Utility of The Paris System (TPS) for upper urinary tract cytopathology: correlation with histology follow-up and UroVysion fluorescence in situ hybridization (FISH) analysis.

INTRODUCTION: The Paris System (TPS) provides a uniform reporting system of urine cytology based on well-defined cytologic criteria. Due to their rarity, there are limited data on the utility of TPS in upper urinary tract (UUT) lesions and follow-up histology of cases with abnormal cytology. We aimed to evaluate the utility of TPS for UUT lesions by correlating the cytologic diagnoses using TPS criteria with subsequent histology. Additionally, the diagnostic utility of UroVysion (Abbott) fluorescence in situ hybridization (FISH) was assessed. MATERIALS AND METHODS: A total of 148 UUT cytology specimens were retrospectively identified (2018-2022). Cytologic interpretation was performed using TPS, and then correlated with the findings of concurrent or subsequent histologic specimens. The performance of UroVysion FISH was analyzed. Sensitivity and specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting high-grade urothelial carcinoma (HGUC) were determined. RESULTS: Among 83 patients who had concurrent or subsequent histologic specimens, cyto-histologic discrepancy was seen in 7 cases (8.4%). The sensitivity, specificity, PPV, and NPV using TPS criteria for detecting HGUC were 87%, and 92%, 96.4%, and 73%, respectively. UroVysion FISH was performed in 21 patients with atypical cytologic findings. The sensitivity and specificity of UroVysion for detecting HGUC was 75% and 86%, respectively, while PPV and NPV were 86% and 75%, respectively. CONCLUSIONS: In our experience, the application of TPS criteria for reporting upper urinary cytology was reliable at detecting UUT lesions, especially HGUC. UroVysion FISH was a valuable ancillary test for detecting HGUC of UUT.

Intraoperative evaluation of sentinel lymph nodes in patients with breast cancer treated with systemic neoadjuvant therapy.

AIMS: Touch preparation (TP) and frozen section (FS) are the two methods routinely used in the intraoperative evaluation (IOE) of sentinel lymph nodes (SLNs) to detect metastases in patients with breast cancer. Both methods are extremely sensitive and specific in the primary surgery (non-neoadjuvant systemic therapy (non-NST)) setting. Since NST introduces unique challenges in the IOE of SLNs, the aim was to determine the accuracy of TP and FS in the IOE of SLNs in the NST setting and compare the results with the non-NST setting and to examine factors that contribute to any differences. METHODS: We analysed 871 SLNs from 232 patients (615 SLNs from NST and 256 SLNs from non-NST settings) between 2016 through 2019. RESULTS: In the NST group, TP alone (n=366) had a sensitivity of 45.7% and specificity of 99.7%; FS alone (n=90) had a sensitivity of 83.3% and specificity of 100%. When both TP and FS (n=135) were used, the sensitivity was 80.3% and the specificity was 98.6%.In the non-NST group, TP alone (n=193) had a sensitivity of 66.7% and specificity of 100%; FS alone (n=22) had a sensitivity and specificity of 100%; and combined TP and FS (n=34) had a sensitivity and specificity of 100% and 96%, respectively. CONCLUSIONS: Evaluating SLNs intraoperatively in the NST setting can be challenging secondary to therapy-related changes. In the NST setting, FS has higher sensitivity and specificity compared with TP for the IOE of SLNs and should be the preferred method.

The current practice of telecytology for rapid on-site evaluation (ROSE): Practical considerations and limitations.

Advances in digital imaging technology and development of high-speed internet has brought a change in ROSE practice from the traditional in-person to remote evaluation. The rapid expansion of image-guided procedures to obtain tissues for diagnosis and ancillary testing has put a huge demand on cytopathologists' time to perform on-site adequacy assessment. The technology of transmitting digital slide images in real-time via the internet from procedure site that can be viewed remotely and provide preliminary diagnosis, has had a huge impact on the practice of ROSE. Telecytology (TC) has increased the efficiency of cytopathologists, by cutting down on travel time to procedure sites and eliminate the long wait time between procedures/needle passes. It also provides the cytopathologist with the flexibility of covering ROSE procedures occurring at several locations simultaneously. The options and design of TC systems are driven by clinical needs, availability of resources and case volume. A buy-in from stakeholders early in the process, infrastructure planning and information technology (IT) support are critical for the successful implementation of TC. Training of staff, validation study and compliance training should be performed according to established guidelines. There are different TC platforms commercially available in the market today, these include static image sharing, real-time video streaming, robotic microscopy and whole slide imaging (WSI). Additionally, low-cost TC system can be built and designed using equipment that are available off-the-shelf. The intent of this review is to highlight the current practices of TC, the pros and cons of each system are discussed.

Selective deployment of dynamic telecytology for rapid evaluation of cytology smears: assessment of workflow processes and role of cytopathology fellows as on-site operators.

INTRODUCTION: The deployment of telecytology (TC) requires a substantial investment of financial and human resources. To offset the high demand for rapid on-site evaluation, we performed a limited deployment of dynamic TC and have detailed the workflow processes and the role of trainees. MATERIALS AND METHODS: TC systems were installed in radiology suites with a high volume of cases. Validation was performed using retrospective and prospective cases. Cytotechnologists and cytopathology fellows were the operators of the instrument. TC malignant and benign diagnoses were correlated with the final sign-out diagnoses. RESULTS: Of the 120 cases, 50 (41.6%) were fine needle aspirations and 70 (58.3%) were touch imprint smears of core biopsy specimens. The cytotechnologists were the operators for 34 cases (28.3%) and cytology fellows for 86 cases (71.6%). Adequacy concordance with the final diagnosis was 100% and 98.5% in the retrospective and prospective cases, respectively. In the prospective cases, concordance of TC with the final diagnosis of malignancy was 42 of 45 (93.3%), with 2 of 45 (4.4%) discordant and a downgrade rate of 2.7%. For the benign diagnoses, the concordance was 90%. For the malignant diagnoses, the sensitivity of TC was 97.67% (95% confidence interval [CI], 87.71 to 99.94%; specificity, 81.82%; 95% CI, 48.22% to 97.72%). The positive predictive value was 95.45% (95% CI, 85.69% to 98.66%), the negative predictive value was 90.00% (95% CI, 55.98% to 98.45%), and the accuracy was 94.44% (95% CI, 84.61% to 98.84%). CONCLUSIONS: TC can be deployed in a limited fashion as an option for cytopathologists to offset the high demand for rapid on-site evaluations. Trainee participation in TC service is important for building confidence and honing their cytology skills.

Significance of Oil-Red-O positive macrophages in bronchoalveolar lavage in diagnosing E-cigarettes or vaping product use-associated lung injury: A case series.

BACKGROUND: Lipid-laden macrophages detected by Oil-Red-O (ORO) stain in fresh bronchoalveolar lavage (BAL) specimens have been proposed as a potential diagnostic marker for E-cigarettes or vaping product use-associated lung injury (EVALI). However, studies are few, and the sensitivity and specificity of the test have not been thoroughly investigated. METHODS: We performed ORO stain on fresh BAL specimens from six confirmed EVALI and 36 non-EVALI patients. After semi-quantitative analysis, the sensitivity and specificity of ORO-positive macrophages (OPM) for detection of EVALI were calculated. RESULTS: No significant difference in cytomorphology or raw macrophage count was observed between EVALI and non-EVALI groups (49% vs 55% of all nucleated cells). However, with ORO stain, all EVALI specimens (6/6) showed a high percentage (≥50% of all macrophages) of OPM (mean 87%), and large (≥25% of host macrophage nuclear size) lipid droplets (mean 42%), while the majority of non-EVALI specimens showed a low percentage of OPM (32/36, mean 10%), and small lipid droplets (34/36, mean 6%). The differences between the two groups in both high OPM and large lipid droplet rates are statistically significant (P < .0001 for both comparisons). The combined sensitivity and specificity of high OPM and large lipid droplets for diagnosing EVALI were 100% and 94%, respectively. CONCLUSION: In BAL specimens obtained from patients with clinically suspected EVALI, a high percentage of OPM with large lipid droplets showed high sensitivity and specificity for the diagnosis of EVALI and may serve as a potentially useful tool in the evaluation of vaping-related lung injury, improving diagnostic accuracy.

Secondary Angiosarcoma With C-MYC Amplification Following Prophylactic Bilateral Mastectomy and Autologous Breast Reconstruction: Report of a Case and Review of the Literature.

In this article, we report a very rare case of secondary angiosarcoma in a young woman with no prior history of breast cancer who had bilateral prophylactic mastectomies with autologous reconstruction due to a strong family history of breast cancer and BRCA1 gene variant of uncertain significance. The surgery was complicated by recurrent fat necrosis requiring several excisions and additional reconstruction followed by the development of localized lymphedema and subsequent angiosarcoma in the reconstructed breast 10 years later. The angiosarcoma was high grade with prominent epithelioid features associated with abundant tumor-infiltrating lymphocytes. Amplification of C-MYC locus 8q21.24 was demonstrated by fluorescence in situ hybridization study. We postulate that chronic trauma from several surgeries including tissue hypoxia and impaired lymphatic drainage may have provided a milieu for angiogenesis and mutagenic transformation. Amplification of C-MYC locus 8q21.24 was most likely a strong oncogenic driver of angiosarcoma. To the best of our knowledge, this is the first report of its kind in the literature.

Stereotactic Vacuum-Assisted Needle Biopsy Outcomes of Non-calcified Mammographic Lesions.

RATIONALE AND OBJECTIVES: To identify the outcomes of stereotactic vacuum-assisted large bore biopsies performed on sonographically-occult non-calcified mammographic lesions (NCL). MATERIALS AND METHODS: In an IRB-approved retrospective study, we reviewed all NCL that underwent stereotactic biopsy from January 1, 2014 to December 31, 2017 at our institution, comparing patient age, lesion type, size and location with pathology outcome (benign, high-risk or malignant) using Wilcoxon-Mann-Whitney or Fisher's exact tests as appropriate. Multivariable logistic regression models were developed to decrease benign biopsies in our cohort with diagnostic performance assessed using receiver operating characteristic curve and area under the curve (AUC). RESULTS: Of 222 biopsied lesions in 213 patients, 79.3% (176/222) were benign, 5.9% (13/222) malignant, and 14.9% (33/222) high-risk. NCL were less likely to be malignant compared to calcifications biopsied in the same period [5.9% vs 19.0% (243/1279), p < 0.001]. All 42 asymmetries and 33 architectural distortions were benign, while 8.7% (4/46) of masses and 8.9% (9/101) of focal asymmetries were malignant. Cancers were associated with older age (mean 65.2 vs 52.7 years, p < 0.001), smaller size (mean 9.5 mm vs 15.5 mm, p < 0.01), and concurrent breast cancer (p < 0.01) compared to benign/high-risk lesions. Multivariable logistic regression model using patient age >50 years, lesion type, and size <15 mm had a high diagnostic performance [AUC=0.89, 95%CI (0.83, 0.94)], and yielded the highest PPV [0.24; 95%CI (0.13, 0.38)], and highest number of avoided, unnecessary biopsies (172/209, 82%). CONCLUSION: NCL biopsied under stereotactic guidance have low cancer yield (5.9%). A multivariate model integrating age, lesion size and type could potentially help avoid unwarranted biopsies in our cohort.

Performance of a clinical and imaging-based multivariate model as decision support tool to help save unnecessary surgeries for high-risk breast lesions.

PURPOSE: To investigate the performance of an imaging and biopsy parameters-based multivariate model in decreasing unnecessary surgeries for high-risk breast lesions. METHODS: In an IRB-approved study, we retrospectively reviewed all high-risk lesions (HRL) identified at imaging-guided biopsy in our institution between July 1, 2014-July 1, 2017. Lesions were categorized high-risk-I (HR-I = atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ and atypical papillary lesion) and II (HR-II = Flat epithelial atypia, radial scar, benign papilloma). Patient risk factors, lesion features, detection and biopsy modality, excision and cancer upgrade rates were collected. Reference standard for upgrade was either excision or at least 2-year imaging follow-up. Multiple logistic regression analysis was performed to develop a multivariate model using HRL type, lesion and biopsy needle size for surgical cancer upgrade with performance assessed using ROC analysis. RESULTS: Of 699 HRL in 652 patients, 525(75%) had reference standard available, and 48/525(9.1%) showed cancer at surgical excision. Excision (84.5% vs 51.1%) and upgrade (17.6%vs1.8%) rates were higher in HR-I compared to HR-II (p < 0.01). In HR-I, small needle size < 12G vs ≥ 12G [32.1% vs 13.2%, p < 0.01] and less cores [< 6 vs ≥ 6, 28.6%vs13.7%, p = 0.01] were significantly associated with higher cancer upgrades. Our multivariate model had an AUC = 0.87, saving 28.1% of benign surgeries with 100% sensitivity, based on HRL subtype, lesion size(mm, continuous), needle size (< 12G vs ≥ 12G) and biopsy modality (US vs MRI vs stereotactic) CONCLUSION: Our multivariate model using lesion size, needle size and patient age had a high diagnostic performance in decreasing unnecessary surgeries and shows promise as a decision support tool.

Role of cytotechnologists in rapid onsite adequacy assessment of cytology materials for diagnostic workup and specimen allocation for ancillary testing using a standardized protocol.

INTRODUCTION: Data on the performance of cytotechnologists in assessing specimen adequacy of needle core biopsies (NCB) is scant and their role in specimen triaging for ancillary studies have not been well established. MATERIALS AND METHODS: We retrospectively analyzed rapid onsite evaluation (ROSE) performed exclusively by cytotechnologists on 248 NCB and fine-needle aspiration (FNA) specimens. Overall adequacy and accuracy rates were determined by comparing to final diagnosis. We also reviewed the process of specimen allocation for ancillary testing to determine whether specimens were appropriately triaged at the time of ROSE. RESULTS: Of the 248 cases, 222 (89.5%) were touch imprint and 26 (10.5%) were FNA smears. The overall adequacy rate was 73.4% (182 of 248). Concordance for "adequate" interpretation by ROSE with unequivocal malignant or benign diagnoses on final interpretation was 95.6%. The sensitivity, specificity, and accuracy of ROSE for a final "positive for malignancy" were 89.2% (95% CI 83.04% to 93.69%), 43.24% (95% CI 31.77% to 55.28%), and 73.87% (95% CI 67.57% to 55.28%), respectively. Cases with "positive for malignancy" on final diagnosis were "adequate" by ROSE in 89.1% (132 of 148) and "inadequate" in 10.8% (16 of 148), P < 0.0001. Ancillary tests were performed in 168 of 248 (67.7%); the majority were immunohistochemical stains for determining tumor subtype. Predictive biomarkers were performed successfully in 100% of metastatic breast cancers. CONCLUSIONS: Cytotechnologists performed at a high level of competency in providing ROSE and allocating specimens for ancillary testing, which were performed successfully in the majority of cases. Implementation of a standardized protocol for tissue management/prioritization is of paramount importance to maximize tissue preservation and minimize wastage.

Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies.

CONTEXT.­: Immunohistochemical expression of mismatch repair (MMR) protein is a well-accepted method for routine screening for Lynch syndrome with relatively high sensitivity and specificity. Occasionally, however, immunohistochemistry (IHC) can yield an equivocal result with poor reproducibility and the potential for misdiagnosis. OBJECTIVE.­: To determine the frequency and significance of indeterminate MMR IHC expression in patients routinely screened for Lynch syndrome and correlation with germline mutation studies. DESIGN.­: Semiquantitative scoring of MMR IHC was performed by image analysis in 479 cases, of which 380 were colorectal and 99 endometrial cancer. Scores of 10% or more, less than 10%, and 0% were used as cutoffs for retained, indeterminate, and loss of expression, respectively. Negative and indeterminate IHC results were confirmed by mutational studies. RESULTS.­: Four hundred eighteen of 479 cases (87.2%) were reported as retained expression, 45 (9.3%) as loss of expression, and 16 (3.3%) as indeterminate expression. Fifteen of 45 (33.3%) and 8 of 16 (50%) with loss and indeterminate expression, respectively, were found to have Lynch syndrome by germline studies. The overall frequency of Lynch syndrome in our patient population was 4.8% (23 of 479), and 34.7% of these (8 of 23) were associated with indeterminate IHC expression. In the indeterminate group, MLH1 germline mutation was the most frequent (6 of 13; 46.2%), followed by MSH6 (4 of 13; 30.7%). CONCLUSIONS.­: Our findings provide further evidence that indeterminate IHC should be further investigated for possible MMR germline mutation. Guidelines for interpretation of MMR IHC and the establishment of more objective criteria for defining indeterminate results are important to improve the sensitivity and specificity of the IHC assay.

Phase 1 study of ARQ 761, a ß-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis.

BACKGROUND: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a ß-lapachone (ß-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death. METHODS: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200). RESULTS: A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m2 as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06). CONCLUSIONS: ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.

Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657).

PURPOSE: Several pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post-neoadjuvant pathologic tumor staging-residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)-have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined. METHODS: Using data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation. RESULTS: Among 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies. CONCLUSIONS: These data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse.

Using a novel NQO1 bioactivatable drug, beta-lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer.

Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2 O2 ) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells "hyperactivates" PARP1, causing metabolic catastrophe and NAD ± keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.

Cutaneous adnexal adenocarcinoma with exquisite sensitivity to trastuzumab.

BACKGROUND: Cutaneous adnexal adenocarcinoma is a rare cancer that is occasionally human epidermal growth factor receptor-2 (HER-2)-positive, and demonstrates variable response to HER-2 inhibitors. METHODS: We report a case of adnexal adenocarcinoma of the scalp in a 56-year-old man. He underwent wide local excision with cervical node dissection followed by radiation, but had extensive local recurrence. RESULTS: Pathology demonstrated a poorly differentiated adnexal adenocarcinoma with HER-2 overexpression by immunohistochemistry (IHC) and high HER-2 gene amplification by fluorescence in situ hybridization. The patient was treated with trastuzumab-based therapy with dramatic response and clinical resolution of the tumor. Upon pausing trastuzumab, he developed local relapse, but had an excellent response to restarting trastuzumab monotherapy. He lacks visible disease 43 months after the initial diagnosis. CONCLUSION: We believe the exquisite sensitivity of the primary carcinoma and subsequent recurrence to trastuzumab therapy was due to strong HER-2 expression both at the protein and gene level. © 2017 Wiley Periodicals, Inc. Head Neck 39: E69-E71, 2017.

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and ß-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with ß-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and ß-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.

Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, ß-lapachone.

Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H: Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD(+)/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. SIGNIFICANCE: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.

Significantly increased PELP1 protein expression in primary and metastatic triple-negative breast carcinoma: comparison with GATA3 expression and PELP1's potential role in triple-negative breast carcinoma.

PELP1 is a novel coregulator of nuclear hormone receptors and is implicated in playing a role in driving breast cancer and enhancing metastatic potential. The PELP1 protein expression and potential role of PELP1 in triple-negative breast carcinoma (TNBC) have not been well characterized. We investigated PELP1 expression by immunohistochemistry in primary and metastatic triple-negative tumors in human tissues and compared its expression with GATA-binding protein 3 (GATA3), a novel diagnostic marker for TNBC. We examined the expression of PELP1 and GATA3 in 70 primary TNBC cases and found that PELP1 had a significantly higher frequency of expression compared to GATA3 (96% versus 46%; P < .0001). The mean extent score of expression of PELP1 was also significantly higher than GATA3's expression (3.87 ± 0.07 versus 0.91 ± 0.15; P < .0001). PELP1 had stronger staining intensity than GATA3. Furthermore, PELP1 immunoreactivity was consistently maintained in paired primary and metastatic TNBC cases (100%). The frequency of PELP1 expression (100%) in metastatic triple-negative tumors was higher than that of GATA3 (40%) in the same tumors (P < .0001). These findings indicate that PELP1 is a much more sensitive marker than GATA3 for TNBCs. PELP1 may have diagnostic utility for metastatic TNBC in appropriate settings, such as history of primary TNBC in cases where the primary is negative for GATA3, mammaglobin, and GCDFP-15. The diffuse and strong nuclear immunoreactivity of PELP1 in most cases suggests that PELP1 may be a molecular target for the treatment of TNBC. We hope that this study will provide insights into the role of PELP1 in TNBC.