Durvalumab with or without tremelimumab plus chemotherapy in HRR non-mutated, platinum-resistant ovarian cancer (KGOG 3045): A phase II umbrella trial.

AIM: We investigated the efficacy and safety of durvalumab (D) with or without tremelimumab (T) in addition to single-agent chemotherapy (CT) in patients with platinum-resistant recurrent ovarian cancer (PROC) lacking homologous recombination repair (HRR) gene mutations. PATIENTS AND METHODS: KGOG 3045 was an open-label, investigator-initiated phase II umbrella trial. Patients with PROC without HRR gene mutations who had received ≥2 prior lines of therapy were enrolled. Patients with high PD-L1 expression (TPS ≥25%) were assigned to arm A (D + CT), whereas those with low PD-L1 expression were assigned to arm B (D + T75 + CT). After completing arm B recruitment, patients were sequentially assigned to arms C (D + T300 + CT) and D (D + CT). RESULTS: Overall, 58 patients were enrolled (5, 18, 17, and 18 patients in arms A, B, C, and D, respectively). The objective response rates were 20.0, 33.3, 29.4, and 22.2%, respectively. Grade 3-4 treatment-related adverse events were observed in 20.0, 66.7, 47.1, and 66.7 of patients, respectively, but were effectively managed. Multivariable analysis demonstrated that adding T to D + CT improved progression-free survival (adjusted HR, 0.435; 95% CI, 0.229-0.824; P = 0.011). Favorable response to chemoimmunotherapy was associated with MUC16 mutation (P = 0.0214), high EPCAM expression (P = 0.020), high matrix remodeling gene signature score (P = 0.017), and low FOXP3 expression (P = 0.047). Patients showing favorable responses to D + T + CT exhibited significantly higher EPCAM expression levels (P = 0.008) and matrix remodeling gene signature scores (P = 0.031) than those receiving D + CT. CONCLUSIONS: Dual immunotherapy with chemotherapy showed acceptable response rates and tolerable safety in HRR non-mutated PROC, warranting continued clinical investigation.

Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045.

Choosing an optimal concomitant drug for combination with poly-ADP ribose polymerase (PARP) inhibitor based on patient-specific biomarker status may help increase to improve treatment efficacy in patients with ovarian cancer. However, the efficacy and safety of different PARP inhibitor-based combinations in patients with homologous recombination repair (HRR) mutations have not been evaluated in ovarian cancer. In this sub-study of Korean Gynecologic Oncology Group (KGOG) 3045, we compared the efficacy and safety of two olaparib-based combinations and biomarkers of patients with platinum-resistant ovarian cancer with HRR gene mutations. Patients were randomized to receive either olaparib (200 mg twice a day) + cediranib (30 mg daily) (Arm 1, n = 16) or olaparib (300 mg) + durvalumab (1,500 mg once every 4 weeks) (Arm 2, n = 14). The objective response rates for Arm 1 and Arm 2 were 50.0% and 42.9%, respectively. Most patients (83.3%) had BRCA mutations, which were similarly distributed between arms. Grade 3 or 4 treatment-related adverse events were observed in 37.5% and 35.7% of the patients, respectively, but all were managed properly. A high vascular endothelial growth factor signature was associated with favorable outcomes in Arm 1, whereas immune markers (PD-L1 expression [CPS ≥10], CD8, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) were associated with favorable outcomes in Arm 2. The activation of homologous recombination pathway upon disease progression was associated with poor response to subsequent therapy. Based on comprehensive biomarker profiling, including immunohistochemistry, whole-exome and RNA sequencing and whole blood-based analyses, we identified biomarkers that could help inform which of the two combination strategies is appropriate given a patient's biomarker status. Our findings have the potential to improve treatment outcome for patients with ovarian cancer in the PARP inhibitor era.

Frequency of peripheral PD-1+regulatory T cells is associated with treatment responses to PARP inhibitor maintenance in patients with epithelial ovarian cancer.

BACKGROUND: Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis) are becoming the standard of care for epithelial ovarian cancer (EOC). Recently, clinical trials of triple maintenance therapy (PARPi+anti-angiogenic agent+anti-PD-1/L1) are actively ongoing. Here, we investigated the immunological effects of PARPi or triple maintenance therapy on T cells and their impact on clinical responses. METHODS: We collected serial blood from EOC patients receiving PARPi therapy (cohort 1: PARPi, n = 49; cohort 2: olaparib+bevacizumab+pembrolizumab, n = 31). Peripheral T cells were analyzed using flow cytometry and compared according to the PARPi response. Progression-free survival (PFS) was assessed according to prognostic biomarkers identified in a comparative analysis. RESULTS: Regulatory T cells (Tregs) were suppressed by PARPi therapy, whereas PD-1 was not significantly changed. Short PFS group exhibited a higher percentage of baseline PD-1+Tregs than long PFS group, and the patients with high percentage of PD-1+Tregs before treatment showed poor PFS in cohort 1. However, the expression of PD-1 on Tregs significantly decreased after receiving triple maintenance therapy, and the reduction in PD-1+Tregs was associated with superior PFS in cohort 2 (P = 0.0078). CONCLUSION: PARPi suppresses Tregs, but does not affect PD-1 expression. Adding anti-PD-1 to PARPi decreases PD-1+Tregs, which have negative prognostic value for PARPi monotherapy.

Prone position PET/CT is useful in reducing gravity-dependent opacity-related [18F]fluorodeoxyglucose uptake.

OBJECTIVES: This study aimed to investigate whether performing [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in the prone position could reduce [18F]FDG uptake in dependent lungs. METHODS: Patients who underwent [18F]FDG PET/CT in both supine and prone positions from October 2018 to September 2021 were reviewed retrospectively. [18F]FDG uptake of dependent and nondependent lungs was analysed visually and semi-quantitatively. A linear regression analysis was performed to examine the association between the mean standardised uptake value (SUVmean) and the Hounsfield unit (HU). RESULTS: A total of 135 patients (median age, 66 years [interquartile range: 58-75 years]; 80 men) were included. Dependent lungs showed significantly higher SUVmean and HU than nondependent lungs on supine position PET/CT (sPET/CT, 0.59 ± 0.14 vs. 0.36 ± 0.09, p < 0.001; - 671 ± 66 vs. - 802 ± 43, p < 0.001, respectively) and prone position PET/CT (pPET/CT, 0.45 ± 0.12 vs. 0.42 ± 0.08, p < 0.001; - 731 ± 67 vs. - 790 ± 40, p < 0.001, respectively). Linear regression analysis revealed a strong association between the SUVmean and HU in sPET/CT (R = 0.86, p < 0.001) and moderate association in pPET/CT (R = 0.65, p < 0.001). One hundred and fifteen patients (85.2%) had visually discernible [18F]FDG uptake in the posterior lung on sPET/CT, which disappeared on pPET/CT in all but one patient (0.7%, p < 0.001). CONCLUSIONS: [18F]FDG uptake of the lung had moderate-to-strong associations with HU. Gravity-dependent opacity-related [18F]FDG uptake can be effectively reduced on prone position PET/CT. CLINICAL RELEVANCE STATEMENT: Prone position PET/CT effectively reduces gravity-dependent opacity-related [18F]fluorodeoxyglucose uptake in the lung, potentially improving diagnostic accuracy in evaluating nodules in dependent lungs and offering a more accurate assessment of lung inflammation parameters in interstitial lung disease evaluations. KEY POINTS: • The study evaluated whether performing [18F]fluorodeoxyglucose ([18F]FDG) PET/CT could reduce [18F]FDG uptake in lungs. • In prone and supine position PET/CT, the [18F]FDG uptake and Hounsfield unit were moderately to strongly associated. • Prone position PET/CT can reduce gravity-dependent opacity-related [18F]FDG uptake by the posterior lung.

Enhanced Enzymatically Amplified Metallization on Nanostructured Surfaces for Multiplexed Point-of-Care Electrical Detection of COVID-19 Biomarkers.

Inexpensive yet sensitive and specific biomarker detection is a critical bottleneck in diagnostics, monitoring, and surveillance of infectious diseases such as COVID-19. Multiplexed detection of several biomarkers can achieve wider diagnostic applicability, accuracy, and ease-of-use, while reducing cost. Current biomarker detection methods often use enzyme-linked immunosorbent assays (ELISA) with optical detection which offers high sensitivity and specificity. However, this is complex, expensive, and limited to detecting only a single analyte at a time. Here, it is found that biomarker-bound enzyme-labeled probes act synergistically with nanostructured catalytic surfaces and can be used to selectively reduce a soluble silver substrate to generate highly dense and conductive, localized surface silver metallization on microelectrode arrays. This enables a sensitive and quantitative, simple, direct electronic readout of biomarker binding without the use of any intermediate optics. Furthermore, the localized and dry-phase stable nature of the metallization enables multiplexed electronic measurement of several biomarkers from a single drop (<10 µL) of sample on a microchip.This method is applied for the multiplexed point-of-care (POC) quantitative detection of multiple COVID-19 antigen-specific antibodies. Combining a simple microchip and an inexpensive, cellphone-interfaced, portable reader, the detection and discrimination of biomarkers of prior infection versus vaccination is demonstrated.

Incidence of postoperative thrombotic events in ovarian cancer patients with a de-escalated prophylactic strategy: A retrospective cohort study.

OBJECTIVE: This study aimed to determine the incidence of thrombotic events in ovarian cancer patients following a de-escalated prophylactic strategy and to stratify risk groups. METHODS: We reviewed the records of patients who underwent debulking surgery for ovarian cancer at a single institution between January 2007 and May 2019. We identified clinically diagnosed and radiologically confirmed cases of thrombotic events-classified as pulmonary thromboembolism (PE), deep vein thrombosis (DVT), and other thrombotic events-within 6 months of debulking surgery. RESULTS: After excluding 13 patients diagnosed with thromboembolism at the baseline or during neoadjuvant chemotherapy, 799 were analyzed. Since the introduction of medical prophylaxis at our institution in 2009, 482 patients (60%) received medical prophylaxis with subcutaneous injection of low molecular weight heparin for 5 days with mechanical prophylaxis, whereas 317 (40%) received mechanical prophylaxis only. After debulking surgery, thrombotic events occurred in 28 patients (3.5%) including PE (n = 11), DVT (n = 10), and other thrombotic events (n = 7). Multivariable analysis identified age, body mass index (BMI), and operative duration as independent risk factors associated with thrombotic events. A thrombotic event was an independent prognostic factor for overall survival (HR 2.17, 95% CI 1.16-4.1). A cut-off analysis for pre-operative identifiable risk factors showed age < 57 years and BMI < 21 could help define low-risk groups. One patient from 172 low-risk patients (0.58%) experienced a thrombotic event. CONCLUSIONS: The thrombotic event incidence was low in our cohort. A de-escalated prophylaxis strategy may be considered in young (age < 57 years) and lean (BMI < 21) patients.

Usefulness and potential pitfalls of pre-operative PET-CT in patients with endometrial cancer undergoing one- and two-step sentinel lymph node mapping: Do negative findings on PET-CT negativity really indicate node negativity?

OBJECTIVE: We investigated the utility of Positron emission tomography-Computed tomography (PET-CT) in the setting of two different sentinel lymph node (SLN) mapping techniques; the conventional cervical injection method (one-step) and the two-step method, which involves fundal injection followed by cervical injection. METHODS: Patients with endometrial cancer undergoing FDG PET-CT followed by laparoscopic or robotic surgical staging with SLN mapping at the Yonsei Cancer Center between July 2014 and April 2021 were stratified into the PET-positive group (with suspected or likely lymph nodes metastasis) and PET-negative group. A chart review was performed for the number of harvested SLNs, patterns of SLN metastases, and recurrence. RESULTS: Among 466 patients undergoing one-step (n = 276) and two-step (n = 190) SLN mapping, LN metastasis was identified in 21 of 434 PET-negative and 18 of 32 PET-positive patients. The sensitivity and specificity of PET-CT for diagnosing lymph node metastasis were 46.2% and 96.7%, respectively. Among PET-positive patients with LN metastasis, anatomical distribution was concordant in 14/18 patients (77.8%). Among PET-negative patients, four (2.3%) had metastatic para-aortic SLNs, including three (1.7%) with isolated para-aortic metastases; metastatic para-aortic SLNs were exclusively found in the two-step group. Among PET-positive patients, para-aortic SLN metastasis was identified in 35.7% of two-step and 16.7% of one-step group. Among the 21 PET false-negative patients, recurrence was seen in four patients (19%) after a median follow-up of 34 months (range: 7-70 months). CONCLUSIONS: PET-CT served as a useful guide to clinicians with high anatomical concordance rate in patients with LN metastasis. However, despite high specificity, sensitivity was limited. SLN metastasis pattern, especially at the para-aortic level, indicates that the two-step SLN technique might be useful in PET-negative and PET-positive patients.

Prone position [18F]FDG PET/CT to reduce respiratory motion artefacts in the evaluation of lung nodules.

OBJECTIVES: 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron-emission tomography/computed tomography (PET/CT) is widely used to evaluate lung nodules, although respiratory motion artefacts may occur. We investigated the value of prone position PET/CT (pPET/CT) in lung nodule evaluation compared with standard supine position PET/CT (sPET/CT). METHODS: We retrospectively reviewed 28 consecutive patients (20 men; age, 65.6 ± 12.1 years) with a lung nodule (size, 16.8 ± 5.5 mm) located below the sub-carinal level who underwent [18F]FDG PET/CT in a standard supine position and additional prone position. The maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), difference of diaphragm position between PET and CT (DDP), Dice's similarity coefficient (DSC) and occurrence of mis-registration were analysed. The [18F]FDG uptake of 20 biopsy-confirmed (15 malignant) nodules was evaluated visually. RESULTS: pPET/CT yielded a significantly higher SUVmax, lower MTV and shorter DDP than with sPET/CT (p = 0.043, 0.007 and 0.021, respectively). Mis-registration occurred in 53.6% of cases in sPET/CT and in 28.6% of cases in pPET/CT (p = 0.092). Among the 15 patients with mis-registration in sPET/CT, 10 patients (66.7%) did not show mis-registration in pPET/CT. DSC was higher in pPET/CT than in sPET/CT in 18 out of 28 patients (64.3%). In visual analysis, malignant nodules exhibited a higher [18F]FDG uptake positivity than benign nodules in pPET/CT (93.3% vs. 40.0%, p = 0.032) but not in sPET/CT (80.0% vs. 40.0%, p = 0.131). CONCLUSIONS: pPET/CT reduces respiratory motion artefact and enables more-precise measurements of PET parameters. KEY POINTS: • In prone position PET/CT, the decrease in the blurring effect caused by reduced respiratory motion resulted in a higher SUVmax and lower MTV in lung nodules than that with supine position PET/CT. • Prone position PET/CT was useful to interpret correctly malignant lung nodules as being positive in individual cases that had a negative result in supine position PET/CT.

Comparison of outcomes between the one-step and two-step sentinel lymph node mapping techniques in endometrial cancer.

INTRODUCTION: Fluorescence image-guided sentinel lymph node (SLN) biopsy using a two-step mapping technique incorporates sequential injection of indocyanine green into the bilateral uterine cornus, followed by cervical injection. Outcomes were compared with the conventional cervical (one-step) method . METHODS: Patients with FIGO stage I-III endometrial cancer who underwent laparoscopic or robotic staging, including SLN biopsy, from May 2014 to December 2018, were retrospectively reviewed. Patient characteristics, pre-operative imaging, SLN detection pattern, pathologic result, adjuvant, and recurrence locations were analyzed. RESULTS: A total of 199 patients received one-step (n=123) and two-step (n=76) SLN biopsy. Para-aortic SLN were more frequently identified in the two-step group. Lower and upper para-aortic SLN were identified in 67.1% and 38.2%, respectively, in the two-step group and in 18.7% and 5.7% in the one-step group (p<0.001). The number of para-aortic SLN harvested was superior in the two-step group (p<0.001). Metastatic para-aortic SLN were found in 7.9% of the two-step group and 2.4% of the one-step group (p=0.070). In detecting nodal metastasis, the sensitivities of the one- and two-step methods were 91.7% and 100.0%, negative predictive values were 99.0% and 100.0%, false-negative rates were 8.3% and 0%, and accuracy rates were 99.1% and 100.0%, respectively. The one-step method identified only three out of eight para-aortic lymph node metastases and missed five para-aortic lymph node metastases. There was no missed para-aortic lymph node metastasis in the two-step group. Recurrence was observed in two patients (2.6%; vaginal vault and adrenal gland) in the two-step group and seven patients (5.7%) including three nodal recurrences in the one-step group (p=0.307). DISCUSSION: Two-step SLN mapping improved the para-aortic SLN detection rate, a known pitfall of conventional cervical injection. Proper evaluation of aortic nodal status will assist in the tailoring of adjuvant and prevent undertreatment of patients with isolated para-aortic metastasis.

Celiac plexus block with botulinum toxin in severe chronic pancreatitis-A case report.

WHAT IS KNOWN AND OBJECTIVE: The botulinum toxin (BoNT) has been widely used for various conditions associated with pain. CASE DESCRIPTION: Here, we report a case where celiac plexus block (CPB) with BoNT relieved intractable chronic pancreatic pain without complications. CPB was performed at the L1 level under fluoroscopic guidance, and 50 IU BoNT was injected on each side. After 15 weeks, pain was decreased to 0/10 on a visual analogue scale, without opioids or tramadol. WHAT IS NEW AND CONCLUSION: Our case demonstrates the efficacy of CPB with BoNT in intractable pain due to severe chronic pancreatitis.

Predicting labor induction success by cervical funneling in uncomplicated pregnancies.

AIM: Predictive accuracy of cervical funneling for successful vaginal delivery prior to labor induction was compared to that of conventional methods such as Bishop score and cervical length. METHODS: Prospective observational study was conducted on nulliparous women at 38 gestational weeks or more with intact membranes who delivered vaginally following labor induction. Transvaginal ultrasound was performed prior to labor induction to evaluate the cervix, to determine the cervical length and to check for the presence of funneling. Following pelvic examinations, the Bishop score was calculated. Predictive accuracy of the three different methods, namely cervical funneling, cervical length and Bishop, were compared. RESULTS: A total of 235 nulliparous women with intact membranes were recruited. Of these, 194 women (82.6%) had successful vaginal deliveries following induction. Cervical funneling was observed in 105 women (44.7%). The rate of successful vaginal delivery was significantly higher in women with cervical funneling than in those without funneling (90.5% vs 76.2%, P < 0.004). Multivariable analysis showed that cervical funneling, similar to traditional measures such as the Bishop score and cervical length, was an independent predictor of successful vaginal delivery following labor induction (odds ratio = 2.95; 95% confidence interval: 1.38-6.47; P = 0.007). CONCLUSIONS: Similar to the conventional methods of cervical evaluation, such as the Bishop score and cervical length, cervical funneling may serve as a useful and valid predictor of successful vaginal deliveries prior to labor induction.

Triple rule-out CT angiography protocol with restricting field of view for detection of pulmonary thromboembolism and aortic dissection in emergency department patients: simulation of modified CT protocol for reducing radiation dose.

Background Triple rule-out computed tomography (TRO CT) is a CT protocol designed to simultaneously evaluate the coronary, aorta, and pulmonary arteries. Purpose To evaluate potential diagnostic performance of TRO CT with restricted volume coverage for detection of pulmonary thromboembolism (PTE) and aortic dissection (AD). Material and Methods This study included 1224 consecutive patients with acute chest pain who visited the emergency department and underwent TRO CT using a 128-slice dual-source CT. Image data were reconstructed according to the display field of view (DFOV) of coronary CT angiography (CCTA) and TRO CT protocols in each patient. The presence of PTE and AD was evaluated by independent observers in each DFOV. The radiation dose was calculated to evaluate the potential benefits by restricting z-axis coverage to cardiac scan range instead of the whole thorax. Results Among all patients, 22 cases with PTE (1.9%) and nine cases with AD (0.8%) were found. Except for one PTE case, all cases were detected on both DFOV of TRO CT and CCTA. Mean effective dose for evaluation of entire thorax and cardiac scan coverage were 5.9 ± 1.1 mSv and 3.5 ± 0.7 mSv, respectively. Conclusion Isolated PTE and AD outside the CCTA DFOV rarely occur. Therefore, modified TRO CT protocol using cardiac scan coverage can be adopted to detect PTE and AD with reduced radiation dose.

Human epidermal growth factor receptor-2 expression and subsequent dynamic changes in patients with ovarian cancer.

Human epidermal growth factor receptor-2 (HER2)-targeting drugs are increasingly being incorporated into therapeutic paradigms for non-breast cancers, yet studies on HER2 expression in ovarian cancer (OC) are inadequate. Here, we studied the HER2 status and dynamic changes in OC by reviewing the records of patients who underwent HER2 testing at a single institution. Clinical parameters, including histology, BRCA status, and immunohistochemistry (IHC), were evaluated alongside HER2 expression, timing, and anatomical location. Among 200 patients, 28% and 6% exhibited expression scores of 2+ and 3+, respectively. HER2 3+ scores were observed in 23%, 11%, 9%, and 5% of mucinous, endometrioid, clear cell, and high-grade serous tumors, respectively, and were exclusively identified in BRCA-wildtype, mismatch repair-proficient, or PD-L1-low-expressing tumors. The TP53 mutation rate was low, whereas ARID1A, KRAS, and PIK3CA mutations were relatively more prevalent with HER2 scores of 2+ or 3+ than with 0 or 1+. Four of the five tumors with an HER2 3+ score exhibited ERBB2 amplification. Among 19 patients who underwent multiple time-lagged biopsies, 11 showed increased HER2 expression in subsequent biopsies. Patients with HER2-overexpressing OC exhibited distinct histological, IHC, and genomic profiles. HER2-targeting agents are potential options for BRCA-wildtype patients, particularly as later lines of treatment.

[18F]FDG PET/CT is useful in discriminating invasive adenocarcinomas among pure ground-glass nodules: comparison with CT findings-a bicenter retrospective study.

PURPOSE: Predicting the malignancy of pure ground-glass nodules (GGNs) using CT is challenging. The optimal role of [18F]FDG PET/CT in this context has not been clarified. We compared the performance of [18F]FDG PET/CT in evaluating GGNs for predicting invasive adenocarcinomas (IACs) with CT. METHODS: From June 2012 to December 2020, we retrospectively enrolled patients with pure GGNs on CT who underwent [18F]FDG PET/CT within 90 days. Overall, 38 patients with 40 ≥ 1-cm GGNs were pathologically confirmed. CT images were analyzed for size, attenuation, uniformity, shape, margin, tumor-lung interface, and internal/surrounding characteristics. Visual [18F]FDG positivity, maximum standardized uptake value (SUVmax), and tissue fraction-corrected SUVmax (SUVmaxTF) were evaluated on PET/CT. RESULTS: The histopathology of the 40 GGNs were: 25 IACs (62.5%), 9 minimally invasive adenocarcinomas (MIA, 22.5%), and 6 adenocarcinomas in situ (AIS, 15.0%). No significant differences were found in CT findings according to histopathology, whereas visual [18F]FDG positivity, SUVmax, and SUVmaxTF were significantly different (P=0.001, 0.033, and 0.018, respectively). The size, visual [18F]FDG positivity, SUVmax, and SUVmaxTF showed significant diagnostic performance to predict IACs (area under the curve=0.693, 0.773, 0.717, and 0.723, respectively; P=0.029, 0.001, 0.018, and 0.013, respectively). In the multivariate logistic regression analysis, visual [18F]FDG positivity discriminated IACs among GGNs among various CT and PET findings (P=0.008). CONCLUSIONS: [18F]FDG PET/CT demonstrated superior diagnostic performance compared to CT in differentiating IAC from AIS/MIA among pure GGNs, thus it has the potential to guide the proper management of patients with pure GGNs.

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer.

Objective: Effective functional biomarkers that can be readily used in clinical practice to predict poly(ADP-ribose) polymerase inhibitor (PARPi) sensitivity are lacking. With the widespread adoption of PARPi maintenance therapy in ovarian cancer, particularly in patients with BRCA mutation or HR deficiencies, accurately identifying de novo or acquired resistance to PARPi has become critical in clinical practice. We investigated RAD51 immunohistochemistry (IHC) as a functional biomarker for predicting PARPi sensitivity in ovarian cancer. Methods: Ovarian cancer patients who had received PARPi and had archival tissue samples prior to PARPi exposure ("pre-PARPi") and/or after progression on PARPi ("post-PARPi") were selected. RAD51 IHC expression was semi-quantitatively evaluated using the H-score in geminin (a G2/S phase marker)- and γH2AX (a DNA damage marker)-positive tissues. A RAD51 H-score of 20 was used as the cutoff value. Results: In total, 72 samples from 56 patients were analyzed. The median RAD51 H-score was 20 (range: 0-90) overall, 10 (0-190) in pre-PARPi samples (n = 34), and 25 (1-170) in post-PARPi samples (n = 19). Among patients with BRCA mutations, RAD51-low patients had better progression-free survival (PFS) after PARPi treatment than RAD51-high patients (P = 0.029). No difference was found in PFS with respect to the genomic scar score (P = 0.930). Analysis of matched pre- and post-PARPi samples collected from 15 patients indicated an increase in the RAD51 H-score upon progression on PARPi, particularly among pre-PARPi low-RAD51-expressing patients. Conclusion: RAD51 is a potential functional IHC biomarker of de novo and acquired PARPi resistance in BRCA-mutated ovarian cancer and can be used to fine-tune ovarian cancer treatment.

Serial Circulating Tumor DNA Analysis with a Tumor-Naïve Next-Generation Sequencing Panel Detects Minimal Residual Disease and Predicts Outcome in Ovarian Cancer.

Circulating tumor DNA (ctDNA) may aid in personalizing ovarian cancer therapeutic options. Here, we aimed to assess the clinical utility of serial ctDNA testing using tumor-naïve, small-sized next-generation sequencing (NGS) panels. A total of 296 patients, including 201 with ovarian cancer and 95 with benign or borderline disease, were enrolled. Samples were collected at baseline (initial diagnosis or surgery) and every 3 months after that, resulting in a total of 811 blood samples. Patients received adjuvant therapy based on the current standard of care. Cell-free DNA was extracted and sequenced using an NGS panel of 9 genes: TP53, BRCA1, BRCA2, ARID1A, CCNE1, KRAS, MYC, PIK3CA, and PTEN. Pathogenic somatic mutations were identified in 69.2% (139/201) of patients with ovarian cancer at baseline but not in those with benign or borderline disease. Detection of ctDNA at baseline and/or at 6 months follow-up was predictive of progression-free survival (PFS). PFS was significantly poorer in patients with detectable pathogenic mutations at baseline that persisted at follow-up than in patients that converted from having detectable ctDNA at baseline to being undetectable at follow-up; survival did not differ between patients without pathogenic ctDNA mutations in baseline or follow-up samples and those that converted from ctDNA positive to negative. Disease recurrence was also detected earlier with ctDNA than with conventional radiologic assessment or CA125 monitoring. These findings demonstrate that serial ctDNA testing could effectively monitor patients and detect minimal residual disease, facilitating early detection of disease progression and tailoring of adjuvant therapies for ovarian cancer treatment. SIGNIFICANCE: In ovarian cancer, serial circulating tumor DNA testing is a highly predictive marker of patient survival, with a significantly improved recurrence detection lead time compared with conventional monitoring tools.

Morphologic classification of congenital short pancreas on multidetector computed tomography.

OBJECTIVE: The objective of this study was to assess the imaging characteristics and classify congenital short pancreas on the basis of morphologic features on multidetector computed tomography (MDCT) and to determine the associated diseases and congenital anomalies of each type. METHODS: We conducted a retrospective search from 2006 to 2012 using the keywords "short pancreas," "agenesis or hypoplasia of the dorsal pancreas," or "hypoplasia of the ventral pancreas." Clinical data and images were analyzed; finally, 24 patients with congenital short pancreas were included in this study. Imaging features of the 3 types of congenital short pancreas and their associated anomalies on MDCT were evaluated. RESULTS: Congenital short pancreas was classified into type 1 (agenesis or hypoplasia of the dorsal pancreas): no congenital anomaly but presence of diabetes mellitus (45%); type 2 (agenesis or hypoplasia of the pancreatic uncinate process): intestinal malrotation (100%); and type 3 (combined hypoplasia or agenesis of the uncinate process and dorsal pancreas): a spectrum of various congenital anomalies, including abdominal heterotaxy and abnormal spleen (100%). CONCLUSIONS: Recognizing the spectrum of agenesis or hypoplasia of the pancreas and morphologic classification of congenital short pancreas on MDCT may help radiologists detect and understand disease associated with congenital short pancreas.

RAD51/geminin/γH2AX immunohistochemical expression predicts platinum-based chemotherapy response in ovarian high-grade serous carcinoma.

OBJECTIVE: The RAD51 assay is a recently developed functional assay for homologous recombination deficiency (HRD) that reflects real-time HRD status. We aimed to identify the applicability and predictive value of RAD51 immunohistochemical expression in pre- and post-neoadjuvant chemotherapy (NAC) samples of ovarian high-grade serous carcinoma (HGSC). METHODS: We evaluated the immunohistochemical expression of RAD51/geminin/γH2AX in ovarian HGSC before and after NAC. RESULTS: In pre-NAC tumors (n=51), 74.5% (39/51) showed at least 25% of γH2AX-positive tumor cells, suggesting endogenous DNA damage. The RAD51-high group (41.0%, 16/39) showed significantly worse progression-free survival (PFS) compared to the RAD51-low group (51.3%, 20/39) (p=0.032). In post-NAC tumors (n=50), the RAD51-high group (36.0%, 18/50) showed worse PFS (p=0.013) and tended to present worse overall survival (p=0.067) compared to the RAD51-low group (64.0%, 32/50). RAD51-high cases were more likely to progress than RAD51-low cases at both 6 months and 12 months (p=0.046 and p=0.019, respectively). Of 34 patients with matched pre- and post-NAC RAD51 results, 44% (15/34) of pre-NAC RAD51 results were changed in the post-NAC tissue, and the RAD51 high-to-high group showed the worst PFS, while the low-to-low group showed the best PFS (p=0.031). CONCLUSION: High RAD51 expression was significantly associated with worse PFS in HGSC, and post-NAC RAD51 status showed higher association than pre-NAC RAD51 status. Moreover, RAD51 status can be evaluated in a significant proportion of treatment-naïve HGSC samples. As RAD51 status dynamically changes, sequential follow-up of RAD51 status might reflect the biological behavior of HGSCs.

Multifaceted Effects of Kinase Inhibitors on Pancreatic Cancer Cells Reveals Pivotal Entities with Therapeutic Implications.

Pancreatic cancer is one of the most aggressive forms of cancer and is the seventh leading cause of cancer deaths worldwide. Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of pancreatic cancers. Most pancreatic cancers are recalcitrant to radiation, chemotherapy, and immunotherapy, highlighting the urgent need for novel treatment options for this deadly disease. To this end, we screened a library of kinase inhibitors in the PDAC cell lines PANC-1 and BxPC-3 and identified two highly potent molecules: Aurora kinase inhibitor AT 9283 (AT) and EGFR kinase inhibitor WZ 3146 (WZ). Both AT and WZ exhibited a dose-dependent inhibition of viability in both cell lines. Thus, we conducted an in-depth multilevel (cellular, molecular, and proteomic) analysis with AT and WZ in PANC-1 cells, which harbor KRAS mutation and exhibit quasimesenchymal properties representing pancreatic cancer cells as having intrinsic chemoresistance and the potential for differential response to therapy. Elucidation of the molecular mechanism of action of AT and WZ revealed an impact on the programmed cell death pathway with an increase in apoptotic, multicaspase, and caspase 3/7 positive cells. Additionally, the key survival molecule Bcl-2 was impacted. Moreover, cell cycle arrest was observed with both kinase inhibitors. Additionally, an increase in superoxide radicals was observed in the AT-treated group. Importantly, proteomic profiling revealed differentially regulated key entities with multifaceted effects, which could have a deleterious impact on PDAC. These findings suggest potential targets for efficacious treatment, including a possible increase in the efficacy of immunotherapy using PD-L1 antibody due to the upregulation of lactoferrin and radixin. Furthermore, combination therapy outcomes with gemcitabine/platinum drugs may also be more effective due to an increase in the NADH dehydrogenase complex. Notably, protein-protein interaction analysis (STRING) revealed possible enrichment of reactome pathway entities. Additionally, novel therapy options, such as vimentin-antibody--drug conjugates, could be explored. Therefore, future studies with the two kinases as monotherapy/combination therapy are warranted.