Medicine

A Gene Therapy for Hereditary Nonpolyposis Colorectal Cancer using CRISPR-Cas9 Nickase

Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited disorder characterized by an increased risk of developing colorectal cancer before age 50. HNPCC is predominantly caused by genetic mutations in MLH1 and MSH2, which are involved in DNA mismatch repair. Current standard practice is t...
More

Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited disorder characterized by an increased risk of developing colorectal cancer before age 50. HNPCC is predominantly caused by genetic mutations in MLH1 and MSH2, which are involved in DNA mismatch repair. Current standard practice is to perform prophylactic colectomy, resulting in debilitating aftereffects for life. Though the genetic cause of HNPCC is well-known, there are currently no available treatments that target these mutations. Herein we describe a novel treatment protocol using a CRISPR-Cas9n-based genetic therapy to restore DNA mismatch repair. First, gRNA and template DNA targeting the most prevalent mutation clusters in MLH1 and MSH2 as well as CRISPR-Cas9n elements will be packaged into an integrase-deficient lentiviral vector. Then, the viral vector will be used to transduce human colonic tumor-derived organoids as well as administered systemically in mouse models of HNPCC. Mice will be monitored clinically and for signs of disease progression. At termination, colonic tissue will be harvested and analyzed for restoration of the wild-type MLH1 and MSH2 sequence and biochemical markers of HNPCC. This protocol offers an alternative strategy using CRISPR-Cas9n-based gene therapy to prevent tumor formation in patients, avoid morbid surgery, and significantly improve quality of life.
Less

Review of Hereditary non-polyposis colorectal cancer

The purpose of this paper is to provide a review of hereditary non-polyposis colorectal cancer. This paper covers the causes, epidemiology, pathophysiology, histology, diagnosis, and treatment for the disease.

Clear cell and papillary renal cell carcinomas in hereditary papillary renal cell carcinoma (HPRCC) syndrome: a case report

Background Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, dis...
More

Background Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, distinctive histological features of RCC are described according to the familial renal cell carcinoma syndrome. To date, no clear cell RCC has been reported in HPRCC syndrome. Case presentation We describe the case of a 51-year-old man with a germline MET mutation detected on peripheral blood testing, and no germline VHL mutation, who developed numerous papillary tumors but also unexpectedly clear cell renal cell carcinomas. During the follow-up, an adrenal metastasis was observed 7 years after the initial diagnosis corresponding to a clear cell RCC metastasis. By immunohistochemistry, clear cell tumors showed focal cytokeratin 7, moderate racemase, and diffuse and membranous CAIX expression, while papillary tumors expressed strong diffuse cytokeratin 7 and racemase without CAIX positivity. Using FISH, VHL deletion was observed in one of the clear cell tumors, and the metastatic clear cell tumor presented a trisomy of chromosomes 7 and 17. These last genomic alterations are usually detected in papillary RCC, highlighting the potential link between both histological subtypes of tumors and the HPRCC syndrome. Conclusions The pathologist must be aware that the presence of a non-papillary RCC associated with numerous papillary tumors should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study.
Less

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome

In hereditary leiomyomatosis and renal cell carcinoma syndrome, fumarate hydratase–deficient renal cell carcinomas typically present as aggressive, unilateral, often cystic masses with heterogeneous enhancement. These tumors can metastasize early, making appropriate imaging and staging critical fo...
More

In hereditary leiomyomatosis and renal cell carcinoma syndrome, fumarate hydratase–deficient renal cell carcinomas typically present as aggressive, unilateral, often cystic masses with heterogeneous enhancement. These tumors can metastasize early, making appropriate imaging and staging critical for diagnosis and management. Teaching point: When a renal lesion suspected of RCC is identified in a patient with cutaneous and uterine leiomyomas, HLRCC should be evaluated, which is important for future genetic counseling.
Less

A Non-Hereditary Case of Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is believed to result from an autosomal dominant mutation in the fumarate hydratase (FH) gene on chromosome 1. It is characterized by leiomyomas, mainly uterine or cutaneous, and renal cell carcinoma (RCC). The most common type of R...
More

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is believed to result from an autosomal dominant mutation in the fumarate hydratase (FH) gene on chromosome 1. It is characterized by leiomyomas, mainly uterine or cutaneous, and renal cell carcinoma (RCC). The most common type of RCC associated with HLRCC is type II papillary RCC although other types are seen. Of note, chromophobe RCC has not been described in previously documented cases of HLRCC. HLRCC is typically associated with germline mutations with occasional somatic mutations reported, however, to the best of our knowledge, none have yielded the full phenotype until now. Herein, we report a case of a 45-year-old woman who underwent a hysterectomy following a year of heavy vaginal bleeding, yielding a diagnosis of uterine leiomyomas. Eight months later, the patient presented with hematuria and was subsequently found to have a left renal mass. Following a left radical nephrectomy, histologic exam revealed a chromophobe RCC with FH deficiency.
Less

A Case of Metastatic Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome-Associated Renal Cell Carcinoma Treated with a Sequence of Axitinib and Nivolumab Following Cytoreductive Nephrectomy

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) associated renal cell carcinoma (RCC) is an aggressive form of type 2 papillary RCC caused by deficiency of the fumarate hydratase gene. For patients with metastatic disease, no standard treatment has been established with dismal progn...
More

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) associated renal cell carcinoma (RCC) is an aggressive form of type 2 papillary RCC caused by deficiency of the fumarate hydratase gene. For patients with metastatic disease, no standard treatment has been established with dismal prognosis. We report a case of metastatic HLRCC-associated RCC in a 65-year-old Japanese male whose clinical features mimicked advanced renal pelvic cancer. A durable response was achieved with a sequence of axitinib and nivolumab after cytoreductive and diagnostic nephrectomy. Their potential therapeutic roles in the management of metastatic HLRCC-associated RCC have been discussed based on its molecular and biological backgrounds.
Less

Prostate-specific Membrane Antigen: Alpha-labeled Radiopharmaceuticals

A Systematic Review on Artificial Intelligence Evaluating Metastatic Prostatic Cancer and Lymph Nodes on PSMA PET Scans

<jats:p>Early detection of metastatic prostate cancer (mPCa) is crucial. Whilst the prostate-specific membrane antigen (PSMA) PET scan has high diagnostic accuracy, it suffers from inter-reader variability, and the time-consuming reporting process. This systematic review was registered on PROSPERO (...
More

<jats:p>Early detection of metastatic prostate cancer (mPCa) is crucial. Whilst the prostate-specific membrane antigen (PSMA) PET scan has high diagnostic accuracy, it suffers from inter-reader variability, and the time-consuming reporting process. This systematic review was registered on PROSPERO (ID CRD42023456044) and aims to evaluate AI’s ability to enhance reporting, diagnostics, and predictive capabilities for mPCa on PSMA PET scans. Inclusion criteria covered studies using AI to evaluate mPCa on PSMA PET, excluding non-PSMA tracers. A search was conducted on Medline, Embase, and Scopus from inception to July 2023. After screening 249 studies, 11 remained eligible for inclusion. Due to the heterogeneity of studies, meta-analysis was precluded. The prediction model risk of bias assessment tool (PROBAST) indicated a low overall risk of bias in ten studies, though only one incorporated clinical parameters (such as age, and Gleason score). AI demonstrated a high accuracy (98%) in identifying lymph node involvement and metastatic disease, albeit with sensitivity variation (62–97%). Advantages included distinguishing bone lesions, estimating tumour burden, predicting treatment response, and automating tasks accurately. In conclusion, AI showcases promising capabilities in enhancing the diagnostic potential of PSMA PET scans for mPCa, addressing current limitations in efficiency and variability.</jats:p>
Less

A Single Canal in a Mandibular Second Molar: A Case Report

Root canal anatomy of mandibular second molars differs among individuals. With the aid of the latest dental technologies in endodontics, the present case report highlights the diagnostic tools required to confirm the morphology of the root canal, and the treatment of uncommon root anatomy of a singl...
More

Root canal anatomy of mandibular second molars differs among individuals. With the aid of the latest dental technologies in endodontics, the present case report highlights the diagnostic tools required to confirm the morphology of the root canal, and the treatment of uncommon root anatomy of a single-canal single-rooted mandibular second molar. Clinicians should be aware of the various anatomic variations that each tooth may present in order to achieve a satisfactory result. Furthermore, in order to improve the quality of care delivered to their patients, practitioners must have the necessary knowledge and abilities to utilize the diagnostic and therapeutic instruments at their disposal.
Less

Comprehensive evaluation of root and root canal morphology of mandibular second molars in a Saudi subpopulation evaluated by cone-beam computed tomography

Background The study's goal was to use Cone Beam Computed Tomography (CBCT) to assess the root and root canal anatomy of mandibular second molars with C-shaped root canal configurations in residents of the Hail district. The impact of gender and side on the frequency of root canal morphology was co...
More

Background The study's goal was to use Cone Beam Computed Tomography (CBCT) to assess the root and root canal anatomy of mandibular second molars with C-shaped root canal configurations in residents of the Hail district. The impact of gender and side on the frequency of root canal morphology was considered. Methods The sample size for this study was 304 untreated mandibular second molars with completely developed roots on the right and left sides. Using CBCT on the teeth, the root form and canal morphology for each root are based on Vertucci's classification. The occurrence of canals in the shape of a C. The prevalence and resemblance of the left and right sides or men and females were investigated. The Chi-square test was performed to evaluate the findings. Results Of the 304 mandibular second molars studied, 286 teeth had two roots (94.1%), whilst 13 (4.3%) were C-shaped root canal systems. 77 molars (25.3%) had two canal orifices, 219 (72.0%) had three canal orifices, and six (2.0%) and one (0.3%) had four and five root canal orifices, respectively. Type IV was the most common for mesial root, accounting for 57.7% of the sample (n = 176). For distal root, the most common occurrence was type I, which occurred 282 times (96.60%). The most prevalent root canal morphology was the presence of two canals in the mesial root and one canal in the distal root of teeth with two distinct roots (variant 3). (69.4%). The overall prevalence of C-shaped root canal systems is (4.3%) (n = 13). Conclusions The patient's race is an undeniable factor that influences root canal anatomy. The root canal morphology of mandibular second molars revealed significant differences between Saudi subpopulations. The majority of mandibular second molars had two roots and three root canals. When treating these molars, the presence of a C-shaped root canal system must be taken into account.
Less