Evaluation of the international Ki67 working group cut point recommendations for early breast cancer: comparison with 21-gene assay results in a large integrated health care system.

PURPOSE: The International Ki67 Working Group (IKWG) has developed training for immunohistochemistry (IHC) scoring reproducibility and recommends cut points of ≤ 5% and ≥ 30% for prognosis in ER+, HER2-, stage I/II breast cancer. We examined scoring reproducibility following IKWG training and evaluated these cut points for selecting patients for further testing with the 21-gene Recurrence Score (RS) assay. METHODS: We included 307 women aged 50+ years with node-negative, ER+PR+HER2- breast cancer and with available RS results. Slides from the diagnostic biopsy were stained for Ki67 and scored using digital image analysis (IA). Two IHC pathologists underwent IKWG training and visually scored slides, blinded to each other and IA readings. Interobserver reproducibility was examined using intraclass correlation (ICC) and Kappa statistics. RESULTS: Depending on reader, 8.8-16.0% of our cohort had Ki67 ≤ 5% and 11.4-22.5% had scores ≥ 30%. The ICC for Ki67 scores by the two pathologists was 0.82 (95% CI 0.78-0.85); it was 0.79 (95% CI 0.74-0.83) for pathologist 1 and IA and 0.76 (95% CI 0.71-0.80) for pathologist 2 and IA. For Ki67 scores ≤ 5%, the percentages with RS < 26 were 92.6%, 91.8%, and 90.9% for pathologist 1, pathologist 2, and IA, respectively. For Ki67 scores ≥ 30%, the percentages with RS ≥ 26 were 41.5%, 51.4%, and 27.5%, respectively. CONCLUSION: The IKWG's Ki67 training resulted in moderate to strong reproducibility across readers but cut points had only moderate overlap with RS cut points, especially for Ki67 ≥ 30% and RS ≥ 26; thus, their clinical utility for a 21-gene assay testing pathway remains unclear.

Cytotoxicity and Genotoxicity of Epoxy Resin-Based Root Canal Sealers before and after Setting Procedures.

Epoxy resin-based sealers are commonly used for successful endodontic treatment. This study aimed to evaluate the cytotoxicity and genotoxicity of epoxy resin-based sealers under unset and set conditions. Three epoxy resin-based sealers were used: Adseal, AH Plus, and Dia-Proseal. To test cytotoxicity, an agar overlay test and a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay were performed using unset and set sealers on L929 mouse fibroblasts. The genotoxicity test of the comet assay was performed using the same cell line. Extract dilutions in the culture media were used as test materials for the MTT and comet assays. The comet tail produced by the damaged DNA was calculated by image analyses. Statistical analyses were performed using one-way analysis of variance and Tukey's post hoc test. Unset sealers did not show defined decolorized areas. Hardened specimens of resin-based sealers showed circular discolored zones in the agar overlay test. Dia-Proseal was the least cytotoxic after hardening. These results were confirmed in the MTT assay. Cell viability was significantly higher in cells treated with hardened sealers in both groups than that in cells treated with freshly mixed sealers in the MTT assay. Unset AH Plus® and Dia-Proseal™ significantly increased cell viability with decreasing dilution. Adseal™ was the least cytotoxic. Freshly mixed Adseal™ was more genotoxic when freshly mixed than when set. Unset epoxy resin-based sealers were generally more cytotoxic and genotoxic than set materials. Cytotoxicity does not always match the genotoxicity results; therefore, various test tools are required to test toxicity. It is necessary to properly evaluate the toxic effects to establish a biocompatibility test that mimics clinical conditions.

Effects of Fucoidan Powder Combined with Mineral Trioxide Aggregate as a Direct Pulp-Capping Material.

The development of direct pulp-capping materials with favorable biological and structural properties is an important goal in restorative dentistry. Fucoidan is a sulfated, fucose-containing polysaccharide obtained from brown seaweed, with a wide range of applications; however, its use as a direct pulp-capping material has not been examined. This study aimed to evaluate the mechanical, physical, and biological effects of fucoidan combined with conventional mineral trioxide aggregate (MTA) for direct pulp capping. The capping materials were created using Portland cement (80 wt%) and zirconium oxide (20 wt%) as base components, compared with base components plus 5 wt% fucoidan (PZF5) and base components plus 10 wt% fucoidan (PZF10). The initial and final setting time, compressive strength, chemical components, cell viability, adhesion, migration, osteogenesis, and gene expression were analyzed. Fucoidan significantly reduced the initial and final setting time, regardless of quantity. However, the compressive strength was lower for PZF5. Sulfur levels increased with fucoidan. The biological activity improved, especially in the PZF5 group. Cell migration, Alizarin Red S staining, and alkaline phosphatase activity were upregulated in the PZF5 group. Fucoidan is a useful regenerative additive for conventional pulp-capping materials because it reduces the setting time and improves cell migration and osteogenic ability.

Evaluation of Tensile Bond Strength between Self-Adhesive Resin Cement and Surface-Pretreated Zirconia.

The tensile bond strength between zirconia subjected to different surface-pretreatment methods and methacryloyloxydecyl-dihydrogen-phosphate (MDP)-containing self-adhesive resin cement was evaluated herein. Eighty-eight cylindrical zirconia specimens were randomly divided into the following four groups based on the pretreatment method: (1) no treatment, (2) air abrasion, (3) HNO3/HF etching, and (4) zirconia-nanoparticle coating. The tensile bond strength of the zirconia−resin-cement complexes was investigated. One-way ANOVA and post hoc tests were performed at a 95% significance level, and the Weibull modulus was calculated. Fracture patterns were visualized by SEM. The surface roughness of the specimens without resin bonding was evaluated by AFM. The tensile bond strength of the specimens decreased as follows: Groups 3 > 4 > 2 > 1 (28.2 ± 6.6, 26.1 ± 5.7, 16.6 ± 3.3, and 13.9 ± 3.0 MPa, respectively). Groups 3 and 4 had significantly higher tensile bond strengths (p < 0.05) and lower fracture probabilities than those of Groups 1 and 2. They also showed both mixed failure and resin-cement cohesive failure, whereas Groups 1 and 2 showed mixed failure exclusively. The zirconia−resin tensile bond was stronger after HNO3/HF etching or ZrO2-nanoparticle coating than after air abrasion or no treatment. The estimated surface roughness decreased as follows: Groups 3 > 4 > 2 > 1. The combination of zirconia pretreated with HNO3/HF etching or ZrO2-nanoparticle coating and an MDP-containing self-adhesive resin cement can increase the clinical longevity of zirconia restorations by preventing their decementation.

Mitotic counts in one high power field in breast core biopsies is equivalent to counts in 10 high power fields.

Mitotic rate is an important prognostic predictor in invasive breast carcinoma. Current guidelines recommend counting mitoses from 10 contiguous high power fields (HPFs) in the core biopsy. We propose a method to score mitotic activity in 1 HPF at the most mitotically active area of the tumour edge, or the interface between invasive tumour and benign breast tissue. We propose a score of 1, 2, or 3, corresponding to ≤1, 2, or ≥3 mitoses in 1 HPF, respectively. A total of 141 breast core biopsies with corresponding surgical excisions were blindly examined. We counted the number of mitotic figures in 1 HPF and in 10 contiguous HPFs in the core biopsy and compared with the mitotic count from 10 contiguous HPFs in the excision which is considered the gold standard. Concordance rates and interobserver agreement rates were calculated. The concordance rate was 82.3%, 78.7% and 82.3% between 1 HPF versus 10 HPFs in the core biopsy, 1 HPF in the core biopsy versus 10 HPFs in the excision and 10 HPFs in the core biopsy vs 10 HPFs in the excision, respectively. In the core biopsy, all three investigators agreed in 73.8% and 83.7% of the cases using the 1 HPF method and the 10 HPFs method, respectively; in the excision specimen, agreement was reached in 82.3% of the cases. The 1 HPF method showed similar concordance rate and interobserver agreement compared to the conventional method in the prediction of the mitotic score in the excision in all score groups. When stratified by mitotic score, the 1 HPF method predicted superior correlation with excision in the score 1 group than the 10 HPFs method, but not in the score 2 or 3 groups. From these findings we conclude that the proposed 1 HPF method can be used in clinical practice to grade invasive breast carcinomas in core biopsies, with the possibility of being utilised in small biopsies with less than 10 HPFs of invasive carcinoma.

Visual and anatomical outcomes associated with treat-and-extend administration of intravitreal aflibercept for neovascular age-related macular degeneration.

PURPOSE: To investigate the visual and anatomical outcomes associated with treat-and-extend (TAE) regimen of intravitreal (IVT) aflibercept in eyes with treatment naïve neovascular age-related macular degeneration (nvAMD). METHODS: A retrospective chart review of eyes that underwent IVT aflibercept injections for nvAMD between May 2014 and March 2018 was performed. The primary outcome was the change in best corrected visual acuity (BCVA) at 12 months. Secondary outcomes included the change in central retinal thickness (CRT), subretinal fluid (SRF) and intraretinal fluid (IRF). RESULTS: Data from 213 eyes of 213 patients (138 female, 65%) met the inclusion criteria. The mean (SD) age of the patients was 80.4 (± 9.2) years. The mean baseline BCVA (0.92 ± 0.50 logMAR, improved by 0.20 (± 0.40) logMAR units at 12 months (p < 0.001). Seventy-two (34%) eyes gained ≥ 0.3 logMAR and 47 (22%) eyes achieved BCVA ≤ 0.3 logMAR at 12 months. Baseline BCVA, patient age, and the number of aflibercept injections received were predictors of the change in BCVA at 12 months. Mean CRT improved from 347 (± 117) µm at baseline to 246 (± 55) µm at 12 months (p < 0.001). The percentage of eyes with SRF and IRF on SD-OCT declined from 63 to 21% and from 60 to 26% at 12 months, respectively. CONCLUSION: A TAE regimen of IVT aflibercept in treatment naïve nvAMD is associated with good visual and anatomical outcomes in routine clinical practice. Resolution of exudation occurred in about half of nvAMD cases at 12 months. Individualized administration of IVT aflibercept may reduce injection burden.

Topography of choriocapillaris flow deficit predicts development of neovascularization or atrophy in age-related macular degeneration.

PURPOSE: To evaluate the relationship between choriocapillaris (CC), flow deficits (FD), and structural optical coherence tomography (OCT) biomarkers, and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy (cRORA) or macular neovascularization (MNV). METHODS: Consecutive patients with iAMD were sequentially reviewed to define three equal sized groups: progressed to MNV, progressed to cRORA, or remained stable over 12 months of follow-up. Odds ratios for progression to cRORA and MNV were estimated by logistic regression for intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), subretinal drusenoid deposits (SDDs), high central drusen volume, fellow eye with late AMD, and peripheral and central CC FD. RESULTS: Thirty iAMD eyes from 30 patients were enrolled into each group. The CC FD was greater in the peripheral sectors of the macula of eyes which progressed to cRORA compared to the other two groups (P < 0.0001). The central CC FD was also significantly impaired in eyes that progressed to cRORA or MNV compared to eyes that did not progress (P = 0.001 and P = 0.02, respectively). CC FD in the peripheral macula was significantly and independently associated with the development of cRORA, while CC FD in the center was significantly and independently associated with the development of MNV. CONCLUSIONS: While the CC is diffusely impaired throughout the macula in iAMD eyes that progress to cRORA, it is relatively spared in the more peripheral macula among eyes which progress to MNV. These differential findings may have implications for the pathophysiology of the different late-stage manifestations of AMD.

CHORIOCAPILLARIS FLOW DEFICITS AS A RISK FACTOR FOR PROGRESSION OF AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the association between choriocapillaris (CC) flow deficits and structural optical coherence tomography biomarkers and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy. METHODS: Retrospective analysis of consecutive patients with iAMD with a minimum follow-up of 12 months. Odds ratios of intraretinal hyperreflective foci, hyporeflective drusen cores, subretinal drusenoid deposits, the presence of drusen volume ≥0.03 mm3 within a central 3-mm circle, fellow eye with late stage of AMD, and CC flow deficits at baseline and months of follow-up were estimated from logistic regression. RESULTS: A total of 112 eyes with iAMD were included. Eyes that progressed were significantly more likely to show intraretinal hyperreflective foci, hyporeflective drusen cores, and drusen volume ≥0.03 mm3. The CC flow deficit was also significantly greater in eyes that developed complete retinal pigment epithelial and outer retinal atrophy. Intraretinal hyperreflective foci, hyporeflective drusen cores, drusen volume ≥0.03 mm3, and higher CC flow deficits were significantly and independently associated with the development of complete retinal pigment epithelial and outer retinal atrophy. CONCLUSION: The CC flow deficit was significantly greater in iAMD eyes that progressed to complete retinal pigment epithelial and outer retinal atrophy and remained an independent risk factor when structural optical coherence tomography biomarkers were considered. CC flow deficits may be useful for enhancing risk stratification and prognostication of patients with iAMD.

Initial Evaluation of a Novel Modulated Radiofrequency-based Bladder Denervation Device.

OBJECTIVE: To determine if targeted and modulated radiofrequency ablation (RFA) of the urinary bladder using our novel ablation device (Denerblate) reduces bladder nerve density, potentially leading to a novel strategy for the management of overactive bladder. METHODS: Fifteen pigs were divided into 4 groups: control (n = 3), 1-week (n = 4), 4-week (n = 4) and 12-week (n = 4) survival times. Denerblate was deployed on the trigone area of the bladder. Three 240-second cycles of modulated RFA were applied with 30 seconds between cycles. At the end of each survival term, urinary bladders were harvested for histopathologic evaluation. Nerve count and density were manually calculated. RESULTS: All procedures were successfully completed, and all animals survived to the desired time points. Mean nerve density (nerves/mm2) was highest in the control and 1-week survival group compared to the 4-week and 12-week groups, both of which demonstrated significant diminishment. Nerve density in the bladder neck at control, 1 week, 4 weeks, and 12 weeks were 1.8, 1.35, 0.87, and 0.12, respectively (P <.001). Nerve density in the bladder trigone area at control, 1 week, 4 weeks, and 12 weeks were 1.5, 0.98, 0.65, and 0.112, respectively (P <.001). Epithelial heat injury was observed in 14.3% at 1 week, 10.7% at 4 weeks, but completely resolved by 12 weeks. CONCLUSION: In the porcine model, modulated RFA delivered by our novel device reduced nerve density in the bladder neck and trigone by 88.6% and 88.9% at 12 weeks without evidence of lasting epithelial injury.

Laser Endoscopic X-Ray-Guided Intrarenal Tract: Comparison Among Renal Access Modalities in the Porcine Kidney.

Introduction and Objectives: Laser endoscopic X-ray-guided intrarenal tract (LEXIT) is a recently described holmium laser retrograde access technique for creating percutaneous access during a percutaneous nephrolithotomy. We compared bleeding, ease of access, and the time to achieve access for each of the following three modalities: LEXIT, retrograde Lawson puncture wire, and antegrade 18-gauge nephrostomy needle access in the porcine kidney. Methods: Eight pigs underwent an average of five nephrostomy accesses per kidney under simultaneous laparoscopic vision at 5 mm Hg insufflation pressure. Data collected included: access time (seconds), bleeding intensity (scale: 1 [no bleeding] - 10 [severe bleeding]), bleeding duration (seconds), accuracy of caliceal entry, and surgeon comfort with the technique (scale: 1 [very easy] - 10 [very difficult]). Results: A total of 64 nephrostomy accesses were obtained. The speed of nephrostomy access with LEXIT was significantly faster than the nephrostomy needle and Lawson wire (p < 0.001). Bleeding intensity (p = 0.002) and severity (p = 0.001) were lower with the Lawson puncture wire, followed by LEXIT and then by the nephrostomy needle. LEXIT was rated as easier in acquiring access within the upper pole (p = 0.003) and interpolar calices (p < 0.001). Histopathology demonstrated no difference in parenchymal damage between LEXIT and nephrostomy needle (p = 0.18); however, LEXIT was associated with significantly increased peri-tract thermal injury, although within a narrow focus of 1.6 mm (p < 0.01). Conclusion: Among the three renal access techniques, LEXIT provided the fastest access times and greatest ease of access specifically for upper pole and interpolar calices. Also, bleeding with LEXIT was significantly less compared with the standard antegrade nephrostomy needle access. Histopathological analysis demonstrated that the holmium laser resulted in focal thermal tissue effects similar in range to the blunt tissue trauma caused by the 18-gauge nephrostomy needle.

Expression and prognostic utility of PD-L1 in patients with squamous cell carcinoma of the bladder.

OBJECTIVES: Checkpoint inhibitors are approved for the treatment of urothelial bladder cancer. However, there have been no reports on the prognostic value of programmed-death receptor ligand 1 (PD-L1) expression in squamous cell carcinoma (SCC) of the bladder. We assessed the relationship between PD-L1 expression, clinicopathological features, and oncologic outcomes in bladder SCC. METHODS AND MATERIALS: Immunohistochemistry of PD-L1 was performed on 151 radical cystectomy specimens with pure SCC treated in Mansoura, Egypt from 1997 to 2004. RESULTS: Median patient age was 52 years (range: 36-74 years) and median length of follow up was 63 months (range: 1-100 months). Schistosomiasis was present in 81% of the specimens and 93% had muscle-invasive disease on pathologic staging. PD-L1 expression was negative in 50 (33%) of the specimens. Negative PD-L1 expression was associated with higher pathologic tumor stage (P = 0.04), higher grade lesions (P = 0.01), and the presence of lymphovascular invasion (P < 0.01). Kaplan-Meier analyses showed that negative PD-L1 expression is associated with worse recurrence-free (P = 0.01) and worse cancer-specific survival (P = 0.01). Multivariable Cox regression analyses showed negative PD-L1 expression was an independent predictor of disease recurrence (hazards ratio 2.05, 95% confidence interval 1.06-3.96, P = 0.03) and cancer-specific mortality (hazards ratio 2.89, 95% confidence interval 1.22-6.82, P = 0.02). CONCLUSIONS: Negative PD-L1 expression is associated with higher pathologic tumor stage, higher grade lesions, presence of lymphovascular invasion, and worse oncologic outcomes after radical cystectomy for SCC. These findings support the need for the inclusion of patients with bladder SCC into immunotherapy clinical trials.

Carving out another slice of the pie: Exceptional response to single agent imatinib in an asian female never-smoker with advanced NSCLC with a de-novo PDGFR-α N848 K mutation.

Non-small cell lung cancer (NSCLC) has emerged as a paradigm for clinical application of precision medicine as optimal therapy is commonly chosen based on genomic biomarkers identified in a patient's tumor sample. Recurrent driver alterations are well described, however, a need to continually identify rare variants remains clinically relevant. We identified an incident case of advanced NSCLC with a PDGFR-α N848 K activation loop mutation with no other concurrent oncogenic drivers. Amino acid sequence alignment confirmed homology to the imatinib-sensitive KIT N822 K activation loop mutation observed in GIST. The patient achieved a 2-year response to single agent imatinib that is ongoing. While PDGFR-α N848 K is rare among public sequencing databases our cases strongly suggests functional relevance and highlights the importance of studying rare variants in NSCLC.

Spectrum of Cribriform Proliferations of the Prostate: From Benign to Malignant.

CONTEXT: - The presence of cribriform glands/ducts in the prostate can pose a diagnostic challenge. Cribriform glands/ducts include a spectrum of lesions, from benign to malignant, with vastly different clinical, prognostic, and treatment implications. OBJECTIVE: - To highlight the diagnostic features of several entities with a common theme of cribriform architecture. We emphasize the importance of distinguishing among benign entities such as cribriform changes and premalignant to malignant entities such as high-grade prostatic intraepithelial neoplasia, atypical intraductal cribriform proliferation, intraductal carcinoma of the prostate, and invasive adenocarcinoma (acinar and ductal types). The diagnostic criteria, differential diagnosis, and clinical implications of these cribriform lesions are discussed. DATA SOURCES: - Literature review of pertinent publications in PubMed up to calendar year 2017. Photomicrographs obtained from cases at the University of California at Irvine and authors' collections. CONCLUSIONS: - Although relatively uncommon compared with small acinar lesions (microacinar carcinoma and small gland carcinoma mimickers), large cribriform lesions are increasingly recognized and have become clinically and pathologically important. The spectrum of cribriform lesions includes benign, premalignant, and malignant lesions, and differentiating them can often be subtle and difficult. Intraductal carcinoma of the prostate in particular is independently associated with worse prognosis, and its presence in isolation should prompt definitive treatment. Patients with atypical intraductal cribriform proliferation, intraductal carcinoma of the prostate, or even focal cribriform pattern of invasive adenocarcinoma in biopsies would not be ideal candidates for active surveillance because of the high risk of adverse pathologic findings associated with these entities.

Diagnosis of paraganglioma as a pancreatic mass: A case report.

Paragangliomas are rare neoplasms that arise from the chromaffin cells of the autonomic nervous system. Although paragangliomas can occur anywhere paraganglia are present, they tend to occur in the head, neck, and retroperitoneum. Rarely, paragangliomas can occur in the peripancreatic area and present as a pancreatic mass, creating a diagnostic challenge for the clinician, radiologist, and pathologist. Here, we present a case of a 70-year-old woman with history of breast carcinoma who presented with chronic constipation, early satiety, and an abdominal mass. Her first abdominal CT described a 3.6 cm × 5 cm × 4.5 cm cystic and solid mass involving the pancreatic tail that was suspicious for a pancreatic neoplasm. A subsequent abdominal CT described a 5.9 cm multilobulated solid and cystic lesion close to the pancreatic tail. Endoscopic ultrasound-guided fine-needle aspirate of the mass demonstrated scant to moderate cellularity of a heterogeneous population of atypical cells, some with epithelioid morphology and others appearing neuroendocrine-like. By morphology and immunohistochemical stains, an extra-adrenal paraganglioma or pheochromocytoma was considered as a possible diagnosis. The surgical resection specimen confirmed the diagnosis of paraganglioma. This case demonstrates the importance of awareness of paragangliomas in the differential diagnosis of a fine-needle aspiration of a pancreatic mass to avoid erroneous diagnosis.

Multi-institutional Evaluation of Upper Urinary Tract Biopsy Using Backloaded Cup Biopsy Forceps, a Nitinol Basket, and Standard Cup Biopsy Forceps.

OBJECTIVE: To compare the performance of 3 contemporary ureteroscopic biopsy devices for the histopathologic diagnosis of upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively reviewed 145 patients who underwent 182 urothelial biopsies using 2.4F backloaded cup biopsy forceps, a nitinol basket, or 3F standard cup biopsy forceps at 3 tertiary academic centers between 2011 and 2016. Experienced genitourinary pathologists provided an assessment of each specimen without knowledge of the device used for biopsy. For patients who underwent nephroureterectomy without neoadjuvant chemotherapy within 3 months of biopsy-proven UTUC diagnosis, the biopsy grade was compared with both the grade and stage of the surgical specimen. RESULTS: Biopsy utilization varied among the 3 institutions (P <.0001). Significant variabilities in specimen size (P = .001), the presence of intact urothelium (P = .008), and crush artifact (P = .028) were found among the biopsy devices. The quality of specimens from backloaded cup forceps was rated similarly to the nitinol basket (P >.05) and was favored over standard cup forceps specimens. Grade concordance was not affected by specimen size (P >.05), morphology (P >.1), or location (P >.5). No difference existed among the devices in the rate of acquiring a grade concordant biopsy; however, the backloaded cup forceps provided concordant biopsies that could be distinguished as low- and high-grade (P = .02). CONCLUSION: The backloaded cup forceps and nitinol basket obtained a higher quality urothelial specimen compared with standard cup forceps. Ureteroscopic biopsy device selection did not significantly impact the accuracy of the histologic diagnosis of UTUC.

Diffusion-weighted imaging in hemorrhagic abdominal and pelvic lesions: restricted diffusion can mimic malignancy.

Diffusion-weighted imaging (DWI) is an increasingly utilized sequence in the assessment of abdominal and pelvic lesions. Benign lesions containing hemorrhagic products, with conglomerates of tightly packed blood cells or fibers, can have restricted water diffusion on DWI and apparent diffusion coefficient maps. Such lesions can have restricted diffusion erroneously attributed to malignancy. This review illustrates benign hemorrhagic lesions displaying restricted diffusion, with histopathologic correlation in relevant cases.

Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells.

BACKGROUND: Current and recent smoking have been associated with a greater risk of prostate cancer recurrence and mortality, though the underlying mechanism is unknown. METHODS: To determine if telomere shortening, which has been associated with poor outcomes, may be a potential underlying mechanism, we prospectively evaluated the association between smoking status and telomere length in 567 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays (TMA), we measured telomere length in cancer and benign tissue, specifically stromal cells in the same TMA spot using a telomere-specific fluorescence in situ hybridization assay. Smoking status was collected via questionnaire 2-years before diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per-cell telomere signals were determined for each man for stromal cells and cancer cells by smoking categories. In sub-analyses, we restricted to men without major co-morbidities diagnosed before prostate cancer. RESULTS: Overall, there were no associations between smoking status and telomere length or variability in stromal cells or cancer cells. However, among men without comorbidities, current smokers and former smokers who quit <10 years ago had the most variable telomere length in stromal cells (29.3% more variable than never smokers; P-trend = 0.0005) and in cancer cells (27.7% more variable than never smokers; P-trend = 0.05). Among men without comorbidities, mean telomere length did not differ by smoking status in stromal cells or cancer cells. CONCLUSION: Telomere variability in prostate cells may be one mechanism through which smoking influences poor prostate cancer outcomes.

Collision and composite tumors; radiologic and pathologic correlation.

The terms composite and collision tumors have been used interchangeably throughout radiological literature. Both composite and collision tumors involve two morphologically and immunohistochemically distinct neoplasms coexisting within a single organ. However, collision tumors lack the histological cellular intermingling seen in composite tumors. Composite tumors often arise from a common driver mutation that induces a divergent histology from a common neoplastic source while collision tumors may arise from coincidental neoplastic change. The purpose of this review is to provide an overview of abdominal composite and collision tumors by discussing hallmark radiographic and pathological presentations of rare hepatic, renal, and adrenal case studies. A better understanding of the presentation of each lesion is imperative for proper recognition, diagnosis, and management of these unique tumor presentations.

Dual occurrence of ALK G1202R solvent front mutation and small cell lung cancer transformation as resistance mechanisms to second generation ALK inhibitors without prior exposure to crizotinib. Pitfall of solely relying on liquid re-biopsy?

Development of the acquired ALK G1202R solvent front mutation and small cell lung cancer (SCLC) transformation have both been independently reported as resistance mechanisms to ALK inhibitors in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients but have not been reported in the same patient. Here we report an ALK+ NSCLC patient who had disease progression after ceritinib and then alectinib where an ALK G1202R mutation was detected on circulating tumor (ct) DNA prior to enrollment onto a trial of another next generation ALK inhibitor, lorlatinib. The patient's central nervous system (CNS) metastases responded to lorlatinib together with clearance of ALK G1202R mutation by repeat ctDNA assay. However, the patient developed a new large pericardial effusion. Resected pericardium from the pericardial window revealed SCLC transformation with positive immunostaining for synaptophysin, chromogranin, and ALK (D5F3 antibody). Comprehensive genomic profiling (CGP) of the tumor infiltrating pericardium revealed the retainment of an ALK rearrangement with emergence of an inactivating Rb1 mutation (C706Y) and loss of exons 1-11 in p53 that was not detected in the original tumor tissue at diagnosis. The patient was subsequently treated with carboplatin/etoposide and alectinib, but had rapid clinical deterioration and died. The patient never received crizotinib. This case illustrates that multiple/compound resistance mechanisms to ALK inhibitors can occur and provide supporting information that loss of p53 and Rb1 are important in SCLC transformation. If clinically feasible, tissue-based re-biopsy allowing histological examination and CGP remains the gold standard to assess resistance mechanism(s) and to direct subsequent rational clinical care.

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers.

BACKGROUND: Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer-specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios. MATERIALS AND METHODS: We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next-generation sequencing-based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities. RESULTS: A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination. CONCLUSIONS: Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. The Oncologist 2017;22:152-157Implications for Practice: Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic problem but has important prognostic and therapeutic implications. Approaches to aid histologic analysis may improve clinician and pathologist confidence in this increasingly common clinical scenario. Our series provides early support for incorporating paired comprehensive genomic profiling in clinical situations in which determination of metastatic recurrence versus a distinct second primary cancer would influence patient management.