tbuckley/cabot-search huggingface dataset:
An overview of international regulatory frameworks for mesenchymal stromal cell‐based medicinal products: From laboratory to patient
Authors: Javier López‐Beas, Juan A. Guadix, Beatriz Clares, Jose L. Soriano‐Ruiz, José L. Zugaza, Patricia Gálvez‐Martín
Journal: Medicinal Research Reviews (2020)

Abstract Human mesenchymal stromal cells (hMSCs) are emerging as one of the most important cell types in advanced therapies and regenerative medicine due to their great therapeutic potential. The development of hMSC‐based products focuses on the use of hMSCs as biological active substances, and they are considered medicinal products by the primary health agencies worldwide. Due to their regulatory status, the development of hMSC‐based products is regulated by specific criteria that range from the design phase, nonclinical studies, clinical studies, to the final registration and approval. Patients should only be administered hMSC‐based products within the framework of a clinical trial or after the product has obtained marketing authorization; in both cases, authorization by health authorities is usually required. Considering the above, this paper describes the current general regulatory requirements for hMSC‐based products, by jurisdiction, to be implemented throughout their entire development process. These measures may provide support for researchers from both public and private entities and academia to optimize the development of these products and their subsequent marketing, thereby improving access to them by patients.
Safety and efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab in clinical practice for patients with chemorefractory metastatic colorectal cancer: A retrospective comparative study.
Authors: Yoshinori Kagawa, Yohei Nose, Taishi Hata, Kenji Kawai, Takuya Sakamoto, Kohei Murakami, Yoshiteru Katsura, Yoshiaki Ohmura, Toru Masuzawa, Atsushi Takeno, Yutaka Takeda, Kohei Murata
Journal: Journal of Clinical Oncology (2020)

112 Background: Trifluridine/tipiracil (FTD/TPI) significantly improves overall survival (OS) in patients with chemorefractory metastatic colorectal cancer (mCRC). The phase I/II C-TASKFORCE study of FTD/TPI + bevacizumab (Bev) for patients with mCRC who are refractory to standard chemotherapy demonstrated promising efficacy results. FTD/TPI + Bev were linked to significant and clinically relevant improvements in progression-free survival (PFS) and OS compared with FTD/TPI monotherapy and a favorable safety profile in a Danish randomized trial. This retrospective study investigated the safety and efficacy of FTD/TPI alone or in combination with Bev for patients with refractory mCRC in clinical practice. Methods: We reviewed the outcomes of patients with chemorefractory mCRC who received FTD/TPI alone (monotherapy; 35 mg/m 2 , twice daily on days 1–5 and 8–12 in a 28-day cycle) or FTD/TPI + Bev (combination; 5 mg/kg, days 1 and 15) in our institution since 2014. We compared the safety and efficacy of the monotherapy and combination regimens. Adverse events were evaluated using Common Terminology Criteria for Adverse Eventsv4.0. Median PFS and OS were analyzed using the Kaplan–Meier method. Results: In total, 56 patients received chemotherapy containing FTD/TPI. Twenty-four patients were treated with monotherapy, and 32 patients received the combination regimen. The median PFS was 1.8 months in the monotherapy arm, versus 4.7 months in the combination arm (hazard ratio [HR] = 0.28; 95% confidence interval [CI] = 0.15–0.51; P &lt; 0.0001). The median OS was 6.3 months for the monotherapy arm, versus 11.7 months for the combination arm (HR = 0.25; 95% CI = 0.13–0.48; P &lt; 0.0001). There was no significant difference in the rates of adverse events between the groups excluding neutropenia. Neutropenia (Grade 3 or worse) developed in five patients (20.8%) in the monotherapy arm and 17 patients (53.1%) in the combination arm ( P = 0.030). There were no treatment-related deaths. Conclusions: In patients with chemorefractory mCRC, FTD/TPI + Bev significantly improved PFS and OS versus FTD/TPI monotherapy.
Effect size as a tool to identify subpopulations with improved clinical outcomes in metastatic colorectal cancer.
Authors: Stephanie Leigh Fricke, Jeremy D. Kratz, Noelle K. LoConte, Sam Joseph Lubner, Daniel Mulkerin, Kristina A. Matkowskyj, Jens C. Eickhoff, Dustin A. Deming
Journal: Journal of Clinical Oncology (2020)

252 Background: ASCO defined meaningful trial endpoints in colorectal cancer (CRC) to include OS HR ≤0.67 (Ellis, JCO 2014). This measure is limited in identifying treatment benefit for subgroups from heterogeneous populations. Effect size (Glass’s Δ) calculates the absolute difference in median clinical outcomes normalized to the control group standard deviation. We hypothesized that durable effect sizes ≥2 would be useful in predicting which trials possess subgroup populations of clinical significance despite a HR &gt; 0.67. Methods: Prospective phase II-III trials in metastatic CRC from the ASCO Meeting Library (2016-2019) were cataloged by clinical outcomes of PFS and OS. Effect size was calculated from trials reporting confidence intervals and compared with absolute difference in clinical outcome, hazard ratio and therapeutic intervention. Trials with an indeterminant HR, yet effect size &gt; 2 were reviewed in subgroup analyses. Results: 385 abstracts were reviewed with 99 clinical analyses available for effect size calculation. Absolute difference in PFS correlated with effect size (R = 0.64) and was inversely proportional to HR (R = -0.63). The absolute difference in OS correlated with effect size (R = 0.69) and was inversely proportional to HR (R = -0.57). When stratified by clinically significant HR (defined ≤0.67), median effect size for PFS was 13.7±13.3 (SD) which was significantly different from HR &gt; 0.67 with median effect size 1.0±3.8 (p &lt; 0.001). Median effect size for OS when stratified by HR ≤0.67 was 3.7±2.5 which was significantly different when compared to endpoints with HR &gt; 0.67 with median effect size 0.9±1.4 (p &lt; 0.003). Subgroup populations with survival benefit included combination checkpoint blockade durvalumab/tremelimumab vs supportive care with effect size 3.1 (HR 0.72; NCT02870920). First-line PFS benefit was predicted in KRAS wildtype liver-limited CRC treated with FOLFOX+cetuximab vs FOLFOX+bevacizumab by effect size of 3.2 (HR 0.80; NCT01836653). Conclusions: Effect size holds potential as a measure to delineate improved clinical outcomes from heterogeneous populations and could identify those trials for which further subgroup analysis should be explored.
Severe desaturations increase psychomotor vigilance task-based median reaction time and number of lapses in obstructive sleep apnoea patients
Authors: Samu Kainulainen, Brett Duce, Henri Korkalainen, Arie Oksenberg, Akseli Leino, Erna S. Arnardottir, Antti Kulkas, Sami Myllymaa, Juha Töyräs, Timo Leppänen
Journal: European Respiratory Journal (2020)

Current diagnostic parameters estimating obstructive sleep apnoea (OSA) severity have a poor connection to the psychomotor vigilance of OSA patients. Thus, we aimed to investigate how the severity of apnoeas, hypopnoeas and intermittent hypoxaemia is associated with impaired vigilance.We retrospectively examined type I polysomnography data and corresponding psychomotor vigilance tasks (PVTs) of 743 consecutive OSA patients (apnoea-hypopnoea index (AHI) ≥5 events·h-1). Conventional diagnostic parameters (e.g. AHI and oxygen desaturation index (ODI)) and novel parameters (e.g. desaturation severity and obstruction severity) incorporating duration of apnoeas and hypopnoeas as well as depth and duration of desaturations were assessed. Patients were grouped into quartiles based on PVT outcome variables. The odds of belonging to the worst-performing quartile were assessed. Analyses were performed for all PVT outcome variables using binomial logistic regression.A relative 10% increase in median depth of desaturations elevated the odds (ORrange 1.20-1.37, p<0.05) of prolonged mean and median reaction times as well as increased lapse count. Similarly, an increase in desaturation severity (ORrange 1.26-1.52, p<0.05) associated with prolonged median reaction time. Female sex (ORrange 2.21-6.02, p<0.01), Epworth Sleepiness Scale score (ORrange 1.05-1.07, p<0.01) and older age (ORrange 1.01-1.05, p<0.05) were significant risk factors in all analyses. In contrast, increases in conventional AHI, ODI and arousal index were not associated with deteriorated PVT performance.These results show that our novel parameters describing the severity of intermittent hypoxaemia are significantly associated with increased risk of impaired PVT performance, whereas conventional OSA severity and sleep fragmentation metrics are not. These results underline the importance of developing the assessment of OSA severity beyond the AHI.
Is splenectomy for dissecting splenic hilar lymph nodes justified in scirrhous type of gastric cancer?
Authors: Tsutomu Hayashi, Takaki Yoshikawa, Ayako Kamiya, Keichi Date, Takeyuki Wada, Sho Otsuki, Yukinori Yamagata, Hitoshi Katai, Toshirou Nishida
Journal: Journal of Clinical Oncology (2020)

359 Background: Splenectomy for dissecting splenic hilar nodes (#10) should be avoided for most gastric cancer considering high morbidity and no survival benefit, while that is often selected in scirrhous type of gastric cancer because this special type frequently invades the whole stomach and the #10 nodes. Splenectomy is necessary for dissecting #10, however, survival benefit of dissecting #10 is unclear. Methods: Patients who had scirrhous gastric cancer and underwent D2 total gastrectomy with splenectomy in National Cancer Center Hospital, Japan, between 2000 to 2011 were retrospectively analyzed. The therapeutic value index was calculated by multiplying the metastatic rate of each nodal station and the 5-year survival of patients who had metastasis to each node. Results: In total, 144 patients were eligible for the present study. The most frequent metastatic site was the nodes along the lessar curvature (#3, 57%), followed by the nodes along the right gastro-epiploic artery (#4d, 45%), the right nodes located at the cardia (#1, 34%), the nodes along the left gastro-epiploic artery (#4sb, 23%), the inferior nodes at the pyloric ring (#6, 22%), the nodes along the left gastric artery (#7, 21%), the nodes along the short gastric artery (#4sa, 18%), the nodes along the cardiac branched artery (#2, 15%), the nodes around the spleen (#10, 15%), the distal nodes along the splenic artery (#11d, 15%), the proximal nodes along the splenic artery (#11p, 13%), the nodes around the celiac artery (#9, 13%), and the nodes along the common hepatic artery (#8a, 10%). These lymph nodes had a metastatic rate of more than 10%. The node with the highest index was #3(18), followed by #4d(13.4), #1(9.59), #4sa(5.85), #4sb(5.75), #10(4.86), #7(4.16), #11d(4.16), #11p(3.87), #2(3.07), #8a(2.08), and #9(1.39). The index of #10 was exceeded that of #2, #7, #8a, and #9 which are the key nodes dissected in D2. Conclusions: The metastatic rate of splenic hilar nodes was relatively high, and the therapeutic index was the sixth highest in the fifteen regional lymph nodes included in D2 dissection. Splenectomy for dissecting splenic hilar nodes would be justified in scirrhous type of gastric cancer considering its survival benefit.
Abstract 17489: Long Term Echocardiographic Follow-Up as Predictor of Ventricular Arrhythmias in Super-Responders to Cardiac Resynchronization Therapy
Authors: Aafke C van der Heijden, Ulas Hoke, C J Borleffs, Joep Thijssen, Ron Wolterbeek, Enno T van der Velde, Martin J Schalij, Lieselot van Erven
Journal: Circulation (2013)

Background: Super-response to cardiac resynchronization therapy (CRT) is associated with extensive left ventricular (LV) reverse remodelling, resulting in significantly improved clinical outcome, e...
Impact of dose reductions on clinical outcomes among patients (pts) with metastatic pancreatic cancer (mPC) treated with liposomal irinotecan (nal-IRI) in oncology clinics in the United States.
Authors: Paul Cockrum, Andy Surinach, George P. Kim, Daniel Mercer, Jim M. Koeller, Rebecca A. Miksad
Journal: Journal of Clinical Oncology (2020)

665 Background: The recommended starting dose for nal-IRI is 70mg/m 2 (free base, equivalent to 80 mg/m 2 salt-based dosing). This study evaluates the impact of nal-IRI dose reductions on clinical outcomes. Methods: Using the nationwide Flatiron Health electronic health record-derived database, de-identified data were extracted and analyzed for adult mPC pts treated with nal-IRI Jan 2014-Jan 2019 and who initiated treatment at approximately the recommended dose (RD), 70mg/m2 +/- 5mg. Initial dose was derived from structured medication records, prioritizing administrations. The cumulative dose (CD) of nal-IRI over the first six weeks of treatment, the presence of dose reductions (DR) – (a decrease ≥ 7mg/m2), overall survival (OS) from treatment initiation, and duration of treatment (DoT) were assessed. Results: 257 mPC pts treated with nal-IRI (median age: 68y, IQR: 61 - 73) were identified initiating therapy at approximately the RD. 26.5% (N = 68) of pts experienced a DR during treatment. Mean 6-week CD was 175.8 mg/m 2 (SD: 77.9) among pts with no DR. For pts with DR, mean CD was 191.8 mg/m 2 (53.2). Median DoT was 6.1 wks (IQR: 2.1 – 15.3). Pts that experienced a DR had a longer median DoT: 15.1 wks (7.1 – 23.0) vs 4.3. wks (2.1 – 12.1) for pts with no DR. Overall Median OS (mOS) was 4.2 months (95% CI: 3.7 – 5.4). mOS for DR pts was 7.2 mos (95% CI: 5.5 – 9.7) and 3.7 mos (3.0 – 4.1) for pts who did not experience a DR. Conclusions: This real-world analysis suggests that reducing the dose of subsequent administrations of nal-IRI during treatment is associated with pts remaining on therapy longer, experiencing a larger CD, and a with longer OS. Additional real-world prospective studies are necessary to characterize the impact of nal-IRI dosing on clinical outcomes.
Licensure of a Diphtheria and Tetanus Toxoids and Acellular Pertussis, Inactivated Poliovirus, <i>Haemophilus influenzae</i> Type b Conjugate, and Hepatitis B Vaccine, and Guidance for Use in Infants
Authors: Sara E. Oliver, Kelly L. Moore
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

On December 21, 2018 the Food and Drug Administration (FDA) licensed a hexavalent combined diphtheria and tetanus toxoids and acellular pertussis (DTaP) adsorbed, inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib) conjugate (meningococcal protein conjugate) and hepatitis B (HepB) (recombinant) vaccine, DTaP-IPV-Hib-HepB (Vaxelis; MCM Vaccine Company),* for use as a 3-dose series in infants at ages 2, 4, and 6 months (1). On June 26, 2019, after reviewing data on safety and immunogenicity, the Advisory Committee on Immunization Practices (ACIP)† voted to include DTaP-IPV-Hib-HepB in the federal Vaccines for Children (VFC) program.§ This report summarizes the indications for DTaP-IPV-Hib-HepB and provides guidance for its use.
Comparing survival outcomes for neoadjuvant therapy versus adjuvant therapy in the management of stage 1 pancreatic adenocarcinoma: A National Cancer Database study.
Authors: Samit Kumar Datta, Geoffrey Bellini, Maharaj Singh, Nicholas Sich, James L. Weese, Federico Augusto Sanchez, Nalini Guda, Wesley Allan Papenfuss, Aaron Chevinsky
Journal: Journal of Clinical Oncology (2020)

664 Background: We are in the midst of a paradigm shift in the treatment of stage 1 pancreatic ductal adenocarcinoma (PDAC) from surgery first followed by adjuvant therapy (AT) to Neoadjuvant therapy (NAT) first followed by surgery and this is reflected in the current NCCN guidelines as well. Data comparing these two modalities are limited. AIM: To compare long term survival between Surgery + AT and NAT + Surgery in a large National Cancer Database for stage 1 PDAC. Methods: We identified patients with the NCDB with surgically resected AJCC clinical stage 1, 1A, and 1B PDAC between 2004-2016. Patients were stratified into two groups to assess outcomes: AT and NAT. Patients with incomplete survival and sequence of therapy were excluded. Baseline demographic data, 90-Day Mortality, Median survival, and Hazard ratios (HR) for survival was evaluated. Results: 9017 pts with Clinical stage 1, 1A, 1B PDAC between 2004-2016 were identified. Of these 7453 pts had surgery followed by AT; and 1564 pts had NAT followed by surgery. There was a statistically significant difference in age (66.0±9.9 years for AT vs. 64.7±9.78 years for NAT, p &amp;lt; 0.001) but no difference in Charlson Comorbidity Scoring (p = 0.618) or sex (p = 0.073). 90-Day Mortality was 0.35% in the AT group compared to 0.83% in the NAT group (p = &amp;lt; 0.001). Median survival was 28.5 (95% CI 26.5-29.9) months in the NAT group compared to 25.4 (95% CI 24.7-26.1) months in the AT group. With AT as the reference group for survival, there was a HR of 0.904 (95% CI 0.845-0.968, p = 0.003) for NAT. Conclusions: In this retrospective cohort of patients, NAT was associated with increased overall survival. However, NAT was associated with an increased 90 day mortality. A randomized, controlled trial is necessary to further support the superiority of NAT in the management of stage 1 PDAC.
Real-world efficacy and biomarker of nivolumab for advanced gastric cancer.
Authors: Ryohei Kawabata, Yukinori Kurokawa, Takaomi Hagi, Takeshi Omori, Jin Matsuyama, Kazumasa Fujitani, Motohiro Hirao, Yusuke Akamaru, Tsuyoshi Takahashi, Makoto Yamasaki, Taroh Satoh, Yuichiro Doki
Journal: Journal of Clinical Oncology (2020)

388 Background: Although nivolumab demonstrated survival benefit and a manageable safety profile in previously-treated advanced gastric cancer in a phase III trial (ATTRACTION-2), the efficacy of nivolumab in real-world and predictive factors of responses to nivolumab for advanced gastric cancer remain unclear. We evaluated the efficacy of nivolumab and compared clinicopathological characteristics with responses to nivolumab and long-term survivals in patients with gastric cancer. Methods: 205 patients with unresectable or recurrent gastric cancer who were treated with nivolumab as 3rd or more line treatment were enrolled from 23 institutions. Tissue specimens were collected in 199 patients. PD-L1 expression of tumor specimens defined as tumor positive score (TPS) and combined positive score (CPS) and mismatch repair (MMR) were analyzed by immunohistochemistry. Tumor responses were assessed according to RECIST version 1.1. Hyper progressive disease (HPD) was defined as ≥two folds increase in tumor growth rate. Results: 138 out of 205 enrolled patients had measurable lesions. Response rate and HPD rate were 16.7% (23/138) and 22.0% (29/132), respectively. Response rate was significantly higher in patients with performance status (PS) 0-1, non-peritoneal diseases, CPS ≥10, and MMR deficient patients. On the other hand, PS 2-3 and liver metastases were predictive factors of HPD. Patients with CPS≥10 and MMR deficiency showed significantly better progression-free (P = 0.005, P = 0.001) and overall survivals (P = 0.005, P = 0.002). TPS showed no significant association with any outcomes. Conclusions: Real-world efficacy of nivolumab was shown in previously-treated advanced gastric cancer. CPS and MMR could be the useful biomarkers for the efficacy of nivolumab treatment as well as PS and metastasis site. Clinical trial information: UMIN000032164.
Genetic variants in R-Spondin/RNF43 complex and gene expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.
Authors: Francesca Battaglin, Yi Xiao, Joshua Millstein, Andreas Seeber, Hiroyuki Arai, Jingyuan Wang, Alberto Puccini, Ryuma Tokunaga, Madiha Naseem, Shivani Soni, Martin D. Berger, Afsaneh Barzi, Wu Zhang, Sebastian Stintzing, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

190 Background: Wnt signaling deregulation is a primary driver of colorectal carcinogenesis. RNF43 is a key suppressor of Wnt activation while R-Spodin inhibits RNF43 activity. RNF43 mutations are associated with the serrated neoplasia pathway, BRAF mutation and MSI. We hypothesized that genetic variants in the R-Spodin/RNF43 complex and corresponding genes expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 17 functional SNPs within RNF43/ ZNRF3, LGR4/5 and RSPO1/2/3 was analyzed in 129 pts treated with first-line FOLFIRI/cet and 107 pts treated with FOLFIRI/bevacizumab (bev). Gene expression levels were measured from tumor tissue samples from 102 pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. False discovery rate (FDR) for gene expression analysis was computed using the Benjamini-Hochberg approach (significant Q &lt; 0.1). Results: In the cet cohort, pts with the C/C genotype of ZNRF3 rs132531 had significantly shorter overall survival compared to any T allele carriers (mOS: 20.3 vs 52 mo) in both univariable (HR 3.61, 95% CI 1.65-7.88, P &lt; .001) and multivariable analysis (adjusted P = .01). Conversely, RSPO1 rs4652964 any G allele carriers showed increased tumor response (TR) rates compared to the A/A genotype (83 vs 66 %, P = .04). These associations were not observed in bev arm. Lower gene expression levels of RNF43 were associated with shorter PFS in pts with right-sided tumors receiving FOLFIRI/cet ( P = .006, Q &lt; 0.1). RSPO1 expression levels were also associated with TR in the same subgroup (70 vs 10% in high vs low; P = .001, Q &lt; .05). RNF43 expression was associated with TR in pts with left-sided tumors (82% in high vs 58% in low, P = .014, Q = 0.1). Conclusions: Our results provide the first evidence that germline polymorphisms and tumor gene expression levels of RNF43/ ZNRF3 and RSPO1 may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and contribute to modulate anti-EGFRs activity.