bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES).
Authors: Fizazi Karim , Cook Natalie , Barthélémy Philippe , Bernard-Tessier Alice , Baldini Capucine , Peters Niamh , Nykänen Pirjo , Ikonen Tarja , Pohjanjousi Pasi , Mattila Leena , Jouhi Lauri , Vuorela Annamari , Garratt Chris , Utriainen Tapio
Published: February 2022

18

Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.
Impact of provider education on prostate cancer genetic counseling referrals.
Authors: Moody Emily , Larson McCall , Greenberg Samantha , Jump Taylor , Bell Mckenzie , Gygi Jesse , Garcia Lisa , Dougherty Desiree , O Neil Brock , Lynch Steven C , Haslem Derrick S. , Gill David Michael
Published: February 2022

59

Background: Guidelines recommend germline genetic not only for men with advanced and metastatic prostate cancer but also those with NCCN-high risk disease. Many men harboring germline DNA repair defects would not have met criteria for testing under previous guidelines (Nicolosi et al, JAMA Oncol 2019). Knowledge of germline mutations is pertinent due to recent regulatory approval of PARP inhibitors olaparib and rucaparib and guides screening for first-degree relatives who are at increased risk for other cancers (Pritchard et al, NEJM 2016). Knowledge gaps for germline genetic testing have been previously described (Loeb et al, Cancer Treat Res Commun 2020). Through a series of educational sessions, we sought to increase utilization of appropriate genetic services for men with prostate cancer. Methods: Starting March 2021, virtual educational presentations were held for nurse navigators, urologists, and medical oncologists throughout our large community-based healthcare system. Surveys were distributed following each presentation to measure clinicians’ perception of their knowledge regarding prostate cancer genetics referrals on a five-step scale. Prostate cancer patient referral data was measured from September 2020 to August 2021, six months prior to and after the presentations. Results: Self-reported understanding of prostate cancer genetics referral practices following the educational presentations increased by an average of 1.7/5 steps (2.5 to 4.2/5) for physicians and 1.4/5 steps (2.9 to 4.1/5) for nurse navigators. From March to August 2021, there were 107 genetic referrals for prostate cancer (average 17.8 referrals/month) compared to 49 referrals from September 2020 to February 2021 (8.2 referrals/month). Conclusions: Prostate cancer genetics referrals increased 118% following educational presentations to urologists, medical oncologists, and nurse navigators. This correlates with an improvement in self-reported knowledge gaps. Provider education interventions may improve access to genetic services for men with prostate cancer. The increase in referrals likely does not account for all patients meeting criteria for germline testing. Work is ongoing to calculate the number of referrals as a proportion of the eligible population.[Table: see text]
A phase Ib, open-label study evaluating the safety and efficacy of ipatasertib + rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pook David William , Geynisman Daniel M. , Carles Joan , De Braud Filippo G. , Joshua Anthony M. , Perez-Gracia Jose Luis , Llácer Pérez Casilda , Shin Sang Joon , Fang Bruno , Barve Minal A. , Maruzzo Marco , Bracarda Sergio , Kim Miso , Kerloeguen Yannick , Gallo Jorge Daniel , Maund Sophia , Harris Adam , Huang Kuan-Chieh , Sutaria Dhruvitkumar S. , Gurney Howard
Published: February 2022

95

Background: mCRPC remains an incurable disease with unmet need for improved therapies. PARP inhibition has demonstrated antitumor activity, and preclinical studies suggest synergy between PARP and AKT inhibition. This phase Ib trial (NCT03840200) sought to determine the maximum tolerated dose of PARP inhibitor rucaparib (ruca) with AKT inhibitor ipatasertib (ipat) and explore early safety and efficacy in patients (pts) with mCRPC. Methods: The study had 2 parts: a part 1 dose-escalation phase (cohort [C]1: ipat 300 mg QD + ruca 400 mg BID; C2a: ipat 300 mg QD + ruca 600 mg BID; C2b ipat 400 mg QD + ruca 400 mg BID; C3: ipat 400 mg QD + ruca 600 mg BID) in unselected pts with mCRPC or advanced breast or ovarian cancer, and a Part 2 dose-expansion phase in pts with mCRPC whose previous androgen deprivation therapy failed. The primary safety endpoints were AEs and dose-limiting toxicities, with the goal of identifying a recommended phase II dose (RP2D). The primary efficacy endpoint was prostate-specific antigen (PSA) response (PSA reduction of ≥ 50%) in pts with mCRPC. Secondary efficacy endpoints included ORR per RECIST 1.1, radiographic PFS (rPFS) per Prostate Cancer Working Group 3 and OS in pts with mCRPC. We assessed homologous recombination deficiency (HRD), PIK3CA/ AKT1/ PTEN status and other alterations by next-generation sequencing. Results: Part 1 enrolled 21 pts: 17 with mCRPC, 3 with ovarian cancer and 1 with breast cancer (C1 [n=8], C2a [n=6] and C2b [n=7], C3 [not opened]). Ipat 400 mg QD + ruca 400 mg BID was the selected RP2D. 30 pts enrolled in Part 2, so 37 pts with mCRPC (C2b + Part 2) received the RP2D (median follow-up 93 days). All grade AEs occurred in 37 pts (100%), serious AEs in 8 pts (22%) and AEs leading to treatment modification in 26 pts (70%). The most frequent AEs (all grade and grade 3, respectively) were diarrhea (35 [95%] and 2 [5%]); asthenia (24 [65%] and 4 [11%]); and nausea (24 [65%] and 2 [5%]). There was 1 grade 4 AE (anemia) and no grade 5 AEs. See the table for efficacy data. In biomarker subgroups, the PSA response rate was 50% (3/6) in pts with HRD tumors vs 25% (4/16) in pts with HR-proficient tumors, and 14% (1/7) vs 40% (6/15) in pts with PIK3CA/ AKT1/ PTEN–altered or intact tumors, respectively. Conclusions: The combination of ipat and ruca was well tolerated but did not show clinically relevant antitumor activity in pts with mCRPC, including in predefined biomarker subpopulations. Clinical trial information: NCT03840200. [Table: see text]
Survival outcomes and characterization of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT) who do not achieve an optimal PSA response (PSA ≤0.2 ng/mL).
Authors: Sayegh Nicolas , Tripathi Nishita , Chigarira Beverly , Jo Yeonjung , McFarland Taylor Ryan , Kessel Adam , Nussenzveig Roberto , Li Haoran , Tandar Clara , Goel Divyam , Sahu Kamal Kant , Haaland Benjamin , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj
Published: February 2022

123

Background: In pts with mCSPC undergoing intensified ADT, achieving a PSA nadir ≤0.2 ng/mL “anytime” after the start of treatment was associated with a significantly improved overall survival (OS) versus those with a PSA >0.2 ng/mL: HR 0.17 (95% CI, 0.13-0.23) (Chi AUA 2021, abstract 1281). Our objective was to validate these findings in a real-world population and characterize the clinical and tumor genomic landscape according to PSA response. Methods: In this IRB-approved study, patient-level data were collected retrospectively. Eligibility: presence of mCSPC undergoing intensified ADT with either docetaxel or novel hormonal therapy (NHT) started within 3 months of diagnosis, availability of PSA nadir, and availability of tumor comprehensive genomic profiling (CGP) prior to start of ADT. Variants of unknown significance and genomic aberrations present in <5% pts were excluded. Optimal PSA response (OR): PSA≤0.2 ng/mL. Study endpoints: PFS was calculated per PCWG-2 defined PSA progression or radiographic progression or clinical progression whichever occurred first; OS was defined as start of therapy to date of death or censored after last follow-up. The relationship between PSA nadir and both PFS and OS was assessed in the context of Cox proportional hazards. Gene prevalence was compared using a chi square test. Results: 134 pts were eligible and included. Optimal responders (OR) (n=104) and non-OR (n=30): median age at diagnosis 63 vs 65 years; median PSA at ADT start 18.1 vs 74.5 ng/mL; high volume of disease 48% vs 77%. For OR and non-OR: median PFS, 60.6 vs 13.2 (P<0.001); median OS, 94.9 vs 35.2 months (P<0.001) respectively. Multivariate analysis is described in the table. Conclusions: Only a minority of pts with mCSPC do not achieve an optimal PSA response with intensified ADT. Those non-OR have worse outcomes on treatment with intensified ADT. Herein we externally validate that achieving a PSA nadir ≤0.2 ng/mL is correlated with superior OS. Detailed genomic landscape of these pts will be presented in the meeting.[Table: see text]
Immune system and intestinal microbiota determine efficacy of androgen depletion therapy against prostate cancer.
Authors: Terrisse Safae , Goubet Anne-Gaëlle , Ueda Kosuke , Thomas Andrew M. , Quiniou Valentin , Thelemaque Cassandra , Dunsmore Garett , Clave Emmanuel , Gamat-Huber Melissa , Yonekura Satoru , Derosa Lisa , Culine Stephane , Opolon Paule , Ginhoux Florent , Toubert Antoine , Segata Nicola , McNeel Douglas G. , Fizazi Karim , Kroemer Guido , Zitvogel Laurence
Published: February 2022

168

Background: Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). While it is recognized that ADT has an immunomodulatory effect, little is known about the intestinal microbiome effect on therapeutic outcome of ADT. Methods: We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT. Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients to analyze their feces and blood specimen. Results: In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice, or oral gavage with Akkermansia improved the efficacy of ADT. This appear to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared to HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy. Conclusions: These findings suggest that reversing the intestinal dysbiosis and repairing acquired immune defects in PC patients have a potential impact on the therapeutic outcome of ADT.
Immuno-oncology (IO) combinations +/- VEGF targeted therapy (VEGF TT) in patients (pts) with advanced mit family translocation renal cell carcinomas (tRCC): Results from an international multicenter study.
Authors: Alhalabi Omar , Thouvenin Jonathan , Negrier Sylvie , Vano Yann-Alexandre , Campedel Luca , Hasanov Elshad , Bakouny Ziad , Hahn Andrew Warren , Bilen Mehmet Asim , Choueiri Toni K. , Viswanathan Srinivas Raghavan , Sircar Kanishka , Albiges Laurence , Malouf Gabriel , Tannir Nizar M.
Published: February 2022

343

Background: IO combinations are standard of care for first-line therapy of clear-cell RCC; however, non-clear cell histologies including tRCC were not included in the registrational trials. We previously reported a modest efficacy (objective response rate [ORR] <20%) with IO monotherapy (PD-1 blockade) in tRCC (Boilève et al, JITC. 2018). The efficacy of IO combinations +/- VEGF TT has not been reported. Methods: This is a retrospective, international, multicenter study of pts with tRCC treated with IO-IO or IO+VEGF TT at 11 centers in the US, France, and Belgium. Only pts with confirmed TFE3 or TFEB translocation by fluorescent-in-situ hybridization (FISH) were included. ORR and progression-free survival (PFS) were assessed by RECIST. Overall survival (OS) was assessed by Kaplan-Meier methods. OS was measured from initiation of therapy till death or last follow up. We also assessed the association between OS and baseline prognostic variables. Results: 29 patients with metastatic tRCC were included in this analysis. Median age at starting therapy was 38 (IQR 27, 53) years. Female:Male ratio was 0.9:1. FISH revealed a translocation involving TFE3 and TFEB in 22 and 7 patients, respectively. Most frequent metastatic sites at diagnosis were lungs (76%), liver (52%), retroperitoneal adenopathy (48%), and bone (38%). IMDC risk at diagnosis was favorable (31%), intermediate (45%) and poor (24%). Combinations of IO+VEGF TT and anti-PD1 (L1) + anti-CTLA-4 (IO+IO) were used in 11 and 18 pts, respectively. 17 (59%) pts received IO combinations as 1L, 7 (24%) pts as 2L and 5 (17%) pts as ≥3L. ORR in the IO+IO group was 1/18 (5.5%), while in IO+VEGF TT group was 4/11 (36%). For 20 (69%) pts, progressive disease was the best overall response. At a median follow-up of 12.9 months (mo), median PFS was 3.2 mo and median OS was 13.5 mo for all 29 pts (Table). Median PFS in the IO+IO group was 2.8 mo, and 5.4 mo in IO+VEGF TT group (HR=0.81, 95% CI: 0.35-1.84). Conclusions: In this small retrospective study of tRCC, IO+IO therapy produced modest activity based on low ORR and short PFS while IO+VEGF TT produced numerically higher ORR and longer PFS. Insights into the biological basis of tRCC are necessary to develop more effective therapies for this rare and aggressive RCC variant.[Table: see text]
BAYOU: A phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC).
Authors: Rosenberg Jonathan E. , Park Se Hoon , Dao Tu V. , Castellano Daniel E. , Li Jian-Ri , Mukherjee Som , Howells Kathryn , Dry Hannah , Lanasa Mark C. , Stewart Ross , Bajorin Dean F.
Published: February 2022

437

Background: The prognosis for patients (pts) with advanced UC remains poor, particularly for those unable to tolerate platinum-based chemotherapy. Defects in DNA damage repair (e.g., mutations in homologous recombination repair [HRR] genes) are common in UC and render tumor cells sensitive to poly(ADP-ribose) polymerase (PARP) inhibition. HRR gene mutations (HRRm) and PARP inhibition may enhance the antitumor response of immune checkpoint inhibitors. We conducted a randomized phase II study to evaluate D (anti–PD-L1) in combination with O (a PARP inhibitor) or placebo (P) as a first-line treatment for platinum-ineligible pts with unresectable, stage IV UC (BAYOU; NCT03459846). Methods: Eligible pts were an age of ³18 years with an ECOG performance status (PS) of 0, 1, or 2, histologically or cytologically confirmed transitional cell carcinoma, and who had not received prior systemic therapy for unresectable, stage IV disease. Pts were randomized 1:1 to receive D (1500 mg IV q4w) plus O (orally at 300 mg BID) vs D (1500 mg IV q4w) plus O-matching placebo (P). Pts were stratified according to centrally-determined HRR status (mutant vs wild-type) and Bajorin risk index (a composite of visceral metastases and ECOG PS [0, 1 vs 2]). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 (investigator assessed) in the intention-to-treat (ITT) population. Secondary endpoints included overall survival (OS) in the ITT population and PFS in the subset of pts with HRRm. The data cutoff occurred on October 15, 2020. Results: A total of 154 pts were randomized to receive D+O (n = 78) or D+P (n = 76). Among all randomized pts at baseline, 17%, 42%, and 40% had an ECOG PS of 0, 1, or 2, respectively, and 20% had an HRRm. Median PFS was not significantly different between D+O and D+P in the ITT population (Table). In the subset of pts with HRRm, median PFS was 5.6 months in the D+O group and 1.8 months in the D+P group (Table). In the ITT population, median OS (95% CI) was 10.2 months (7.0–13.9) in the D+O group and 10.7 months (7.2–17.3) in the D+P group (HR 1.07, 95% CI 0.72–1.61). Among all treated pts, grade 3 or 4 treatment-related adverse events occurred in 18% and 9% in the D+O and D+P groups, respectively, with one death due to anemia in the D+P group. Conclusions: The BAYOU study did not meet its primary endpoint. However, the results of pre-planned secondary analyses suggest a potential role for PARP inhibition in UC pts harboring HRRm. No new safety signals were observed. Clinical trial information: NCT03459846. [Table: see text]
First-line pembrolizumab in advanced urothelial carcinoma: Clinical parameters associated with efficacy in the phase 2 KEYNOTE-052 and phase 3 KEYNOTE-361 trials.
Authors: Csoszi Tibor , Powles Thomas , Alva Ajjai Shivaram , Castellano Daniel E. , Ozguroglu Mustafa , O'Donnell Peter H. , Loriot Yohann , Hahn Noah M. , Flechon Aude , Rodriguez-Vida Alejo , De Wit Ronald , Cheng Susanna Y. , Oudard Stephane , Vulsteke Christof , Yu Evan Y. , Lin Jianxin , Imai Kentaro , Homet Moreno Blanca , Balar Arjun Vasant , Grivas Petros
Published: February 2022

521

Background: First-line treatment with pembrolizumab (pembro) monotherapy has shown durable clinical activity in selected patients (pts) with advanced/unresectable or metastatic urothelial carcinoma (UC). In a pooled population of pts with advanced UC from the single-arm phase 2 KEYNOTE-052 (NCT02335424) and the randomized, open-label, phase 3 KEYNOTE-361 (NCT02853305) studies, this exploratory analysis evaluated the relationship between baseline characteristics and clinical outcomes of first-line pembro monotherapy. Methods: Cisplatin-ineligible pts with advanced UC were enrolled in KEYNOTE-052 and chemotherapy-naive pts with advanced UC were enrolled in KEYNOTE-361. For analysis of predictive factors for ORR and OS in pembro-treated pts, the purposeful selection method was used to build the multivariable logistic regression model (ORR) and multivariable Cox model (OS), beginning with a univariable analysis of each independent variable. Any variable in the univariate model with P < 0.10 was a candidate for the multivariate model. The stepwise selection method was used to select the variables in the final model. Significance of the final model was set at P < 0.05. Data cutoff dates were September 26, 2020 (KEYNOTE-052) and April 29, 2020 (KEYNOTE-361). Results: This pooled analysis included 681 pts treated with pembro monotherapy (KEYNOTE-052, N = 374; KEYNOTE-361, N = 307 [170 were cisplatin ineligible]). Median follow-up was 51.9 mo (range, 22.0-65.3). ORR was 29.4% (95% CI, 26.0-32.9; 69 CRs, 131 PRs), and median DOR was 33.2 mo (range, 1.4+ to 60.7+). Median OS was 12.5 mo (95% CI, 11.0-14.6). By multivariate analysis, independent factors significantly associated with higher ORR were PD-L1 status (combined positive score [CPS] ≥10 vs CPS < 10; odds ratio [OR], 1.90 [95% CI, 1.33-2.71]; P = 0.0004), site of metastasis (lymph node only vs visceral disease; OR, 1.66 [95% CI, 1.06-2.59]; P = 0.0265), liver involvement (absent vs present; OR, 1.75 [95% CI, 1.06-2.89]; P = 0.0294), and baseline hemoglobin level ≥10 vs < 10 g/dL; OR, 2.17 [95% CI, 1.09-4.31]; P = 0.0276). Multivariate analysis of OS is displayed in the Table. Conclusions: This exploratory multivariate analysis identified numerous factors, including PD-L1–positive status (CPS ≥10), lymph node only metastasis, and lower ECOG PS score, associated with improved clinical outcomes in pts with advanced UC treated with first-line pembro monotherapy. Clinical trial information: NCT02335424 and NCT02853305. [Table: see text]
Incidence and clinical outcomes of HER2-altered bladder cancer (BC) patients (pts).
Authors: Lattanzi Michael , Niederhausern Andrew , Zheng Junting , Bahadur Nadia , Nichols Chelsea , Barton Laura , Gandhi Fenil , Chan Kimberly , Insinga Alysha , Philip John , Bakker Theodora , Regazzi Ashley Marie , Guercio Brendan John , Teo Min Yuen , Aggen David Henry , Pietzak Eugene J. , Solit David B. , Ostrovnaya Irina , Shah Neil J. , Iyer Gopa
Published: February 2022

556

Background: Bladder cancer has one of the highest rates of human epidermal growth factor receptor 2 (HER2) alteration. Novel HER2-directed agents are being investigated in metastatic BC. We sought to define the incidence and clinical characteristics of HER2-altered BC across disease states. Methods: We retrospectively analyzed our single-institution, clinically annotated cohort of urothelial BC pts with available genomic profiling data (MSK-IMPACT). We quantified the prevalence of HER2 alterations, defined as driver mutation (based on OncoKB), and/or amplification, across BC disease states. We examined the association between HER2 alteration and disease progression and survival. The Kaplan-Meier method was used for time-to-event analyses. Results: A total of 1073 BC pts underwent MSK IMPACT profiling of tumor tissue derived from the following disease states: 36% (n = 380) non-muscle invasive (NMI)BC, 41% (n = 443) muscle invasive (MI)BC, and 23% (n = 250) (met)BC. At initial diagnosis, the median age was 67 years, 77% (n = 822) were male, 86% (n = 928) were white, and 66% (n = 710) were smokers. Overall, 16% (n = 177) of pts had any oncogenic HER2 alteration (Table), including 11% with a HER2 driver mutation and 7% with HER2 amplification The most frequent mutations were S310F (40%, n = 53) and S310Y (14%, n = 19). The rate of HER2 amplification was different among the three groups (p = 0.002), 9% in MIBC and metBC compared to 3% in NMIBC. Among 514 pts with NMIBC, the median time to progression (TTP) to MIBC or metBC was 111.6 months (95% Cl: 85.7-NR). Among NMIBC pts, TTP was significantly shorter for HER2-amplified (n = 17) vs. non-amplified (n = 497) (HR = 1.99, 95%CI: 1.05-3.76, p = 0.034, median 26 vs. 114 months). Among pts with metBC receiving frontline platinum-based chemotherapy (n = 143), the median overall survival (OS) was 25.3 months (95%CI: 18.5-33.9). OS was numerically higher in pts with any oncogenic HER2 alteration (n = 26) compared to wild-type (n = 117) (HR = 0.59, 95% Cl: 0.33-1.07, p = 0.082), though this difference was not statistically significant. The median OS for platinum-refractory metBC pts receiving 2nd line immunotherapy (n = 63) was 10.3 months (95%CI: 7.2-31.6), and the association between OS and HER2 alteration was not significant (HR = 0.57, 95%CI: 0.24-1.37, p = 0.2). Conclusions: HER2 amplification is more frequent in MIBC and metBC than in NMIBC. In NMIBC, HER2 amplification is associated with shorter TTP to MIBC or metBC. HER2 alteration in metBC is associated with a non-significant trend towards improved OS in frontline platinum-treated pts, though this analysis is limited by small sample size.[Table: see text]
Initial results of a phase II study of nivolumab(N) and ipilimumab(I) in genitourinary malignancies with neuroendocrine differentiation.
Authors: McGregor Bradley Alexander , Xie Wanling , Bilen Mehmet Asim , Campbell Matthew T , Mortazavi Amir , Huang Jiaming , Sunkara Rajitha , Ravi Praful , Shah Amishi Yogesh , Baca Sylvan , Sonpavde Guru P. , Bellmunt Joaquim , Siefker-Radtke Arlene O. , Signoretti Sabina , Van Allen Eliezer Mendel , Beltran Himisha , McKay Rana R. , Choueiri Toni K.
Published: February 2022

569

Background: Patients with metastatic genitourinary malignancies with neuroendocrine have limited therapeutic options following platinum therapy. Given encouraging results in initial cohort analysis for small cell urinary tract carcinoma, a cohort of any genitourinary malignancy with neuroendocrine differentiation was added to a multicenter, single arm, multi-cohort phase II trial to evaluate the efficacy of N and I in this setting. (NCT 03333616) Methods: Eligible patients had metastatic or locally advanced genitourinary malignancy with neuroendocrine differentiation with an ECOG performance status of 0-2; they may have received any line of prior therapy excluding prior immunotherapy. Patients underwent baseline biopsy and received treatment with N 3 mg/kg and I 1 mg/kg intravenously every 3 weeks for 4 cycles with continued maintenance of N 480 mg IV every 4 weeks. Imaging was performed at 12 weeks and then every 8 weeks through month 6 and then every 12 weeks thereafter. The primary endpoint was investigator assessed objective response rate (ORR) by RECIST 1.1. Results: A total of 27 patients were enrolled between 06/27/2018 and 06/21/2021, 10 (37%) had urinary tract cancer and 17 (63%) had prostate cancer (19 in expansion cohort, 3 urinary tract and 5 prostate cancer from earlier cohorts). The majority (n=25, 93%) patients received prior systemic therapy. Nine (33%) patients received all 4 doses of N and I during the induction period. Nine (33%) patients (7 of whom received 4 cycles N+I) received N maintenance (median number of cycles 9 (range, 2-37)). Median follow-up was 6.8 (range, 0.9-37.3) months. Objective response was achieved in 8 (30%, 80% CI 18%-44%) patients (Table). Median duration of response was not reached with 4 patients maintaining response >9 months. Median progression-free survival time was 2.6 (95% CI 1.8-6.5) months At time of analysis, 13 (48%) death events were reported due to progressive disease, in which 3 were bladder and 10 were prostate cancer. 8 (30%) patients developed treatment-related grade 3 or higher toxicities; one grade 5 toxicity was deemed treatment-unrelated. Conclusions: In this study we demonstrate N+I resulted in objective responses in patients with genitourinary malignancy with neuroendocrine differentiation. ORR of 50% in small cell carcinoma is bladder cancer is noteworthy and will be evaluated further in ongoing expansion cohort of bladder or upper tract carcinoma with variant histology. Clinical trial information: NCT03333616. [Table: see text]
Study EV-103 cohort L: Evaluating perioperative enfortumab vedotin monotherapy in cis-ineligible muscle invasive bladder cancer (MIBC) (trial in progress).
Authors: Hoimes Christopher J. , Flaig Thomas W. , Srinivas Sandy , Mar Nataliya , Petrylak Daniel P. , O'Donnell Peter H. , Bilen Mehmet Asim , Sasse Carolyn , Yu Yao , Birrenkott Matthew , Rosenberg Jonathan E.
Published: February 2022

TPS587

Background: The current standard of care for patients (pts) with newly diagnosed MIBC is neoadjuvant cisplatin (cis)-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND). For the 20-50% pts who are cis-ineligible, the current standard of care is RC+PLND alone (Galsky Future Oncol 2021). Adjuvant therapy is currently recommended for cis-ineligible patients with high-risk features at cystectomy. Due to the high rates of recurrence in cis-ineligible pts with RC+PLND alone, there is a need to develop new therapies in this setting. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In EV-301, a phase 3 study, EV showed an overall survival (OS) benefit vs chemotherapy in pts with locally advanced (la) or metastatic urothelial carcinoma (mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). EV has also demonstrated activity and a tolerable safety profile in cis-ineligible pts with la/mUC (Yu Lancet Oncol 2021). Given the efficacy of EV in la/mUC, it is being evaluated as perioperative therapy in cis-ineligible MIBC in EV-103 cohort L. Methods: Study EV-103 (NCT03288545) la/mUC and MIBC cohorts were described previously (Hoimes ASCO 2019; Hoimes ASCO-GU 2020). Cohort L was added to evaluate EV monotherapy (n = 50) as perioperative therapy in cis-ineligible pts with MIBC (cT2-T4aN0M0 or cT1-T4aN1M0). Eligible pts are previously untreated for MIBC, ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and agree to undergo curative intent RC+PLND. Pts with pT1 disease are eligible only if they have N1 disease. Pts receive 3 cycles of neoadjuvant EV (1.25 mg/kg IV) on Days 1 and 8 of each 3-week cycle, followed by RC+PLND and then 6 cycles of adjuvant EV starting 8 weeks post-RC on the same schedule. Pathological complete response rate per central pathology review is the primary endpoint. Secondary endpoints include event-free survival and disease-free survival by blinded independent central review and investigator, pathological downstaging rate per central pathology review, OS, safety and tolerability. Cohort L is currently enrolling pts in the US and Canada. Clinical trial information: NCT03288545.
FLASH irradiation induces lower levels of DNA damage ex vivo, an effect modulated by oxygen tension, dose, and dose rate
Authors: Cooper Christian R , Jones Donald , Jones George DD , Petersson Kristoffer
Published: February 2022

Objective:

FLASH irradiation reportedly produces less normal tissue toxicity, while maintaining tumour response. To investigate oxygen’s role in the ‘FLASH effect’, we assessed DNA damage levels following irradiation at different oxygen tensions, doses and dose rates.

Methods:

Samples of whole blood were irradiated (20 Gy) at various oxygen tensions (0.25–21%) with 6 MeV electrons at dose rates of either 2 kGy/s (FLASH) or 0.1 Gy/s (CONV), and subsequently with various doses (0–40 Gy) and intermediate dose rates (0.3–1000 Gy/s). DNA damage of peripheral blood lymphocytes (PBL) were assessed by the alkaline comet assay.

Results:

Following 20 Gy irradiation, lower levels of DNA damage were induced for FLASH, the difference being significant at 0.25% (p < 0.05) and 0.5% O2 (p < 0.01). The differential in DNA damage at 0.5% O2 was found to increase with total dose and dose rate, becoming significant for doses ≥20 Gy and dose rates ≥30 Gy/s.

Conclusion:

This study shows, using the alkaline comet assay, that lower levels of DNA damage are induced following FLASH irradiation, an effect that is modulated by the oxygen tension, and increases with the total dose and dose rate of irradiation, indicating that an oxygen related mechanism, e.g. transient radiation-induced oxygen depletion, may contribute to the tissue sparing effect of FLASH irradiation.

Advances in knowledge:

This paper is first to directly show that FLASH-induced DNA damage is modulated by oxygen tension, total dose and dose rate, with FLASH inducing significantly lower levels of DNA damage for doses ≥20 Gy and dose rates ≥30 Gy/s, at 0.5% O2.
Δίκτυα, καινοτομία και γνώση σε περιοχές απομακρυσμένες γεωγραφικά από τα μεγάλα αστικά κέντρα της Ελλάδας
Authors: Σουριαδάκη Ιωάννα
Published: February 2022

Η παρούσα διδακτορική διατριβή εξετάζει τον τρόπο διάχυσης των νέων γνώσεων και κατά συνέπεια τον τρόπο ανάπτυξης της καινοτομίας των επιχειρήσεων, που δραστηριοποιούνται σε περιοχές της υπαίθρου. Η έρευνα επικεντρώθηκε σε μικρομεσαίες επιχειρήσεις της ελληνικής υπαίθρου, που απασχολούνται σε διάφορους κλάδους της οικονομίας και απέχουν γεωγραφικά από τα πυκνά δίκτυα των μεγάλων αστικών περιοχών και τις οικονομίες αστικοποίησης αυτών. Μεθοδολογικά, στα πλαίσια της παρούσας διδακτορικής διατριβής, επιλέχθηκε ένα δείγμα από 35 μικρομεσαίες επιχειρήσεις σε μη αστικές περιοχές της Ελλάδας και παράλληλα διαμορφώθηκε ένα ειδικά δομημένο ερωτηματολόγιο, που απευθυνόταν στους εκπροσώπους των επιχειρήσεων του δείγματος. Στη συνέχεια τα στοιχεία συλλέχθηκαν μέσω τηλεφωνικών συνεντεύξεων και εφαρμόστηκε ποιοτική ανάλυση για την εξαγωγή των βασικών συμπερασμάτων. Ειδικότερα διαπιστώθηκε συσχέτιση της οργανωτικής εγγύτητας, με τις επιχειρήσεις του δείγματος που δραστηριοποιούνται στον τομέα της ενημέρωσης και της επικοινωνίας, καθώς και στον τομέα των επαγγελματικών, των επιστημονικών και των τεχνικών δραστηριοτήτων, για την ανάπτυξη των καινοτόμων δραστηριοτήτων τους. Αντίθετα οι επιχειρήσεις που απασχολούνται στον γεωργικό τομέα, καινοτομούν με νέες γνώσεις που αποκτούν μέσω της προσωρινής πρόσωπο με πρόσωπο γεωγραφικής εγγύτητας. Παράλληλα η συνεργασία των επιχειρήσεων του δείγματος με πελάτες και η συμμετοχή τους σε εκθέσεις, στοχεύουν στην απόκτηση πληροφοριών όσον αφορά στην αγορά που απευθύνονται και δραστηριοποιούνται οι εν λόγω επιχειρήσεις, ενώ η συνεργασία τους με πανεπιστημιακούς φορείς έχει ως στόχο, τη δημιουργία νέων ιδεών για την εμπορευματοποίηση της καινοτομίας. Τα παραπάνω ευρήματα επιβεβαιώνουν εν μέρει την υφιστάμενη διεθνή βιβλιογραφία, καθιστώντας τη γεωγραφική «θέση» των επιχειρήσεων στην αγορά, ως τον λιγότερο σημαντικό παράγοντα για την ανάπτυξη της καινοτομίας.
Case Report: Hydranencephaly in a female newborn with congenital cytomegalovirus infection
Authors: Dewiyanti Lilia , Diyo Andrew Robert , Afandy Jonathan Edbert , . Jennefer , Pramana Cipta
Published: February 2022

Background: Hydranencephaly is a congenital abnormality of the central nervous system characterized by massive hemispheric necrosis and ventricular dilatation with most of the cerebral hemispheres being replaced by membranous sacs filled with cerebrospinal fluid (CSF). Cytomegalovirus (CMV) infection can be one of the causes of hydranencephaly. The choice of therapy for hydranencephaly is a challenge because of poor prognosis, but now neural stem cell (NSC) transplantation may give new hope.

Case report: We report a case of a female newborn born at term by cesarean section from a gravida 5, para 3, abortus 1 (G5P3A1) mother with suspected hydrocephalus. Head circumference was 35 cm at birth. The baby was born crying immediately, looked active, and did not appear cyanotic, but on the second day, the baby looked less active, moaned, showed acral cyanosis, and had a large fontanelle that was dilated and soft. Signs of hydrocephalus such as Macewen’s sign, setting sun phenomenon, and transillumination were found to be positive. Echocardiographic examination showed floppy interatrial septum and mild mitral regurgitation. Non-contrast computerized tomography (CT) scan of the head showed hydranencephaly. The toxoplasmosis, rubella, CMV, and herpes simplex virus (TORCH) screening showed positive anti-CMV immunoglobulin G (IgG). The baby underwent a ventriculoperitoneal (VP) shunt procedure with a head circumference of 36 cm before surgery. VP shunt was performed with an opening pressure of 15 cmH2O.

Conclusions: After the VP shunt procedure, the baby's general condition improved with the head circumference within normal limits. The baby was discharged from the hospital after 16 days of treatment.
Case Report: Late complications of radiotherapy for breast cancer
Authors: Haddad Anis , Zoukar Olfa , Jemaa Yosra , Zouari Ines , Issa Rahma , Bayar Amel , Khouildi Ghada , Sebri Amal , Naguez Dalel , Boukadida Asma , Ghannouchi Mossaab , Faleh Raja
Published: February 2022

The long term functional and aesthetic impact of breast neoplasia treatment partly reflects the consequences of high dose irradiation of the skin and subcutaneous tissue.

This work, based on a case observed in our department and a review of the literature, aims to discuss certain secondary manifestations following breast irradiation and their therapeutic options.

Our work reports the case of a premenopausal 46-year-old patient, treated for a right breast neoplasia. In July 2019, the patient underwent a Patey with simple postoperative follow-up. Histology substantiated the presence of an infiltrating ductal carcinoma SBRI. Mastectomy was followed by locoregional irradiation and adjuvant chemotherapy.

Thirteen months after the end of irradiation, the patient reconsulted for functional impotence and pain at the level of the right upper limb. The clinical examination showed cutaneous sclerosis and lymphedema. An X-ray showing the non-metastatic fracture of the clavicle. The patient underwent physiotherapy sessions with slight improvement on the functional level and clear improvement on the sensory level with progressive disappearance of pain.

Therapeutic options for complications of breast irradiation include massage, bandages, and physical exercise, often used in combination. The precise localization of the tumor bed and the application of appropriate clinical target volumes and planning target volumes are essential, as these concepts are fundamental for partial breast irradiation and avoid the complications of radiotherapy.
Clinical outcomes of COVID-19 patients with solid and hematological cancer: a meta-analysis and systematic review
Authors: Wahyuhadi Joni , Rusdi Fadhillah Putri , Ranuh I G. M. Aswin R. , Meizikri Rizki , Haq Irwan Barlian Immadoel , Susilo Rahadian Indarto , Al Farabi Makhyan Jibril
Published: February 2022

Background: Previous research has consistently shown the significant difference in outcome between cancerous and non-cancerous patients with coronavirus disease 2019 (COVID-19). However, no studies have compared the clinical manifestation of COVID-19 in hematologic cancers patients and solid cancers patients. Therefore, we analyzed the outcome of COVID-19 patients with hematological cancer and primary solid cancer worldwide through a meta-analysis and systematic review.

Methods: This meta-analysis and systematic review included English language articles published between December 2019 – January 2021 from Pubmed and Google Scholar. The Newcastle Ottawa Score was used to assess the quality and bias of included studies. The outcome measures were case-fatality rate and critical care events for COVID-19 patients with cancer and comorbidities.

Results: The initial search found 8910 articles, of 20 were included in the analysis. Critical care events and mortality were higher in the hematological than primary solid cancer group (relative risk (RR)=1.22 & 1.65; p <0.001). Conversely, mortality was lower in patients with two or fewer comorbidities (RR=0.57; p<0.001) and patients under the 75-year-old group (RR=0.53; p< 0.05).

Conclusions: Hematologic malignancy, age, and the number of comorbidities are predictor factors for worse prognosis in COVID-19 infection.
Hydropneumopericardium: A Rare Complication of an Oesophageal Tumour
Authors: Rodrigues Morais Joana Sofia , Môço Rui
Published: February 2022

Hydropneumopericardium is a rare event with a risk of serious complications. Timely diagnosis and treatment is important as it can improve prognosis. We report the case of a 77-year-old male patient who presented with acute interscapular pain which developed during a meal. An oesophago-pericardial fistula was found in the context of malignant oesophageal disease.
A practice-based clinical evaluation of a novel two-bottle dentine adhesive system
Authors: Burke FJ Trevor , Sands Peter , Crisp Russell J
Published: February 2022

This study evaluated the handling of a recently introduced two bottle dentine adhesive system by a group of practice-based researchers. Twelve evaluators from the practice-based research group, the PREP Panel, were sent explanatory letters, a pack of the material under investigation, G2-Bond Universal, with a request to use it, where indicated, for 10 weeks and then to complete a questionnaire designed to elicit the evaluators' views on the handling of the materials. In total, 568 restorations were placed. The results from the questionnaire indicated good acceptance of the material, despite the fact that it required more clinical steps than the material previously used by the evaluators.

CPD/Clinical Relevance: Results from this evaluation indicate that there is a place in a majority of evaluators' practices for a two-bottle adhesive system.
Covid-19 and the early years workforce
Authors: Hancock Dave
Published: February 2022

What effect has the pandemic had on staff in early years settings including redundancies, turnover and training? Dave Hancock draws on highlights from a year-long survey
Effect of random grating pit displacements on the Talbot image
Authors: Goloborodko Andrey A.
Published: February 2022

An analysis of diffraction images in the deep Fresnel region produced by gratings with random pit displacements around a nominal value is performed in this paper. Such pit displacements can be produced while developing a grating with etchers since the process can be slightly unpredictable. A theoretical prediction to describe the intensity distribution is obtained, produced by the grating at the near field, showing that smoothing of self-images is produced in the Talbot plane. In addition, random pit displacements produce different diffraction behaviors for cosine and binary gratings. It is shown that if the standard deviation of pit displacements is less than 30% of the grating period, the pit image, observed in the Talbot plane, shows some additional intensity fluctuation that leads to its displacement by meaning of the mass center for binary gratings and pit displacements for cosine gratings with some additional structural changes. Theoretical conclusions taken from a direct integration method based on the Rayleigh–Sommerfeld equation are in good agreement with the simulation results.
Broadband unidirectional transverse light scattering in a V-shaped silicon nanoantenna
Authors: Yu Yang , Liu Jinze , Yu Yidu , Qiao Dayong , Li Yongqian , Salas-Montiel Rafael
Published: February 2022

The efficient manipulation of light-matter interactions in subwavelength all-dielectric nanostructures offers a unique opportunity for the design of novel low-loss visible- and telecom-range nanoantennas for light routing applications. Several studies have achieved longitudinal and transverse light scattering with a proper amplitude and phase balance among the multipole moments excited in dielectric nanoantennas. However, they only involve the interaction between electric dipole, magnetic dipole, and up to the electric quadrupole. Here, we extend and demonstrate a unidirectional transverse light scattering in a V-shaped silicon nanoantenna that involves the balance up to the magnetic quadrupole moment. Based on the long-wavelength approximation and exact multipole decomposition analysis, we find the interference conditions needed for near-unity unidirectional transverse light scattering along with near-zero scattering in the opposite direction. These interference conditions involve relative amplitude and phases of the electromagnetic dipoles and quadrupoles supported by the silicon nanoantenna. The conditions can be applied for the development of either polarization- or wavelength- dependent light routing on a V-shaped silicon and plasmonic nanoantennas.
Thermal analysis of the laser-induced thermal deformation of a diffractive optical element in a single-aperture coherent beam combining system
Authors: Wang Hanbin , Xian Yuqiao , Xin Jian , Song Yinglin , Yang Yifeng , Liu Wansheng , Chen Nanyu , Liu Meizhong , Wei Taihui , He Bing
Published: February 2022

Diffractive optical element (DOE) is a critical device for combining multiple laser beams into a single beam in a coherent beam combining (CBC) architecture. This study proposes a determination method for calculating the intrinsic absorption rate of the DOE, and the corresponding experimental system is established. We present a theoretical thermal deformation model of the laser-irradiated DOE based on the thermoelastic equation and thermal conduction theory. The temperature and thermal deformation of the DOE are simulated using different parameters, including the laser power density, substrate size, substrate material, laser incident time, and clamping method. The simulations indicated that the thermal deformation is directly proportional to substrate area and inversely proportional to substrate thickness. The thermal deformation of the DOE can also be decreased by using a two-surface fixing method, and the maximum decrease is 4.4%. The quantitative discussion and analysis of the DOE temperature field and thermal deformation are important for designing a DOE to increase the combining efficiency and improve the combined beam quality of a practical DOE-based CBC system.