bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceptions of Strategies and Intervention Approaches for HIV Self-Management among Ugandan Adolescents: A Qualitative Study
Authors: Mutumba Massy , Mugerwa Henry , Musiime Victor , Gautam Anudeeta , Nakyambadde Hellen , Matama Christine , Stephenson Rob
Published: January 2019

The heightened vulnerability of adolescents to poor HIV care outcomes underscores the need for interventions that create and promote HIV self-management behavioral skills. Adolescents living with HIV (ALHIV) experience a complex array of physical, emotional, and social challenges that constrain their self-care, but the majority of existing psychosocial programs focus primarily on medication adherence. Understanding adolescents’ self-care needs, challenges, and preferences is necessary for developing effective culturally relevant interventions. The involvement of caregivers and stakeholders is also critical to realizing positive self-care outcomes. This article presents the findings from focus group discussions with ALHIV, caregivers, and healthcare providers on self-care. The data were collected as part of formative research in the development of a self-management intervention for Ugandan ALHIV. Participants’ discussions on self-care strategies and intervention approaches provide valuable insights to guide the development of interventions to promote positive HIV care outcomes among Ugandan ALHIV.
Autocrine LTA signaling drives NF-κB and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma
Authors: von Hoff Linda , Kärgel Eva , Franke Vedran , McShane Erik , Schulz-Beiss Kathrin W. , Patone Giannino , Schleussner Nikolai , Kolesnichenko Marina , Hübner Norbert , Daumke Oliver , Selbach Matthias , Akalin Altuna , Mathas Stephan , Scheidereit Claus
Published: January 2019

Persistent NF-κB activation is a hallmark of the malignant Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL). Genomic lesions, Epstein-Barr virus infection, soluble factors, and tumor–microenvironment interactions contribute to this activation. Here, in an unbiased approach to identify the cHL cell-secreted key factors for NF-κB activation, we have dissected the secretome of cultured cHL cells by chromatography and subsequent mass spectrometry. We identified lymphotoxin-α (LTA) as the causative factor for autocrine and paracrine activation of canonical and noncanonical NF-κB in cHL cell lines. In addition to inducing NF-κB, LTA promotes JAK2/STAT6 signaling. LTA and its receptor TNFRSF14 are transcriptionally activated by noncanonical NF-κB, creating a continuous feedback loop. Furthermore, LTA shapes the expression of cytokines, receptors, immune checkpoint ligands and adhesion molecules, including CSF2, CD40, PD-L1/PD-L2, and VCAM1. Comparison with single-cell gene-activity profiles of human hematopoietic cells showed that LTA induces genes restricted to the lymphoid lineage, as well as those largely restricted to the myeloid lineage. Thus, LTA sustains autocrine NF-κB activation, impacts activation of several signaling pathways, and drives expression of genes essential for microenvironmental interactions and lineage ambiguity. These data provide a robust rationale for targeting LTA as a treatment strategy for cHL patients.
Human hematopoietic stem cell maintenance and myeloid cell development in next-generation humanized mouse models
Authors: Sippel Trisha R. , Radtke Stefan , Olsen Tayla M. , Kiem Hans-Peter , Rongvaux Anthony
Published: January 2019

Key Points

Next-generation humanized mice differentially support human HSPC maintenance and myelopoiesis. MISTRG mice support long-term human HSPC maintenance demonstrated by quaternary transplantation and development of human tissue macrophages.
The difference of the gut microbiota of gastric cancer in relation to Helicobacter pylori negativity and positivity.
Authors: Seol Mijin , Lee Yu Ra , Kim Kyung Mi , Shin Cheol Min , Yoon Hyuk , Cho Jae Ho , Song Dong Jin , Kim Nayoung , Park Young Soo , Lee Dong Ho
Published: January 2019

10

Background: Helicobacter pylori (HP) is a major risk factor for gastric cancer, however, only 1-2% of HP(+) people develop adenocarcinoma. In this study, we have compared the intestinal microbiota composition related to HP status among gastric cancer patient using 16SrRNA gene-based metagenomic sequencing analysis and culture-based method. Methods: Stool samples were collected from 18 gastric cancer patients. 16S rRNA genes were sequenced on the Illumina Miseq platform and further analyzed to evaluate the gut bacterial community. The bacteria strains of fecal sample were isolated in aerobic and anaerobic condition. Results: Metagenomics analysis of fecal sample showed four major phyla; Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were dominant. Firmicutes were the most dominant phylum. Within this phylum, the relative abundance of Clostridiales including Ruminococcus was higher in the HP(-) group, whereas Lactobacillales including streptococcus was higher in HP(+) group. In addition the relative abundance of Bacteroidetes in HP(-) group and Actinobacteria (especially, genus Bifidobacterium) in HP(+) group was observed highly. In the bacterial culture-based approach, bacteria strains belonged to Clostridiales such as Clostridium perfringens, Ruminococcus feacis, Blautia sp., Coprococcus comes were isolated in HP(-) sample. In HP(+) sample, Klebsiella, Bacteroides, Bifidobacterium were isolated. Bacillus species, Escherichia/Shigella was enriched regardless of HP exist. Streptococcus was not cultivated in HP(+) group, but isolated in HP(-) group in contrast with metagenome data. Conclusions: We found the intestinal bacterial diversity in the HP(+) group was lower than those in the HP(-) and the microbial composition was different between HP(+) and HP(-). Metagenome analysis showed the order Clostridiales of the phylum Firmicutes were enriched in the HP(-) group while the order Lactobacillales (specially, Streptococcus) were enriched in the HP(+) group. Compared to isolates between two groups, bacteria species belonged to the order Clostridiales such as Clostridium, Ruminococcus , Blautia , Coprococcus were cultivated particularly in HP(-) sample.
Real-world treatment patterns and clinical outcomes in patients receiving second-line (2L) treatment for advanced or metastatic gastric cancer (GC).
Authors: Amonkar Mayur , Gomez-Ulloa David , Kothari Smita , Cheung Winson Y. , Chau Ian , Zalcberg John Raymond , Lara Nuria , Falcone Alfredo
Published: January 2019

102

Background: Despite increased survival demonstrated for patients with advanced / metastatic GC due to 2L chemotherapy, different standard of care options exist. This study aims to describe RW treatment patterns and clinical outcomes in patients with advanced / metastatic GC receiving 2L treatment. Methods: Retrospective chart review study conducted in Australia, Canada, Italy and UK. Patients diagnosed with metastatic / unresectable GC receiving 2L treatment between January 2013 and July 2015 were enrolled. Patient characteristics, treatment patterns and clinical outcomes were captured for 12 months from the start of 2L treatment or until death. Results: 280 patients were included (mean age 60.9 years, 68.9% male). Half of the patients (51.8%) received monotherapy in 2L. Among these, taxanes were most prescribed (69.0%) followed by irinotecan (22.1%). Doublet chemotherapy was the most common combination therapy in 2L (75.6%) with fluoropyrimidine + irinotecan (33.3%) being the most used, followed by fluoropyrimidine + platinum (17.8%). Less than a third of patients (29.3%) received subsequent third-line (3L) treatment; 62.7% received monotherapy [mainly taxanes (69.2%) or irinotecan (19.2%)]. Most 3L patients who had combination therapy received a doublet (86.7%), most frequently fluoropyrimidine combined with irinotecan (53.3%) or platinum (20.0%). The majority of 2L patients (93.6%) had received combination therapy as first-line treatment, of whom 67.9% had received triplet chemotherapy, most commonly anthracycline + fluoropyrimidine + platinum (51.1%). Estimated median real-world progression free survival (PFS) and overall survival (OS) after 2L treatment initiation was 3.09 (95% CI: 2.76-3.68) and 6.54 (5.29-7.76) months, respectively, and estimated probability of PFS and OS at 12 months was 8% and 26%, respectively. Conclusions: The clinical management of advanced / metastatic GC patients in 2L treatment commonly involves taxanes or irinotecan as monotherapy, or irinotecan or platinum-based combinations with fluoropyrimidines. RW clinical outcomes for 2L treatment are similar to randomised controlled trials but remain poor.
Influence of radiation field on safety and efficacy for stage II/III esophageal cancer treated with definitive chemoradiotherapy: An exploratory analysis of JCOG0909.
Authors: Komori Azusa , Hironaka Shuichi , Machida Ryunosuke , Ito Yoshinori , Takeuchi Hiroya , Ogawa Gakuto , Kato Ken , Onozawa Masakatsu , Minashi Keiko , Yano Tomonori , Nakamura Kenichi , Tsushima Takahiro , Hara Hiroki , Nozaki Isao , Ura Takashi , Chin Keisho , Fukuda Haruhiko , Kitagawa Yuko
Published: January 2019

104

Background: JCOG0909, a single-arm confirmatory trial of definitive chemoradiotherapy (dCRT) including salvage treatment, demonstrated promising efficacy and safety for cStage II/III (UICC-TNM 6th) esophageal cancer (EC) (Ito Y, ASCO 2018). Radiation (RT) fields included the elective regional lymph node during initial 41.4 Gy, such as bilateral supraclavicular fossae and superior mediastinal lymph nodes for upper thoracic (Ut), and mediastinal and perigastric lymph nodes for middle thoracic (Mt)/lower thoracic (Lt) EC. It is unclear whether the safety and efficacy are associated with the tumor location in patients with cStage II/III EC treated with dCRT. Methods: Patients who were enrolled in JCOG0909 and underwent dCRT were analyzed. Patients were categorized into three groups according to primary tumor location (Ut/Mt/Lt). We compared adverse events during dCRT, complete response (CR) rate, progression-free survival (PFS) and overall survival (OS) among groups. Results: Ninety-four patients (Ut/Mt/Lt: 16/59/19) were analyzed. The proportions of cStage IIA/IIB/III were 31%/44%/25% in Ut group, 20%/42%/37% in Mt group, and 21%/32%/47% in Lt group, respectively. The summary of safety and efficacy was listed in Table 1. Grade 3-4 leukopenia, neutropenia and thrombocytopenia were more frequently observed in Mt and Lt groups than in Ut group. CR rate was 63% in Ut, 63% in Mt, and 42% in Lt, respectively. 3-year PFS in Ut/Mt/Lt was 60%/59%/47% and 3-year OS was 73%/78%/58%, respectively. Conclusions: The RT field by the tumor location might be associated with efficacy and safety of dCRT for cStage II/III esophageal cancer. [Table: see text]
Comparison of real-world treatment patterns, persistence, healthcare resource utilization (HRU) and costs between octreotide and lanreotide for the treatment of neuroendocrine tumors (NET).
Authors: Huynh Lynn , Cai Beilei , Sharperson Camara , Lejeune Dominique , Duh Mei Sheng , Kim Michelle Kang
Published: January 2019

105

Background: There has been limited research assessing differences between somatostatin analogues (SSAs) as treatments for NET. This study aims to assess treatment pattern, persistence, HRUs and costs among patients (pts) with NET receiving long-acting octreotide versus lanreotide. Methods: Retrospective claims data from Symphony Health Solutions were analyzed for NET pts who initiated octreotide or lanreotide (index date) between 01/2015–11/2017 for ≥ 90 days. Pts with continuous clinical activity (≥ 180 pre and ≥ 90 days post index date) and without prior non-surgical NET treatment were included. A 1:1 propensity score matched sample was used to compare the two SSA groups with respect to treatment persistence (time to treatment discontinuation [TTD] using Kaplan-Meier) and to all cause and NET related HRUs and costs (provider charges for medical services and insurance payments for prescription drugs) using rate ratio (RR) and mean cost difference (CD) with 95% confidence interval (CI). Results: Among 2,043 NET pts identified, a balanced matched cohort of octreotide and lanreotide pts (N = 543 each) was achieved. In both cohorts, mean age was 65 years and baseline Charlson Comorbidity Index was 5.7. Approximately 80% of matched pts initiated monotherapy; others used SSAs in combination with chemo-, targeted or liver-directed therapy as first line therapy. Median TTD was directionally longer but did not reach statistical significance among octreotide vs lanreotide (19.2 vs 17.5 months, p = 0.6). Numerically lower hospitalization rates were observed among octreotide pts (RR [CI]: all cause = 0.87 [0.73, 1.05]; NET related = 0.85 [0.63, 1.15]). Statistically significantly fewer NET related outpatient visits (1.05 vs 1.10 per pts per month [PPPM]; RR [CI]: 0.95 [0.92, 0.99]) and lower total mean costs PPPM were observed for octreotide than lanreotide (CD [CI]: all cause = -$3,701 [-$5,205, -$2,355]; NET related = -$3,752 [-$4,948, -$2,455]). Conclusions: This study shows similar treatment patterns and persistence between SSA cohorts. Octreotide appeared to be associated with less HRU and total costs compared with lanreotide.
Efficacy of three-drug induction chemotherapy followed by preoperative chemoradiation in patients with localized gastric adenocarcinoma (GAC).
Authors: Mizrak Kaya Dilsa , Nogueras-Gonzalez Graciela M. , Das Prajnan , Blum Murphy Mariela A. , Ghazanfari Amlashi Fatemeh , Rogers Jane Elizabeth , Thomas Irene , Shanbhag Namita , Lee Jeffrey H , Bhutani Manoop S. , Weston Brian , Minsky Bruce D. , Matamoros Aurelio Aurelio , Sagebiel Tara L. , Devine Catherine E , Estrella Jeannelyn , Badgwell Brian D. , Ajani Jaffer A.
Published: January 2019

106

Background: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized GAC.Previous studies with two-drug induction chemotherapy showed 70-80% R0 resection rates and 20-30% pCR rates. We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients. Methods: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate). Results: The median follow-up time was 3.5 years (range; 0.4-16.7). Most of the patients were men (60.8%) and the median age was 60 years (range; 21-89). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75%) out of 97 patients underwent planned surgery. R0 resection and pCR rate were 93% and 21%, respectively. Pathologic partial response (< 50% residual carcinoma) rate was 50.7%. The median OS was 6.43 years (95% Cl 3.27-12.36) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72% (95% CI 62-80) and 54% (95% CI 43-64) for the entire cohort and 83% (95% CI 72-91) and 66% (95% CI 53-76) for patients that underwent surgery. Pathological lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.019) were independently associated with longer RFS in the multivariate analysis. Conclusions: Our data show that three-drug combination is feasible without providing substantial advantage in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery.
The impact of muscle mass loss after esophagectomy for esophageal cancer on prognosis.
Authors: Shimoda Yota , Ogata Takashi , Nagasawa Shinsuke , Kumazu Yuta , Hayashi Tsutomu , Yamada Takanobu , Oshima Takashi
Published: January 2019

107

Background: Several reports revealed that preoperative presence of sarcopenia was related with poor prognosis for esophageal cancer. However, the influence of muscle mass loss during perioperative period on prognosis is unknown. The alternation of muscle mass during perioperative period is attractive topic as surgeon have chance to intervene for maintaining muscle mass in perioperative care. The aim of this study was to assess the influence of loss of muscle after esophagectomy to discharge on prognosis. Methods: This study retrospectively analyzed 150 consecutive patients with esophageal and gastroesophageal junction cancer, who underwent the open right thoraco−abdominal approach esophagectomy, pathologically diagnosed as squamous cell carcinoma or adenocarcinoma, between September 2011 and June 2015. Patients who had pathologically diagnosed as T4 or stageⅣ according to the UICC 7th edition TNM classification were excluded. This study investigated the influence of muscle mass loss after esophagectomy to discharge on prognosis. Body composition was analyzed using the Tanita MC−190EM bioelectrical impedance analyzer, evaluated within 1 week before surgery and at discharge. The primary end−point is over−all survival after esophagectomy. Results: The median % muscle mass loss was 4.38% (range −3.3 to +18.8). Patients were divided into two groups based on the % muscle mass loss by cut−off 4.38 (group A: less % muscle mass loss, group B: more % muscle mass loss). N stage (0/1/2/3) was 39/28/6/2 in group A, and 26/23/19/7 in group B. The rate of 2/3 was significantly higher in group B. Postoperative complication rate was 31% (23/75) in group A, and 48% (36/75) in group B. The complication rate was significantly higher in group B. The 3−years survival rate was 89.2% in group A, and 70.9% in group B. Group B was significantly worse for over−all survival than group A (p = 0.033). Multivariate Cox regression analysis showed that the patients who had % muscle mass loss over 4.38 (p = 0.045; HR 2.008; HR 95% CI 1.014−3.977), T2/3 (p = 0.001; HR 3.649; HR 95% CI 1.660−8.019) associated with worse over−all survival. Conclusions: Our study found correlation between loss of muscle after esophagectomy to discharge and worse outcomes.
Role of volume reduction gastrectomy according to tumor location in patients with gastric cancer with a single noncurable factor: REGATTA trial (JCOG0705/KGCA01) supplementary analysis.
Authors: Terashima Masanori , Fujitani Kazumasa , Yang Han-Kwang , Mizusawa Junki , Tsujinaka Toshimasa , Nakamura Kenichi , Katayama Hiroshi , Lee Hyuk-Joon , Lee Jun Ho , Iwasaki Yoshiaki , An Ji Yeong , Takagane Akinori , Park Young-Kyu , Choi Seung Ho , Song Kyo Young , Sasako Mitsuru
Published: January 2019

109

Background: Chemotherapy (CTX) is the standard of care for incurable advanced gastric cancer (AGC). REGATTA trial, which investigated survival benefit of reduction gastrectomy (Gx) in patients (pts) with AGC with a single non-curable factor, failed to demonstrate the superiority of Gx followed by CTX over CTX alone. However, there was a significant interaction between the treatment effect and tumor location in the subset analysis. In addition, treatment effect appeared to be different between Japan and Korea. So, the aim of this supplementary analysis was to explore the subgroups for which volume reduction Gx was beneficial with special reference to the tumor location and country. Methods: REGATTA trial was a randomized phase III trial at 44 institutions in Japan, Korea, and Singapore. Patients with AGC with a single non-curable factor were randomly assigned in each country to CTX alone or Gx plus CTX. The primary endpoint was overall survival (OS). In this analysis, OS was compared according to tumor location, country, and operative procedure. Results: A total of 175 pts (95 in Japan, 80 in Korea) was randomized to CTX alone (86 pts) or Gx followed by CTX (89 pts). MST was 16.6 months in CTX alone and 14.3 months in GX plus CTX (HR 1.09, 95% CI: 0.78–1.52, p = 0.70) (primary analysis). In subgroup analysis according to the country, OS curves were separated between the arms, worse in Gx plus CTX arm in Japan (HR 1.32, 95% CI: 0.85-2.05), whereas, that was not in Korea (HR 0.85. 95% CI: 0.52-1.40). HRs according to tumor location were 2.23 in upper third, 0.95 in middle third, and 0.63 in lower third. OS tended to be better in pts who received distal GX compared with CTX alone (HR = 0.69), and worse in pts who received total GX compared with CTX alone (HR = 1.34). This trend was more remarkable in Korea than in Japan. Multivariate analysis demonstrated that histological type was selected as an independent prognostic factor. Conclusions: Primary CTX is a standard of care for AGC; however, it would be still an open question whether volume reduction Gx have a survival benefit when the tumors located at the distal stomach for which the pts receive distal Gx. Clinical trial information: UMIN000001012.
A retrospective analysis of neoadjuvant chemotherapy followed by surgery or definitive chemoradiotherapy in patients with advanced esophageal squamous cell carcinoma.
Authors: Nakatsumi Hiroshi , Komatsu Yoshito , Nakano Shintaro , Sawada Kentaro , Muranaka Tetsuhito , Kawamoto Yasuyuki , Yuki Satoshi , Uchinami Yusuke , Taguchi Hiroshi , Shirato Hiroki , Ebihara Yuma , Shichinohe Toshiaki , Hirano Satoshi , Sakamoto Naoya
Published: January 2019

115

Background: The standard treatment of resectable esophageal cancer in Japan is neoadjuvant chemotherapy (NAC) followed by surgery, while definitive chemoradiotherapy (CRT) is considered as an alternative treatment. There are no randomized clinical trials comparing NAC and CRT in Japan. The aim of this study was to evaluate the efficacy of NAC or CRT in clinical practice. Methods: We retrospectively analyzed the clinical data of 43 patients (pts) with clinical stage IB/II/III thoracic esophageal squamous cell carcinoma (ESCC) who received NAC (n = 26) or CRT (n = 17) in Hokkaido University Hospital from January 2009 to December 2014. To compare NAC with CRT, Fisher’s exact test or Mann-Whitney U test was used in terms of pts’ characteristics, and Log-rank test was used in progression-free survival (PFS) and overall survival (OS). Results: Pts’ characteristics were as follows; Gender (male/female): 24/2 in NAC and 16/1 in CRT, median age (range): 65y (55-78) in NAC and 72y (57-80) in CRT, primary lesion (Ut/Mt/Lt): 4/12/10 in NAC and 2/9/6 in CRT, clinical stage IB-II/III: 11/15 in NAC and 9/8 in CRT. Four pts (15.4%) in NAC and seven pts (41.2%) in CRT had multiple primary cancer. All pts in NAC and 15 pts in CRT received 5-FU+cisplatin (CDDP), and two pts in CRT received 5-FU+nedaplatin. RT dose in CRT was 50.4Gy in 11 pts, 59.4Gy in five pts and 60Gy in one patient. Four out of 10 pts in NAC with local recurrence received salvage CRT, and three out of 10 pts in CRT with local recurrence received salvage surgery. Median PFS was 21.6 months in NAC and 8.7 months in CRT (HR 1.282, 95% confidence interval (CI) 0.871-1.887, p = 0.203), and median OS was 50.4 months in NAC and 48.6 months in CRT (HR 1.151, 95% CI 0.752-1.761, p = 0.516). 5-year OS rate was 49.7% in NAC and 48.3% in CRT. Conclusions: Definitive CRT showed comparable outcome to NAC followed by surgery in pts with resectable thoracic ESCC. Efficacy of NAC or CRT were not sufficient compared to clinical trials. Improvement in efficacy by development of optimal multimodality therapy was warranted.
A phase I/Ib study of crenolanib with ramucirumab (RAM)/paclitaxel (PTX) as second-line therapy (2L tx) for advanced esophagogastric adenocarcinoma (EGA).
Authors: Greally Megan , Jha Sujata , Yoon Sam S. , Li Jia , Desai Avni Mukund , Won Elizabeth , Kelsen David Paul , Ilson David H. , Janjigian Yelena Yuriy , Aljallad Kathrena , Ku Geoffrey Yuyat
Published: January 2019

116

Background: PTX/RAM as 2L tx for patients (pts) with EGA is a standard-of-care based on the RAINBOW trial (Lancet Oncol 2014;15:1224). However, benefit is modest. Upregulation of the platelet-derived growth factor (PDGF)/PDGF receptor-β (PDGFR-β) pathway causes resistance to VEGF inhibition. Crenolanib is a selective inhibitor of PDGFR-β. We report initial results of the dose escalation phase of a study of crenolanib plus RAM/PTX in pts with previously treated advanced EGA. Methods: This phase I/Ib study is enrolling ECOG PS 0-1 EGA pts with progression on first-line chemo. PTX 80 mg/m2/ day on day 1, 8, 15 and RAM 8mg/kg q 14 days were administered with escalating doses of crenolanib (60, 80, 100 mg BID) after a 7 day “run-in” of crenolanib to assess crenolanib-related toxicities. The primary objective was to determine the maximum tolerated dose (MTD) of crenolanib plus RAM/PTX. Safety and preliminary efficacy were examined. Results: 15 pts were treated; 12 male, median age 58 (32-73), 66% were ECOG PS 1. Primary site was gastric in nine pts, GEJ in 4 pts and esophageal in two pts. Three pts each received crenolanib 60mg BID and 80mg BID, six pts received 100mg BID and three pts received higher doses. At data cutoff, eight pts continued on treatment. 12 pts have completed the DLT evaluation period across 3 dose levels (60 to 100 mg BID). Median treatment duration was 76 days (35-191). The combination was well tolerated, with no DLTs or serious adverse events (SAEs) attributed to study drug. Treatment related adverse events occurred in two pts (17%), all grade 1. These were fatigue, nausea, vomiting and hypertension. Disease progression was the most common reason for treatment discontinuation; no pt discontinued due to study drug related AEs. Nine pts were evaluable for response. One pt had objective response; the disease control rate was 78%. Median PFS and OS were 4.1 and 11.9 months respectively. Conclusions: Crenolanib plus RAM/PTX appears well tolerated at a dose level of 100mg BID. Further evaluation is needed to determine efficacy. Accrual is ongoing at higher doses. Once the MTD is defined, the dose expansion phase will enroll 25 pts. Updated data with pharmacokinetics and biomarkers will be presented. Clinical trial information: NCT03193918.
Systemic chemo (CTX) plus surgery and intraperitoneal (IP) CTX for patients (pts) with gastric cancer (GC) and peritoneal carcinomatosis (PC).
Authors: Greally Megan , Strong Vivian E. , Yoon Sam S. , Chou Joanne F. , Capanu Marinela , Kelsen David Paul , Janjigian Yelena Yuriy , Ilson David H. , Ku Geoffrey Yuyat
Published: January 2019

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Background: The role of IP CTX in pts with GC and PC is unclear. The PHOENIX-GC phase III study (J Clin Oncol 2018;35:1922) did not show overall survival (OS) benefit for IP CTX plus systemic CTX while a retrospective French study suggested benefit for IP CTX and cytoreductive surgery (J Clin Oncol 36:8 [abstr]). Prolonged survival may be possible in pts with chemosensitive disease (dz). Methods: We reviewed GC pts diagnosed with PC (+ve cytology and/or gross dz) at diagnostic laparoscopy (DL). We identified pts treated with gastrectomy and IP floxuridine 1,000mg/ m2/leucovorin 240 mg/m2 ×3d q14d and pts who had CTX alone. Pts with visible dz on imaging were excluded. Progression-free survival (PFS) and OS were calculated from surgery date and estimated using Kaplan-Methods in surgery + IP CTX pts. Pt characteristics were compared using Fisher’s exact test and Wilcoxon Rank-Sum tests. Results: From 2000-2017, 18 pts had surgery + IP CTX (IP); 45 pts received CTX alone. Median age was 50 in IP pts and 65 in CTX only pts (p = 0.002); 94% of IP pts were ECOG PS 0/1 vs. 78% in CTX only pts (p = 0.16). 56% and 67% of pts had gross dz at DL in IP and CTX only pts respectively; remaining pts had +ve cytology only. IP pts received CTX (72% 5-FU/platinum based) for a median 3.3 months before repeat DL. 14/18 pts cleared dz; four pts with residual dz (1 +ve cytology only) had gross dz at baseline. Fourteen pts had R0 resection; 83% of tumors were ypT3-4N+. 4 pts had R1 resection; three had residual gross PC at DL. Pts received IP CTX for a median of 1 month post surgery. Median PFS and OS were 12.4 and 23 months respectively in surgery + IP CTX pts. While there was no difference in PFS in pts with -ve vs. persistently +ve cytology at repeat DL following CTX (15.5 vs. 4.7 months, p = 0.3), median OS was improved in pts who cleared cytology (29 vs. 8 months, p = 0.01). Median PFS and OS were 7 and 13.5 months respectively in CTX only pts. Conclusions: Surgery and IP CTX may have a role in highly select pts with GC and +ve cytology or small-volume gross dz. While survival was encouraging, no pt had OS > 5 years. Surgery and IP CTX may be considered in pts who have a -ve repeat DL after initial CTX. Survival in CTX only pts is comparable with stage IV pts enrolled on clinical trials.
Impact of radiation dose during neoadjuvant chemoradiation on postoperative complications in esophageal (EC) and gastroesophageal junction cancers (GEJC).
Authors: Kastelowitz Noah , Marsh Megan D. , McCarter Martin , Meguid Robert A. , Schefter Tracey E. , Rooke Douglas A. , Stumpf Priscilla , Leong Stephen , Messersmith Wells A. , Lieu Christopher Hanyoung , Leal Alexis Diane , Davis S. Lindsey , Purcell William T. , Mitchell John D. , Weyant Michael J. , Scott Christopher , Goodman Karyn A.
Published: January 2019

119

Background: Neoadjuvant chemoradiation (nCRT) followed by resection is standard of care for operable stage II-III EC and GEJC; however, it can be associated with significant risk of postoperative complications (POC). The CROSS study group reported no increase in POC severity with nCRT using 41.4 Gy compared to surgery alone as defined by the Comprehensive Complication Index (CCI). We applied the CCI metric to evaluate the impact of nCRT radiation dose of < 50 Gy vs. ≥ 50 Gy on POC rates and compared to the CROSS rates. Methods: We retrospectively reviewed 82 pts (2004-2016) with EC or GEJC treated with nCRT followed by resection at our institution. 29 (35%) pts were treated with < 50 Gy (range 39.6-46.8 Gy) and 53 (65%) were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Concurrent chemotherapy were carboplatin/paclitaxel (59%), cisplatin/5-FU (17%), or other (24%). Resection was performed by Ivor Lewis esophagectomy (67%), esophagogastrectomy (14%), or trans-hiatal approach (11%). POC within 30 days were graded using the Clavien-Dindo scale and CCI scores were computed and compared between the two dose groups and with the CROSS nCRT group. Results: CCI scores and complication rates between our < 50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS CCI scores, there was no significant difference in CCI scores between the CROSS study nCRT, < 50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS study. Conclusions: In highly selected EC and GEJC pts, definitive nCRT radiation doses do not appear to increase POC rates. Thus, 50 Gy can likely be delivered without increasing toxicity while also achieving a definitive dose for pts not able or willing to undergo subsequent surgery. [Table: see text]
The impact of infectious complications on long-term prognosis after curative resection for gastric cancer.
Authors: Maezawa Yukio , Aoyama Toru , Tamagawa Hiroshi , Sato Tsutomu , Ogata Takashi , Cho Haruhiko , Oshima Takashi , Yukawa Norio , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka
Published: January 2019

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Background: Several studies have reported that postoperative complications such as anastomotic leakage affect long-term prognosis after gastric cancer surgery. This study aimed to determine whether or not long-term outcomes were affected by the postoperative inflammatory complications in patients who underwent curative resection for gastric cancer. Methods: The patients were retrospectively selected from the medical records of consecutive patients who underwent curative gastrectomy with nodal dissection for gastric cancer at Yokohama City University and Kanagawa Cancer Center from January 2000 to August 2015. Inflammatory complications were evaluated according to the Clavien-Dindo classification. Overall survival (OS) was compared between postoperative inflammatory complications (IC) and no-complication (NC) groups. Results: A total of 2,254 patients were eligible for inclusion in the present study. One hundred seventy-five patients had IC group, while 2,079 patients had not. Operation time (p < 0.001), blood loss (p < 0.001) was significantly greater in the IC group. The incidence of postoperative inflammatory complication grade 2 or higher was 8.5% in which, pancreatic fistula (2.8%), anastomotic leakage (1.8%) were occurred. The mortality rate was 0.18%. The five-year OS rates of the IC and NC groups were 74.9% and 83.2%, respectively. The difference was statistically significant (p = 0.015). Multivariate Cox’s proportional hazard analyses demonstrated that the postoperative inflammatory complications were a significant prognostic factor for OS. Conclusions: Postoperative inflammatory complications have an obvious impact on the OS in curatively resected gastric cancer patients. It is necessary to reduce the incidence of postoperative complications.
Oncologic outcomes after laparoscopic and open distal gastrectomy for advanced gastric cancer: A propensity score matching analysis.
Authors: Chung Yoona , Choi Sung Il , Hong Kyungpyo , Kim Sanghyun
Published: January 2019

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Background: The aim of this study is to investigate the oncologic outcomes as well as short-term outcomes of laparoscopic distal gastrectomy compared with open distal gastrectomy for advanced gastric cancer using propensity-score matching analysis. Methods: A total of 384 patients underwent distal gastrectomy for advanced gastric cancer from July 2006 to November 2016. Data on short- and long-term outcomes were collected prospectively and reviewed. Propensity-score matching was applied at a ratio of 1:1 comparing the laparoscopic distal gastrectomy (LDG) group and open distal gastrectomy (ODG) groups. Results: The LDG group showed longer operative time than the ODG group. However, resumption of diet and length of hospital stay were shorter in the LDG group than in the ODG group (4.7 vs. 5.6 days, p= 0.049 and 9.6 vs. 11.5 days, p= 0.035, respectively).The extent of lymph node dissection in the LDG group was more limited than in the ODG group ( p= 0.002), although there was no difference in the number of retrieved lymph nodes between the two groups. The 3-year overall survival rates were 98% and 86.9% ( p= 0.018), whereas the 3-year recurrence-free survival were 86.3% and 75.3%, p= 0.259) in the LDG and the ODG groups. Conclusions: Laparoscopic distal gastrectomy is safe and feasible for advanced gastric cancer in terms of earlier recovery after surgery and long-term oncologic outcomes.
Safety and efficacy of dasatinib in patients with advanced gastrointestinal stromal tumors refractory to imatinib and sunitinib: A single arm, multicenters, phase 2 trial.
Authors: Li Jian , Zhou Ye , Zhang Xinhua , WU Xiaojun , Zhou Yongjian , Liu Xiufeng , Zhang Bo , Wu Xin , Lin Shen
Published: January 2019

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Background: Regorafenib is recommended to treat advanced gastrointestinal stromal tumor (GIST) refractory to imatinib and sunitinib. However, the efficacy is not satisfied, other active agents need to be explored to advanced patients. Methods: In this single arm, multi-center, phase 2 trial, we enrolled patients aged 18 years and older with advanced GIST who had received previous imatinib and sunitinib treatment. Participants were treated with oral dasatinib 50mg twice a day for 2 weeks. If patients were tolerable, then they received dasatinib 70mg twice a day treatment, to tumor progression or intolerable toxicities. The primary endpoint was RECIST-based progression-free survival (PFS) in the intention-to-treat population. The secondary endpoints included response rate, overall survival (OS) and advent events. ctDNA will be analysis in some patients to explore the sensitive biomarker to dasatinib. Results: From May 2016 to June 2018, 58 patients from nine medical centers were enrolled in this study. Two patients had partial response and disease control rate was 62.0%. The median PFS was 3.0 months (95% CI, 2.6-3.4 months). There was no statistic difference of PFS in both subgroup with different primary mutations and in subgroup with different secondary mutations. The patients with wild type GIST had a trend of longer PFS of 5.5 months. In 4 patients with PDGFRA D842V mutation, two patients had stable disease. The median OS was 14.0 months (95% CI, 10.8-17.2 months). The most frequently observed grade 3 adverse events included anemia (10.3%), diarrhea (1.7%). The analysis of ct DNA is ongoing. Conclusions: Dasatinib is an active treatment for patients with GIST who are refractory to imatinib and sunitnib. This study is registered with ClinicalTrials.gov, NCT02776878 . Clinical trial information: NCT02776878.
An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in patients with relapsed gastric cancer.
Authors: Bang Yung-Jue , Kaufman Bella , Geva Ravit , Stemmer Salomon M. , Hong Sook-Hee , Lee Jong-Seok , Domchek Susan M. , Lanasa Mark C. , Tang Mei , Gresty Christopher , Angell Helen K , Opincar Laura L.M. , Herbolsheimer Pia Maarit , Evans T.R. Jeffry
Published: January 2019

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Background: Olaparib is a PARP inhibitor that has shown activity in relapsed gastric cancer (GC) when combined with chemotherapy. MEDIOLA assesses the efficacy and safety of a chemo-free combination of olaparib and durvalumab, an anti-programmed cell death ligand-1 (PD-L1) agent in patients (pts) with solid tumors, including relapsed GC (NCT02734004). Methods: Eligible pts had GC that relapsed following platinum-containing therapy. Pts received olaparib 300 mg PO BID for a 4-wk run-in to allow for serial biopsies, followed by combination olaparib and durvalumab (1.5 g IV q 4 wks) until progressive disease (PD) as measured by RECIST 1.1. Tumor measurements were taken at baseline, 4 wks and q 8 wks thereafter. Primary endpoints were disease control rate (DCR) at 12 wks, safety, and tolerability. The secondary endpoints included DCR at 28 wks, objective response rate (ORR), duration of response (DoR), progression-free survival, and OS. Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes. Bayesian predictive probability design was used for statistical analysis. Results: Forty pts were included in the safety and 39 in the efficacy analysis. Among 39 pts, median age was 57 yrs (range 28–77). Nineteen pts (48%) had a grade 3 AE; three pts (8%) a grade 4 AE. Most common AEs were anemia, lipase increase, fatigue, dysphagia, hyponatremia, and alkaline phosphatase increase. Ten pts (25%) had immune-mediated AEs, most commonly rash. The ORR was 10%; two pts had complete response; two had partial response. Median DoR was 11.1 months. DCR at 12 wks was 26%. Further efficacy and biomarker data will be presented. Conclusions: The combination of olaparib and durvalumab was tolerable, with no unexpected AEs. All responses occurred after the addition of durvalumab and were durable, suggesting synergistic treatment effect of the combination in some pts. Furthermore, several pts with early PD showed unexpectedly long survival. DCR at 12 wks was below the target (70%) due to a high rate of early PDs following the olaparib run-in. To address the early treatment failures, an upfront addition of more aggressive therapies to the combination should be explored. Clinical trial information: NCT02734004.
A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106).
Authors: Yukami Hiroki , Goto Masahiro , Kii Takayuki , Terazawa Tetsuji , Yamaguchi Toshifumi , Shimamoto Fukutaro , Nishitani Hitoshi , Kawakami Hisato , Shimokawa Toshio , Matsubara Yoshihiro , Sakai Daisuke , Kurokawa Yukinori , Satoh Taroh
Published: January 2019

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Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.
Clinical impact of newly developed sarcopenia after surgical resection for gastric cancer.
Authors: Kim Beom Jin , Lee Eun Sun , Park Jae Yong , Kim Jae Gyu
Published: January 2019

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Background: The purpose of this study was to investigate the risk factors and the clinical impact of of newly developed sarcopenia after surgical resection on the prognosis in patients undergoing radical gastrectomy for gastric cancer. Methods: We retrospectively reviewed clinicopathological data from 430 consecutive GC patients who underwent surgical resection at Chung-Ang University Hospital between January 2011 and December 2015. Their skeletal muscle mass and abdominal fat volume were measured by abdominal CT imaging. Results: A total of 425 patients were analyzed in the study. The mean age was 62 years old and male were 301 (70.8%). Of these, 42 patients (9.9%) were diagnosed as pre-operative sarcopenia. Compared with non-sarcopenic group, pre-operative sarcopenia groups showed more female, higher BMI, less alcoholic, and less smoking. However, there was no significant difference in 5-year overall survival and disease free survival between the groups (p=0.836 and p=0.638, respectively). Among 381 non-sarcopenic patients, 48 patients (12.6%) were diagnosed as newly developed sarcopenia in one year after gastric resection. Compared with non-sarcopenic group, the newly developed sarcopenic group showed more male, more undifferentiated tumor, lower hemoglobin level, less alcoholic, less smoking, and presence of diabetes mellitus. Furthermore, newly developed sarcopenic group showed more total fat area, especially more subcutaneous fat area and lower VFA / SFA ratio in the abdominal CT imaging. However, there was no significant difference in the 5-year overall survival and disease free survival among non-sarcopenic, sarcopenic, and newly developed sarcopenic groups (p=0.521 and p=0.534, respectively). The relationship between preoperative body fat volume and postoperative muscle mass showed a significant correlation (rho = 0.296, p <0.001), but only BMI was significantly associated with long term survival. Conclusions: Although newly developed sarcopenia after surgery did not affect the survival rate, patients with nutritional risk of sarcopenia after surgical resection may require early evaluation of nutritional status and nutritional support.
Evaluation of safety and tolerability of durvalumab (D) and tremelimumab (T) in combination with first-line chemotherapy in patients (pts) with esophageal squamous-cell carcinoma (ESCC).
Authors: Lee Dae Ho , Kim HyeRyun , Keam Bhumsuk , Kato Ken , Kuboki Yasutoshi , Vlahovic Gordana , Takahashi Osamu , Fitts David , Ahn Myung-Ju
Published: January 2019

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Background: Platinum-doublet chemotherapy in first-line (1L) ESCC pts has reached a therapeutic plateau, and new therapeutic strategies are needed. Adding D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) to 1L platinum-based chemotherapy may improve outcome in pts with advanced/metastatic ESCC. Methods: In Part A of this Phase 1b study (NCT02658214), dose-limiting toxicities (DLTs) for D+T (D 1.5 g + T 75 mg on d1, q4w) plus 5-FU+cisplatin (5-FU 800 mg/m2 + cisplatin 80 mg/m2 d1-5, q4w) were evaluated for the first 4 cycles in pts with advanced/metastatic ESCC who were eligible for 1L chemotherapy. The primary objective was safety and tolerability and exploratory objectives included antitumor activity and biomarker analysis. Results: Pts (N = 6) were enrolled to receive D+T + 5-FU+cisplatin between November 13, 2017, and February 14, 2018. Median age was 56 years, 83% were male, and all were ECOG PS 1. Four pts had recurrent disease and 2 were newly diagnosed with advanced/metastatic disease. All 6 pts had ≥1 treatment-related adverse event (trAE), 3 pts had grade ≥3 trAEs. All pts experienced 5-FU+cisplatin-related AEs. All grade ≥3 trAEs were neutropenia and considered due to 5-FU+cisplatin treatment; 2 were grade 3 and 1 was grade 4, which was the only serious trAE reported. Two pts had D- and/or T-related trAEs. Immune-mediated AEs were grade 1 or 2 and included diarrhea (n = 1), pruritus (n = 1), rash (n = 1), and increased AST (n = 1). There were no trAEs that led to discontinuation or death. Two of the 6 pts had a confirmed partial response that was ongoing at data cutoff (June 29, 2018). Conclusions: For patients in the ESCC DLT evaluation cohort, D+T + 5-FU+cisplatin was tolerable, and no unexpected toxicities occurred. No DLTs were observed for this regimen. The majority of trAEs and all trAEs grade ≥3 were attributed to 5-FU+cisplatin, and all were manageable. AEs related to D and/or T were all grade 1 or 2. No treatment discontinuation or death was attributed to trAEs. The study has been expanded to further evaluate this regimen in additional patients for efficacy, safety, and biomarkers. Clinical trial information: NCT02658214.