioBank and 23andMe studied cohorts; eight genetic variants were selected to replicate in our dataset. The allelic association was performed to identify the effective allele and risk was estimated using odds ratio and p-value as level of significance. Multifactor Dimensionality Reduction was used to estimate the cumulative effect of variants in Indians. RESULT: Variant rs3791679 of EFEMP1 was found to be associated with varicose veins in Indians. After observing the association of the EFEMP1 with varicose veins, we further ensued to identify all genetic variants within EFEMP1 to uncover the additional variants associated with this trait. Interestingly, we identified six new variants of EFEMP1 gene that have shown association. Moreover, the cumulative effect of all associated variations was estimated and the risk was 2.7 times higher in cases than controls whereas independently their effect ranges from 0.37-1.58. CONCLUSION: This study identifies EFEMP1 as a potential gene related to the risk of varicose veins in Indians. It also highlights that evaluating the maximum number of variants of a gene rather than focusing solely on replicating single variations offers a more comprehensive and nuanced understanding of the genetic factors contributing to a complex trait like varicose veins.

Fabrication of cellulose-collagen based biosorbent as eco-friendly scavengers for uranyl ions.

The aim of the present research is to fabricate a biosorbent using agricultural waste for removal of uranium from contaminated water i.e. "waste to wealth" approach. Cellulose extracted from wheat straw was mercerized and a novel semi-interpenetrating polymer network (semi-IPN) was fabricated through graft copolymerization of polyvinyl alcohol onto hybrid mercerized cellulose + collagen backbone. Response surface methodology was used for optimization of different reaction parameters as a function of % grafting (195.1 %) was carried out. Semi-IPN was found to possess higher thermal stability. Adsorption results revealed that the optimum parameters for the elimination of uranium using semi-IPN were: adsorbent dose = 0.15 g, pH = 6.0, contact time = 120 min and initial U (VI) concentration = 100 µg/L. The pseudo-second-order kinetic model gave the best description of the adsorption equilibrium data as the calculated qe value is nearest to the experimental qe for the different initial U(VI) concentrations. Adsorption experiments followed Langmuir isotherm with R2 = 0.999. Furthermore, recyclability and reusability studies showed that the adsorption efficiency of semi-IPN was 82 % after 5 cycles indicating the superior recycling execution of fabricated biosorbent. Thus, the fabricated ecofriendly device can be used effectively for the removal of uranium from contaminated wastewater sources.

Complex aortic-arch pseudoaneurysm with aorto-innominate vein fistula in a case of traumatic chest injury.

A patient in his late 30s presented with issues of retrosternal chest pain and palpitations. He had sustained a splinter injury to the left hemithorax a year ago for which he had been managed with a tube thoracostomy. During subsequent evaluations, he was found to have atrial fibrillations and a CT angiography revealed an arch of the aorta pseudoaneurysm with a fistulous communication with the innominate vein, which being a rare condition has no established treatment protocols. Endovascular salvage of the condition required an aortic Ishimaru zone 2 deployment of the thoracic endovascular aortic repair stent graft to provide an adequate landing zone. The elective left subclavian artery revascularisation was obtained by a left carotid artery to left subclavian artery bypass. Post procedure there was complete exclusion of the pseudoaneurysm sac, and the fistulous aorto-venous communication inflow tract. The patient recuperated well and has returned to full active duties.

Research autopsy programmes in oncology: shared experience from 14 centres across the world.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Osteopathic Manipulative Treatment During Post-operative Recovery: A Scoping Review.

Surgery is a common and often necessary treatment option for a wide range of medical conditions, with an estimated 40 to 50 million surgeries performed in the US alone each year. While the various types of surgeries performed may be effective in treating or managing different conditions, the post-operative period can be challenging for patients. Osteopathic manipulative treatment (OMT) is a hands-on approach to medical care that seeks to restore balance and harmony to the body from the lens of an interconnected mind, body, and spirit. Given the potential for adverse events in patients following surgical treatments, OMT may be a viable adjunct post-operatively to enhance patient care and recovery. The purpose of this scoping review is to evaluate the state of current research examining the effectiveness of OMT in improving outcomes in post-operative patients. Three hundred articles were collected; 53 duplicates were removed. Eleven independent reviewers evaluated all 247 articles. Thirty articles were identified, including nine in general surgery, six in cardiothoracic surgery, five in orthopedic surgery, four in spinal surgery, three in neurosurgery, and three others (otolaryngology, oral/maxillofacial, and gynecologic surgery). Post-operative patients were treated with various OMT techniques with myofascial release and muscle energy being some of the most common treatments utilized in all surgical fields. Many studies demonstrated the benefits of OMT usage including significant pain relief, improved and earlier bowel function, and decreased lengths of hospital stay. This study demonstrates how OMT can be effective in reducing post-operative pain, reducing the incidence of post-operative ileus, and shortening the length of stay. Further research into the utilization of OMT in post-operative patients should be considered a potential adjunct to surgical intervention, especially in vulnerable patient populations.

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.

The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

Evaluation of TRIM63 RNA in situ hybridization (RNA-ISH) as a potential biomarker for alveolar soft-part sarcoma (ASPS).

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor with a broad morphologic differential diagnosis. While histology and immunohistochemistry can be suggestive, diagnosis often requires exclusion of other entities followed by confirmatory molecular analysis for its characteristic ASPSCR1-TFE3 fusion. Current stain-based biomarkers (such as immunohistochemistry for cathepsin K and TFE3) show relatively high sensitivity but may lack specificity, often showing staining in multiple other entities under diagnostic consideration. Given the discovery of RNA in situ hybridization (RNA-ISH) for TRIM63 as a sensitive and specific marker of MiTF-family aberration renal cell carcinomas, we sought to evaluate its utility in the workup of ASPS. TRIM63 RNA-ISH demonstrated high levels (H-score greater than 200) of expression in 19/20 (95%) cases of ASPS (average H-score 330) and was weak or negative in cases of paraganglioma, clear cell sarcoma, rhabdomyosarcoma, malignant epithelioid hemangioendothelioma, as well as hepatocellular and adrenal cortical carcinomas. Staining was also identified in tumors with known subsets characterized by TFE3 alterations such as perivascular epithelioid cell neoplasm (PEComa, average H-score 228), while tumors known to exhibit overexpression of TFE3 protein without cytogenetic alterations, such as melanoma and granular cell tumor, generally showed less TRIM63 ISH staining (average H-scores 147 and 96, respectively). Quantitative assessment of TRIM63 staining by RNA-ISH is potentially a helpful biomarker for tumors with molecular TFE3 alterations such as ASPS.

Osteopathic Manipulative Treatment in Dysmenorrhea: A Systematic Review.

The majority of women experience dysmenorrhea during their lifetime. The current standard-of-care treatment consists of nonsteroidal anti-inflammatory drugs, oral contraceptive pills, or intrauterine devices. Osteopathic manipulative treatment (OMT) is a beneficial tool for improving non-musculoskeletal (non-MSK) conditions such as migraines, gastroesophageal reflux disease (GERD), and anxiety. OMT should be utilized to improve other non-MSK conditions, such as dysmenorrhea. The current review aims to evaluate the effects of OMT in women with dysmenorrhea. An extensive search was conducted in Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, Biomedical Reference Collection: Comprehensive, and Nursing & Allied Health Collection: Comprehensive from inception to June 2022. Studies evaluating the use of OMT in patients with dysmenorrhea were included, while editorial/opinion articles were excluded. Three independent reviewers evaluated the studies. Ten studies evaluating the use of OMT in patients with dysmenorrhea were included. Overall, OMT was shown to provide relief of symptoms, including back and menstrual pain; however, there was no guideline on which OMT techniques are the most successful. Numerous positive effects were found, including a reduction in the duration of pain, reduction of pain intensity, and reduction of analgesic use. However, the low number of studies supports the need for further investigations. Dysmenorrhea patients could benefit from a prospective randomized controlled trial targeting spinal facilitation and viscerosomatic reflexes to decrease pain duration, pain intensity, and analgesic use. Non-MSK-focused OMT has a large body of mostly anecdotal evidence for relief of conditions such as migraine, GERD, and anxiety. It has helped when traditional standards of care have failed. Non-MSK-focused OMT research represents a relatively untouched field of research that can have a profound and positive global impact, particularly in areas with poor income/healthcare access.

Self-reducing intrathoracic organo-axial gastric volvulus with paraoesophageal hiatus hernia in a toddler.

A toddler presented with complaints of multiple episodes of vomiting lasting 1 week. He had a history of similar episodes of vomiting several times as an infant. Clinically, he was underweight and had tachypnoea and tachycardia. Laboratory investigations revealed hyponatraemic metabolic acidosis. His chest radiograph revealed an intrathoracic herniation of the stomach with an atypical presence towards the right hemithorax, suggestive of a torsion. A contrast-enhanced CT of the chest and abdomen confirmed an intrathoracic gastric herniation, with an organo-axial gastric volvulus, with no features of strangulation. He underwent an emergency laparotomy and intraoperatively the stomach was found to have reduced to its intra-abdominal position, and the hernia and volvulus had also self-reduced. In view of the multiple symptomatic episodes, an anterior gastropexy was performed to prevent recurrences. The patient recuperated well and has not had any recurrences in the follow-up period. This report adds to the minimalistic literature.

Renal Cell Carcinoma Associated With TSC/MTOR Genomic Alterations: An Update on its Expanding Spectrum and an Approach to Clinicopathologic Work-up.

Renal cell carcinoma (RCC) with tuberous sclerosis complex (TSC)/mammalian target of rapamycin (MTOR) pathway-related genomic alterations have been classically described in hereditary TSC syndrome setting involving germline mutations, whereby cells with a bi-allelic inactivation of genes originate tumors in a classic tumor-suppressor "two-hit" Knudson paradigm. Initial studies of TSC-associated RCC categorized tumors into 3 broad heterogeneous morphologic groups: RCC with smooth muscle stroma, chromophobe-like, and eosinophilic-macrocytic. Recently, a similar morphologic spectrum has been increasingly recognized in novel and emerging entities characterized by somatic mutations in the TSC1/2 and MTOR in patients who do not suffer from the TSC. Correct recognition of RCC with TSC / MTOR mutations is critical for accurate prognostication because such tumors with aggressive behavior have the potential to be tailored to mTOR inhibitors. Whether TSC/MTOR mutated renal epithelial neoplasms represent a distinct molecular class has been confounded by the fact that TSC1/2 , and the gene encoding the downstream protein MTOR, are mutated secondarily in ∼5% of the more common subtypes of RCC, including the commonest subtype of clear cell RCC. This review summarizes the expanding morphologic spectrum of renal tumors with TSC/mTOR pathway alterations, specifically for sporadically occurring tumors where these genomic alterations likely are primary pathologic events. Finally, a practical surgical pathology approach to handling these tumors, and a conceptual framework of renal epithelial tumors with TSC/MTOR mutations as a "family of tumors", is presented.

Hybrid Oncocytic Tumors (HOTs) in Birt-Hogg-Dubé Syndrome Patients-A Tale of Two Cities: Sequencing Analysis Reveals Dual Lineage Markers Capturing the 2 Cellular Populations of HOT.

Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187 , which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.

Gene of the month: VSTM2A.

The V-set and transmembrane domain containing 2A (VSTM2A) gene is located on chromosome 7. In the physiological state, VSTM2A regulates preadipocyte cell differentiation. VSTM2A is highly expressed in normal human brain tissue and minimally expressed in other normal tissues. Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a distinct renal tumour subtype with signature chromosomal copy number alterations and an indolent outcome in the majority of cases. VSTM2A overexpression is highly enriched in this renal cancer subtype and has been shown to have potential diagnostic value in distinguishing MTSCC from renal tumours with overlapping histological appearances.

Impact of sequencing of androgen receptor-signaling inhibition and radiotherapy in prostate cancer: importance of homologous recombination disruption.

PURPOSE: The synergy of combining androgen receptor-signaling inhibition (ARSI) to radiotherapy (RT) in prostate cancer has been largely attributed to non-homologous end joining (NHEJ) inhibition. However, this mechanism is unlikely to explain recently observed trial results that demonstrated the sequencing of ARSI and RT significantly impacts clinical outcomes, with adjuvant ARSI following RT yielding superior outcomes to neoadjuvant/concurrent therapy. We hypothesized this is driven by differential effects on AR-signaling and alternative DNA repair pathway engagement based on ARSI/RT sequencing. METHODS: We explored the effects of ARSI sequencing with RT (neoadjuvant vs concurrent vs adjuvant) in multiple prostate cancer cell lines using androgen-deprived media and validation with the anti-androgen enzalutamide. The effects of ARSI sequencing were measured with clonogenic assays, AR-target gene transcription and translation quantification, cell cycle analysis, DNA damage and repair assays, and xenograft animal validation studies. RESULTS: Adjuvant ARSI after RT was significantly more effective at killing colony forming cells and decreasing the transcription and translation of downstream AR-target genes across all prostate cancer models evaluated. These results were reproduced in xenograft studies. The differential effects of ARSI sequencing were not fully explained by NHEJ inhibition alone, but by the additional disruption of homologous recombination specifically with adjuvant sequencing of ARSI. CONCLUSION: We demonstrate that altered sequencing of ARSI and RT mediates differential anti-AR-signaling and anti-cancer effects, with the greatest benefit from adjuvant ARSI following RT. These results, combined with our prior clinical findings, support the superiority of an adjuvant-based sequencing approach when using ARSI with RT.

Non-steroidal Anti-inflammatory Drugs and Osteopathic Manipulative Treatment for Pain Management in Patients With Osteoarthritis: A Literature Review.

The pathophysiology of osteoarthritis (OA) involves the destruction of articular cartilage and the overgrowth of bone with lipping and spur formation. Nerve endings in the joint capsule and adjacent tissues play a major role in the pain mechanisms of osteoarthritis. This often requires patients to seek pain control measures beyond over-the-counter drugs, such as local anesthetics. Osteopathic manipulation treatment (OMT) is a conservative, non-pharmacological treatment that can be used to help treat chronic pain associated with OA. Other non-pharmacologic therapies include weight loss, exercise, physical therapy (PT), and assistive devices. However, pharmacologic management may be added synergistically to control flares and maintain baseline activities of daily living. While oral non-steroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of treatment for pain and inflammation associated with OA, they have a non-selective inhibitory action that often results in negative side effects when used chronically. The possibility of minimizing these complications through alternate treatments such as topical NSAIDs provides an opportunity for patients to receive adequate pain relief from OA without suffering unnecessary consequences. This literature review seeks to assess the state of research regarding topical NSAIDs and OMT as alternatives to the current gold-standard treatment of OA. The significant inclusion criteria consisted of articles that described the effects of OMT on OA or the use of topical NSAIDs such as Voltaren on OA. Due to the limited articles found, a qualitative analysis was performed, and the salient conclusions are outlined. Alternative pharmacological and non-pharmacological treatments, such as topical diclofenac gel and OMT, have shown promising results in the treatment of pain in OA. It is seen that a majority of patients achieve pain management using NSAIDs, acetaminophen, or topical analgesics. Both diclofenac sodium and OMT have individually been shown to be effective treatments of OA when compared to the use of oral NSAIDs. A holistic treatment approach that utilizes both topical diclofenac sodium and OMT may provide OA patients with an effective option to reduce their moderate to severe chronic pain with limited side effects. Further, high-quality randomized controlled trials are needed to identify whether synergistic effects occur when combining diclofenac sodium gel and OMT for pain relief in patients with OA.

Thermoluminescence dosimeter (TLD) studies of Ca10 K(PO4 )7 :Dy phosphor for applications in radiation dosimetry.

This study reports the thermoluminescence (TL) aspects of Ca10 K(PO4 )7 :Dy phosphor synthesized using a wet chemical method for the first time. The X-ray diffraction (XRD) results confirm the formation of the desired crystalline phase. Surface morphological studies reveal the formation of polyhedrons and agglomerations having an average diameter of 200 nm, while energy dispersive X-ray spectroscopy (EDS) data show the presence and composition of the elements in appropriate amounts. The effect of Dy doping concentration has been studied on the TL properties with exposure to gamma radiations from the Co-60 source. The best TL response has been observed for 5 mol% Dy doping concentration. The glow curve is simple and consists of a single peak at 130°C. The effect of the heating rate has been studied on the TL glow curve, and the heating rate of 5°C/s shows the best TL response. The various TL properties such as annealing conditions, dose-response, TL linearity, fading, and reusability of the prepared phosphor have been studied to check its suitability as a good TL dosimeter (TLD). TL characterization of the phosphor reports that the TL response is linear from 5- to 2000 Gy. The results show that this phosphor can be a good TLD for the dosimetry of gamma radiations from Co-60.

"Oncocytoid Renal Cell Carcinomas After Neuroblastoma" Represent TSC -mutated Eosinophilic Solid and Cystic Renal Cell Carcinomas : Association With Prior Childhood Malignancy and Multifocality With Therapeutic Implications.

The concept of oncocytoid renal cell carcinoma in patients who have survived neuroblastoma as a distinct biologic entity has been controversial since its original description in 1999. This is in part because similar oncocytoid renal cell carcinomas have been described in association with other pediatric cancers, and also because other renal cell carcinoma subtypes (such as MiT family translocation renal cell carcinoma) have been described in children who have survived neuroblastoma. We identified an index case of a child who survived medulloblastoma and developed multifocal bilateral oncocytoid renal cell carcinomas with morphology and immunophenotype compatible with eosinophilic solid and cystic renal cell carcinoma (ESC RCC) and demonstrated that both neoplasms harbored distinctive mutations in the TSC1/TSC2 genes. Remarkably, the child's remaining bilateral multifocal renal neoplasms completely responded to MTOR inhibitor therapy without need for further surgery. To confirm our hypothesis that oncocytoid renal cell carcinomas after childhood cancer represent ESC RCC, we obtained formalin-fixed paraffin-embedded tissue blocks from 2 previously published cases of oncocytoid renal cell carcinoma after neuroblastoma, confirmed that the morphology and immunophenotype was consistent with ESC RCC, and demonstrated that both cases harbored somatic TSC gene mutations. Both expressed markers previously associated with neoplasms harboring TSC gene mutations, glycoprotein nonmetastatic B, and cathepsin K. Of note, one of these patients had 2 ESC RCC which harbored distinctive TSC2 mutations, while the background kidney of the other patient had multiple small cysts lined by similar oncocytoid cells which showed loss of TSC2 protein. We then reviewed 3 of 4 cases from the original 1999 report of oncocytoid renal cell carcinomas after neuroblastoma, found that all 3 demonstrated morphology (including basophilic cytoplasmic stippling) that is characteristic of ESC RCC, showed that all 3 overexpressed glycoprotein nonmetastatic B, and showed that both cases with adequate material demonstrated loss of TSC2 protein and expressed cytokeratin 20 and cathepsin K by immunohistochemistry. In summary, "oncocytoid renal cell carcinomas after neuroblastoma" represent ESC RCC which are often multifocal in patients who have survived childhood cancer, likely representing an incompletely characterized tumor predisposition syndrome. MTOR-targeted therapy represents an effective therapeutic option for such patients to preserve functional nephrons.