The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which ...generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29(hi)24(med), and these cells are tumorigenic, whereas CD29(med)24(-/lo) and CD29(med)24(hi) cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29(hi)24(med); these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant-derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29(hi)24(med) populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance.
Objective
Targeted therapy is an important part of the treatment of lung adenocarcinoma. Tests for EGFR mutation, ALK, ROS1, RET and NTRK gene fusions are needed to make a treatment decision. These ...gene fusions are traditionally detected by fluorescence in situ hybridisation (FISH) or immunohistochemistry. In this study, we investigated whether gene fusions in pulmonary adenocarcinoma could be accurately detected by RNA next‐generation sequencing (RNA‐NGS) and whether cytology cell blocks could be used effectively for this test.
Methods
Archived cytological specimens of lung adenocarcinoma submitted for RNA sequencing between 2019 and 2022 at Fox Chase Cancer Center were retrospectively retrieved. Hybrid capture‐based targeted RNA next generation sequencing was used, which covers 507 fusion genes, including ALK, ROS1, RET and NTRKs, irrespective of their partner genes. DNA NGS, FISH and chromosomal microarray analysis were used to confirm the results of the RNA‐NGS.
Results
A total of 129 lung adenocarcinoma cytology specimens were submitted for molecular testing. Eight of 129 (6.2%) cases were excluded from RNA sequencing as their cell blocks contained inadequate numbers of tumour cells. One case (0.8%) failed to yield adequate RNA. The overall success rate was 93% (120/129). Ten of 120 (8.3%) cytology cases were positive for gene fusions, including 7 ALK, 2 ROS1 fusion genes, and 1 RET fusion gene. Twenty‐two cell block cases were also tested for ALK fusion genes using FISH. However, 11 of 22 (50%) failed the testing due to inadequate material.
Conclusions
Cytology cell blocks can be used as the main source of material for molecular testing for lung cancer. Detection of gene fusions by RNA‐based NGS on cell blocks is convenient and reliable in daily practice.
Gene fusions of EML4‐ALK, RDX‐ROS1 and KIF5B‐RET.
Sarcomatoid renal cell carcinoma is a highly aggressive tumor. It is not a distinct histologic entity as it can be found in any subtypes of renal cell carcinoma. Recent molecular and genetic evidence ...suggest that sarcomatoid component is transformed from a common progenitor of the associated renal cell carcinoma, and the TP53 gene plays a pivotal role in this process. The presence of sarcomatoid carcinoma indicates poor prognosis, which also correlates with the amount of the sarcomatoid component. Therefore, the presence and quantity of sarcomatoid component should be reflected in pathology reports. However, pathology reporting seems to vary among laboratories prompting the need for a unified reporting system. We propose a pathology reporting system similar to that of transformed follicular lymphoma that is consistent with the molecular pathogenesis to ensure uniform reporting.
Endobronchial ultrasound (EBUS)-guided transbronchial needle aspirate (TBNA) is a widely used method of minimally invasive lymph node sampling. The benefit of processing samples by cytologic methods ...versus “core biopsy” is unclear. It is unknown if safety or diagnostic yield varies by needle gauge.
Between June 2018 and July 2019, 40 patients (56 lesions) undergoing EBUS TBNA lymph node evaluation were enrolled in this single-center prospective trial. Patients were chosen by permuted block randomization to undergo EBUS TBNA starting with 22-gauge (22g) or 19-gauge (19g) needles. Separate samples were sent for processing by cytologic methods and histopathology. Surgical pathologists and cytopathologists were blinded to needle size. The primary endpoint was diagnostic yield. Secondary endpoints compared specimen adequacy by rapid onsite evaluation (ROSE), sample adequacy for molecular testing, sample quality, and safety.
Diagnostic yield for histopathologic examination was 87.5% and 83.9% for 19g and 22g respectively (P = 0.625). There was no significant difference in diagnostic yield by cytologic examination based on needle size. There was no significant difference in slide quality. Molecular adequacy for core-biopsy was 77% and 80% for 22g and 19g needles, respectively. Molecular adequacy for cytology cell block was 77% and 80% for 22g and 19g needles, respectively. There were no significant procedural complications.
Both the 22g and 19g EBUS TBNA needles provided a similar diagnostic yield and clinical utility for ancillary testing. Processing techniques by cytologic methods or “core biopsy” showed no significant impact in diagnostic yield or utility of molecular testing.
Thyroglossal duct (TGD) is a developmental anomaly in which a remnant of the thyroid anlage is left in the neck during its descent from the foramen cecum of tongue to final pretracheal position. A ...persistent duct can lead to thyroglossal duct cyst (TGDC). Histologically, TGDC contains an epithelial lining of squamous or pseudostratified ciliated columnar epithelium and ectopic thyroid gland tissue in the duct wall. TGD-associated malignancy is rare, and the majority is papillary thyroid carcinoma (PTC). A total of 242 patients with a diagnosis of TGD-associated lesions were identified in our institute. Two hundred and seventeen cases were diagnosed as TGDC. Sixty-eight of 217 (31.3 %) cases of TGDC had ectopic thyroid tissue in the cystic wall. Thirty-nine cases had preoperative fine needle aspiration (FNA). Of these cases, 37 of 39 (94.9 %) demonstrated macrophages and 19 (48.7 %) also showed cells of squamous and/or columnar epithelial lining. Only two cases showed rare thyroid follicular cells. Thyroid carcinoma was identified in 18 of 242 (7.4 %) cases. All cases were diagnosed as PTC including 12 cases of classic PTC (66.7 %), 3 cases of follicular variant (16.7 %), 2 cases of tall cell variant (11.1 %), and 1 case of classic PTC with focal tall cell features (5.6 %). Nine cases had TGD component (either epithelial lining cysts or ectopic thyroid tissue). Ten patients also underwent total thyroidectomy (67 %). Of these patients, four had no tumor and one had an incidental medullary carcinoma. Five of 10 (50 %) cases had incidental PTC with a size range of 0.1–0.3 cm. Five patients had follow-up by imaging studies; no suspicious or nodular lesions were found in the thyroid. In conclusion, we report an institutional case cohort of 242 patients with TGD-associated lesions, including 217 TGDC and 18 cases of PTC. Only seven cases fulfilled the diagnostic criteria of TGD-associated PTC, i.e., the presence of components of TGD and a normal thyroid. In the remaining 11 cases, we could not differentiate with certainty between pyramidal primary thyroid PTC/Delphian node metastasis or TGD-associated PTC.
Splenosis is a benign condition that is often found in patients with a history of trauma. Most cases are intra-abdominal due to direct seeding of surrounding structures. We report a case of splenosis ...in the pelvis found in a 59-year-old male during a robotic prostatectomy.
Oncocytic adrenocortical tumors (OAT) are rare and often are non-functional. We report a unique case of an estradiol-secreting adrenal oncocytoma in a 31-year-old male discovered upon an infertility ...and gynecomastia work-up. After resection of the 9 cm adrenal mass, the patient's estradiol levels normalized from 83.2 pg/ml to 19.0 pg/ml. Gonadotropins and serum dehydroepiandrosterone sulfate also normalized.
Given the emergence of PSMA-targeted diagnostic agents and therapeutics, we sought to investigate patterns of
expression in RCC and their impacts on RCC outcomes.
We conducted a pooled ...multi-institutional analysis of patients with RCC having undergone DNA and RNA next-generation sequencing.
-high/low expression was defined as the ≥75th/<25th percentile of RNA transcripts per million (TPM). Angiogenic, T-effector, and myeloid expression signatures were calculated using previously defined gene sets. Kaplan-Meier estimates were calculated from the time of tissue collection or therapy start.
We included 1,724 patients in the analysis. FOLH1 expression was significantly higher in clear cell (71%) compared to non-clear cell RCC tumors (19.0 versus 3.3 TPM,
< 0.001) and varied by specimen site (45% primary kidney/55% metastasis, 13.6 versus 9.9 TPM,
< 0.001).
expression was correlated with angiogenic gene expression (Spearman = 0.76,
< 0.001) and endothelial cell abundance (Spearman = 0.76,
< 0.001). While OS was similar in patients with
-high versus -low ccRCC, patients with
-high clear cell tumors experienced a longer time on cabozantinib treatment (9.7 versus 4.6 months, respectively, HR 0.57, 95% CI 0.35-0.93,
< 0.05).
We observed differential patterns of
expression based on histology and tumor site in RCC.
was correlated with angiogenic gene expression, increased OS, and a longer duration of cabozantinib treatment.
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