tbuckley/cabot-search huggingface dataset:
The role of neoadjuvant chemotherapy in elderly patients with borderline or locally advanced pancreatic cancer: Is it safe and feasible?
Authors: Atsushi Oba, Christopher Hanyoung Lieu, Cheryl Lauren Meguid, Sarah Lindsey Davis, Alexis Diane Leal, Tom Purcell, Gentry Teng King, Karyn A. Goodman, Tracey E. Schefter, Ana Luiza Gleisner, Steven Arthur Ahrendt, Stephen Leong, Wells A. Messersmith, Richard D. Shulick, Marco Del Chiaro
Journal: Journal of Clinical Oncology (2020)

685 Background: For borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC), neoadjuvant (NAT) FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP) are standard treatment options and these regimens have shown a survival advantage over single-agent gemcitabine. However, the role of these modern therapeutic regimens in elderly patients is debatable. In this analysis, we evaluated the outcomes of neoadjuvant treatment (NAT) with combination chemotherapy in elderly patients. Methods: 230 consecutive patients who underwent neoadjuvant treatment for BRPC/LAPC discussed and planned for NAT at the University of Colorado Cancer Center from January 2011 to March 2019 were reviewed. 214 patients who received FOLFIRINOX (n = 143) or GnP (n = 71) were eligible for analysis. We divided all patients into three groups ( &lt; 70, 70-74, ≥75 years) and compared the short-term and long-term outcomes. Results: Of 214 patients, patients &lt; 70 (n = 147) received FOLFIRINOX more frequently than the other groups (p &lt; 0.001): FOLFIRINOX: 115 cases, GnP: 32 cases, 70-74 years (n = 33): FOLFIRINOX: 15 cases, GnP: 18 cases, and ≥75 years (n = 34): FOLFIRINOX: 13 cases, GnP: 21 cases. Resection rates were not statistically different between three groups ( &lt; 70: 62%, 70-74: 70%, ≥75 years: 56%, p = 0.504). There was a slight trend towards worse survival in the two older groups (Median Survival Time [MST]: &lt; 70: 23.2 mo., 70-74: 19.5 mo., ≥75 years: 17.6 mo., p = 0.075) The FOLFIRINOX group was superior to GnP group in all three groups (MST: &lt; 70: 25.6 vs 18.2 mo., p = 0.017; 70-74: 33.2 vs 16.1mo., p = 0.029; ≥75 years: not reached vs 16.1 mo., p = 0.135). There were no toxic deaths or 30 day mortality after pancreatectomy in the study population. Conclusions: Neoadjuvant combination chemotherapy regimens were safe and feasible for elderly patients. Neoadjuvant therapy with FOLFIRINOX was associated with a survival advantage vs GnP and is an good option for fit and elderly patients ≥75 years.
Neoadjuvant chemotherapy with docetaxel plus oxaliplatin and S-1 for locally advanced, resectable gastric or gastro-esophageal junction adenocarcinoma: Short-term results from a phase II trial.
Authors: Tomono Kawase, Yukinori Kurokawa, Noboru Kobayashi, Atsushi Takeno, Ryohei Kawabata, Tsuyoshi Takahashi, Makoto Yamasaki, Yuichiro Doki
Journal: Journal of Clinical Oncology (2020)

397 Background: In locally advanced, resectable gastric or gastro-oesophageal junction (EGJ) adenocarcinoma, perioperative the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) is the standard chemotherapy in Europe. However, there is no evidence of neoadjuvant chemotherapy for resectable gastric cancer in Japan. Therefore, we conducted a phase II trial of neoadjuvant chemotherapy with docetaxel plus oxaliplatin, and S-1 (DOS) for locally advanced, resectable gastric or EGJ adenocarcinoma. Methods: Eligible patients had histologically confirmed gastric or EGJ adenocarcinoma of a clinical Stage III according to the 14th Edition of Japanese Classification of Gastric Carcinoma. DOS was administered for two or three preoperative cycles followed by eight postoperative cycles of S-1. Each 3-week cycle of DOS consisted of docetaxel 40 mg/m 2 and oxaliplatin 100 mg/m 2 on day 1 plus S-1 80-120 mg/body on days 1 to 14. Primary endpoint was 3-year progression-free survival rate, and secondary endpoints included overall survival, progression-free survival, response rate, histological response rate, R0 resection rate, and adverse events. Results: Of 50 enrolled patients, 48 (37 gastric and 11 EGJ) were eligible for the analysis. 42 (88%) patients completed two or three preoperative cycles of DOS. The most common grade 3-4 adverse events of DOS were neutropenia (69%), leukopenia (56%), diarrhea (19%), and febrile neutropenia (13%). Of 45 patients who underwent gastrectomy, postoperative morbidities (Clavien-Dindo ≥Grade II) occurred in 12 (27%) patients. R0 resection could be achieved in 43 (90%) patients. 12 (27%) and 30 (67%) of 45 patients achieved pathological response rate of Grade2-3 and Grade1b-3, respectively. There was no treatment-related death. Conclusions: Neoadjuvant DOS for locally advanced, resectable gastric or EGJ adenocarcinoma might be favorable. Long-term results will be published in two years. Clinical trial information: 000017652.
A study into the risk of serious infections in people with hidradenitis suppurativa
Authors: H.H. Lee, K.R. Patel, V. Singam, S. Rastogi, J.I. Silverberg
Journal: British Journal of Dermatology (2020)

Hidradenitis suppurativa (HS), or acne inversa, is a chronic skin disease that affects between 0.3 and 4.0% of the global population. HS often affects skin folds of the body, such as the armpits and groin, and can cause significant inflammation, pain, itch, scarring, and disfigurement. The study researchers are based in the USA. The study's aim was to determine if associations between HS and various serious infections exist, using the National Inpatient Sample, a USA database of inpatient hospitalizations, between the years 2002 and 2012. The study also looked into the cost of care and length of stay of HS patients with serious infections. The study found that HS is associated with higher rates of various serious infections affecting the skin, blood, lungs, bones, joints, heart and brain, as well as antibiotic resistant infections (meaning they can't be easily treated with antibiotic medications). HS inpatients (patients staying in hospital) with serious infections also had increased length of stay and cost of care. In summary, this study found a strong connection between HS and many serious infections, including greatly increased healthcare costs and length of hospitalizations. This summary relates to the study: Associations of cutaneous and extracutaneous infections with hidradenitis suppurativa in U.S. children and adults
Gefitinib resistance caused by a secondary mutation of the epidermal growth factor receptor
Authors: Susumu Kobayashi, Titus J. Boggon, Tajhal Dayaram, Pasi A. Janne, Olivier Kocher, Matthew Meyerson, Bruce E. Johnson, Michael J. Eck, Daniel G. Tenen, Balazs Halmos
Journal: Cancer Research (2005)

2637  Mutations of the epidermal growth factor receptor gene conferring sensitivity to anilinoquinazoline EGFR inhibitors have recently been identified. Despite the typical dramatic tumor responses to such inhibitors, patients will eventually relapse with time and the mechanism of relapse has not been identified. A patient with advanced lung adenocarcinoma with a del747-752 EGFR mutation treated with gefitinib had a durable remission, but relapsed after 24 months of treatment. The DNA sequencing of exons 18-21 of his original specimen as well as his biopsy on relapse demonstrated persistence of the 747-752 deletion. The DNA sequence of his tumor biopsy from his relapse revealed a new, secondary C-to-T base pair change leading to a Thr-Met amino acid substitution at position 790. This amino acid change corresponds to one of the common bcr-abl kinase mutations conferring STI-571 resistance. Structural modeling suggested that this change would lead to the introduction of a bulkier amino acid side chain into a hydrophobic pocket of the ATP-binding site of the EGFR molecule. Further modeling also suggested that this substitution would lead to likely steric hindrance of either erlotinib or gefitinib binding due to the juxtaposition of the methionine side chain and the acetylene or chloride side chain of the anilino group of the respective inhibitor. Plasmid constructs were generated introducing this amino acid change into wild-type, L858R mutant, del747-753insS as well as del747-752 constructs. In transient transfection experiments, equal expression as well as phosphoprotein generation upon EGF stimulation between all the corresponding construct pairs (primary versus resistance mutant) was seen. While gefitinib completely inhibited EGF-stimulated phospho-EGFR generation of the non-resistance mutant constructs at concentrations of 2-20 nM, all four constructs carrying the Thr-Met substitution showed high level resistance to gefitinib with sustained EGFR phosphorylation at concentrations as high as 2 μM. A screen of commercially available EGFR inhibitors demonstrated that one of the screened inhibitors, CL-387,785, inhibited both the del747-752 as well as the del747-752 plus resistance mutant constructs with nearly the same potency with full inhibition observed at a concentration as low as 30nM. CL-387,785 is an irreversible, anilinoquinazoline inhibitor of EGFR. In summary, we have identified a novel, in vivo occurring mutation of the EGFR conferring gefitinib resistance and thereby describe the first resistance mutation in an oncogenic tyrosine kinase in a common epithelial cancer. We also demonstrate an alternative compound which can inhibit this mutant receptor, suggesting that drugs of this class might be useful in patients who relapse while on treatment with gefitinib.
First results of prophylaxis for bacterial and fungal infections in pediatric patients with high-risk acute lymphocytic leukemia (ALL).
Authors: Annick Beaugrand, Renato Guedes Oliveira, Ethel Gorender, Renato Melaragno, Sidnei Epelman
Journal: Journal of Clinical Oncology (2013)

10065 Background: Bacterial and invasive fungal infections remain a major contributor to treatment related morbidity and mortality in cancer patients. It has been published data of potential prevention; in immunocompromised hosts derive primarily from adult studies. However, children differ from adults in terms of the infections types as they develop or manifest, as well as their metabolism of treatment agents. From April 2010 to January 2011, 6 ALL patients received 35 intensive chemotherapy cycles during the first 6 months after diagnosis, 2 died due to infection. Methods: From April 2011 to January 2012, a prospective analysis in 8 high risk ALL patients ( BFM criteria) after 31 cycles of intensive chemotherapy were performed during the first 6 months of treatment followed by antibacterial and antifungal prophylaxis. Drugs are: ciprophloxacin 1000mg per day when weight highest than 30 kg and 500mg per day when lower weigh and fluconazole 100mg per day for the lower weigh and 150mg for the higher. All patient received granulocyte colony-stimulating factor after each cycles until complete neutrophils recovery. Results: In 20/31 cycles, hospitalization was needed, due to febrile neutropenia. Diarrhea, sepsis and renal failure were other reasons for hospitalization. Platelet transfusions and blood transfusions were performed in 12 and 9 hospitalization respectively. The majority of proven infections (n=7) were bacterial, Gram negative (Pseudomonas aeruginosa and Klebsiella spp), Gram positive, Candida (1 cycle). Hospitalization time was between 2 and 25 days (median time 10 days). In 4 cycles, intensive care unit was needed. No death occurred. Conclusions: Bacterial and fungal infections continue to be a leading cause of morbidity and mortality in children receiving intensive therapy. Pharmacologic prophylaxis can contribute to decrease mortality due to infection in this population.
Short- and long-term outcomes following laparoscopic gastrectomy for advanced gastric cancer compared with open gastrectomy.
Authors: Kazuaki Shibuya, Hideki Kawamura, Yosuke Ohno, Nobuki Ichikawa, Tadashi Yoshida, Shigenori Homma, Akinobu Taketomi
Journal: Journal of Clinical Oncology (2020)

369 Background: To investigate the oncological feasibility and technical safety of laparoscopic gastrectomy with D2 lymphadenectomy for advanced gastric cancer. Methods: 186 advanced gastric cancer patients treated by gastrectomy with D2 lymphadenectomy were eligible for inclusion including those with invasion into the muscularis propria, subserosa, and serosa without involvement of other organs, and stages N0–2 and M0. We retrospectively compared the short- and-long term outcomes between laparoscopic gastrectomy and open gastrectomy. Results: We analyzed short-term outcomes by comparing distal- with total gastrectomy results. We found no significant difference for distal gastrectomy for postoperative morbidity (laparoscopic vs. open: n = 4 (4.6%) vs. n = 1 (3.6%); p= 1.00). We also found no significant difference in postoperative morbidity for total gastrectomy (laparoscopic vs. open: n = 2 (4.0%) vs. n = 1 (4.0%); p= 1.00). No deaths occurred in any group. The entire cohort analysis revealed no statistically significant differences in overall- or recurrence-free survival between the laparoscopic and open groups. For overall survival, there were no significant differences between open and laparoscopic groups for clinical stage II or III ( p= 0.29 and 0.27, respectively), and for pathological stage II or III ( p= 0.88 and 0.86, respectively). For recurrence-free survival, there were no significant differences between open and laparoscopic groups for clinical stage II or III ( p= 0.63 and 0.60, respectively), and for pathological stage II or III (p = 0.98 and 0.72, respectively). Conclusions: Laparscopic gastrectomy for advanced gastric cancer compared favorably with open gastrectomy regarding short- and long-term outcomes. Clinical trial information: 160907.
Age-related outcomes in patients with esophageal cancer: A propensity score matched analysis.
Authors: Paige Blinn, Taylor Maramara, Ravi Shridhar, Jamie Huston, Kenneth Lee Meredith
Journal: Journal of Clinical Oncology (2020)

326 Background: Esophageal cancer is increasing in incidence worldwide. It is estimated that there will be 17,650 new cases of esophageal cancer diagnosed, with 16,080 dying from the disease in the United States in 2019. There has been an increase in younger patients diagnosed with esophageal cancer. We sought to evaluate the outcomes in younger patients diagnosed with esophageal cancer. Methods: Utilizing the National Cancer Database we identified patients with esophageal cancer. We then stratified by age &lt; 50, 51-60, 61-70, and &gt; 70 years. Baseline univariate comparisons were made for continuous variables using both the Mann-Whitney U and Kruskal Wallis tests as appropriate. Pearson’s Chi-square test was used to compare categorical variables. Unadjusted survival analyses were performed using the Kaplan-Meier method. All statistical tests were two-sided and p &lt; 0.05 was significant. Propensity score matched analysis was performed and only exact matches were allowed. Results: We identified 20,324 patients ( &lt; 50, 2157), (51-60, 5387), (61-70, 7853), and ( &gt; 70, 4927). T-stages and N stages were higher in the younger age groups p &lt; 0.001 and p &lt; 0.001 respectively. Median lymph nodes positive were highest in the &lt; 50 group (2.2 vs 1.8 vs 1.6 vs 1.7) p &lt; 0.001. Additionally, tumor size was largest in this age cohort (3.7 vs 3.5 vs 3.5 vs 3.2) p = 0.002. Neoadjuvant therapy was administered in 69.4% of patients in the &lt; 50, 68.5% (51-60), 65.5% (61-70), and 49.5% &gt; 70 patients, p &lt; 0.001. The &lt; 50 age group was however more likely to receive adjuvant therapy (22.9% vs 20.5% vs 16.9% vs 13.4%) p &lt; 0.001. Median and overall survival was 49.8 mo and 45% ( &lt; 50), 45.4mo and 43% (51-60), 45.4mo and 43% (61-70), and 35.8mo and 39% &gt; 70, p &lt; 0.001. After propensity score matching, multivariate analysis found that age &lt; 50, male gender, GEJ tumor location, grade, Charleson Deyo score, T-stage N stage, margin, facility volume, neoadjuvant and adjuvant therapy were predictors of survival. Conclusions: Although younger patients present with larger tumors, higher T-stages, and N stages, they are more likely to receive neoadjuvant and adjuvant therapies. It is these therapies which are most likely contributing to improved survival compared to their older counterparts.
Lactation Duration and Long-term Risk for Incident Type 2 Diabetes in Women With a History of Gestational Diabetes Mellitus
Authors: Sylvia H. Ley, Jorge E. Chavarro, Mengying Li, Wei Bao, Stefanie N. Hinkle, Pandora L. Wander, Janet Rich-Edwards, Sjurdur Olsen, Allan Vaag, Peter Damm, Louise G. Grunnet, James L. Mills, Frank B. Hu, Cuilin Zhang
Journal: Diabetes Care (2020)

OBJECTIVE We examined the association of lactation duration with incident type 2 diabetes among women with a history of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS We monitored 4,372 women with a history of GDM participating in the Nurses’ Health Study II for incident type 2 diabetes over 25 years up to 2017. Lactation history was obtained through follow-up questionnaires to calculate lactation duration. Follow-up blood samples were collected from a subset of these women at median age of 58 years through the Diabetes &amp; Women’s Health Study. RESULTS We documented 873 incident cases of type 2 diabetes during 87,411 person-years of follow-up. Longer duration of lactation was associated with lower risk of type 2 diabetes for both total lactation (hazard ratio 1.05 [95% CI 0.83–1.34] for up to 6 months, 0.91 [0.72–1.16] for 6–12 months, 0.85 [0.67–1.06] for 12–24 months, and 0.73 [0.57–0.93] for &amp;gt;24 months, compared with 0 months; P-trend = 0.003) and exclusive breastfeeding (P-trend = 0.002) after adjustment for age, ethnicity, family history of diabetes, parity, age at first birth, smoking, diet quality, physical activity, and prepregnancy BMI. Longer duration of lactation was also associated with lower HbA1c, fasting plasma insulin, and C-peptide concentrations among women without type 2 diabetes at follow-up (all adjusted P-trend ≤0.04). CONCLUSIONS Longer duration of lactation is associated with a lower risk of type 2 diabetes and a favorable glucose metabolic biomarker profile among women with a history of GDM. The underlying mechanisms and impact on diabetes complications, morbidity, and mortality remain to be determined.
Photodynamic therapy produces enhanced efficacy of antitumor immunotherapy by simultaneously inducing intratumoral release of sorafenib
Authors: Xu Sun, Ziyang Cao, Kuirong Mao, Chenxi Wu, Hongmei Chen, Jialiang Wang, Xin Wang, Xiuxiu Cong, Yong Li, Xianying Meng, Xianzhu Yang, Yong-Guang Yang, Tianmeng Sun
Journal: Biomaterials (2020)
Glycoprotein D, a checkpoint inhibitor of early T-cell activation, to improve immunogenicity and efficacy of an HPV-16 vaccine in preclinical studies.
Authors: Hildegund Ertl, Zhiquan Xiang, Yan Li, Andrew Luber, Colin Magowan, Xiang Zhou
Journal: Journal of Clinical Oncology (2020)

71 Background: CD8 + T cells can inhibit tumor progression, but their induction is hampered by the low immunogenicity of most tumor antigens. HSV-1 glycoprotein D (gD), when genetically expressed as a fusion protein with tumor antigens, serves as a checkpoint inhibitor of the B and T cell attenuator (BTLA)-herpes virus entry mediator (HVEM) pathway, which acts early during T cell activation. HSV-1 gD thereby augments antigen-driven CD8 + T cell responses. We describe the immunogenicity and efficacy of a chimpanzee adenoviral vector (AdC) vaccine containing a detoxified E7/E6/E5(AdC-gDE765dt) sequence of HPV-16 fused into gD. Methods: The frequency of HPV-16 E7-specific CD8 + T-cells was assessed by tetramer staining in C57/Bl6 mice 14 days after a single IM vaccination with AdC vectors encoding wild-type or mutant HPV-16 oncoproteins expressed within gD, a non-HVEM-binding form of gD or without gD. Efficacy was tested in a TC-1 tumor cell challenge model with mice receiving no treatment or a single IM vaccine injection 3 days after tumor cell transplantation. Mice were followed for 80 days. Results: The addition of gD increases HPV-16 E7-specific CD8 + T-cell frequencies approximately 10-fold. T cell responses are similar to AdC vaccines expressing wild-type or mutant oncoproteins within gD. All AdC-gDE765dt treated mice show delayed tumor progression after a single vaccination with 50% of animals remaining tumor-free at study completion. Conclusions: These results show that the addition of gD, an early checkpoint inhibitor, which acts locally at the site of T cell stimulation, to an HPV-16 vaccine markedly improves the vaccine’s immunogenicity and efficacy. AdC-gDE765dt is currently in GMP manufacture for Phase 1 investigation in HPV-16 infected patients.
Clinical utility of targeted next generation sequencing (NGS) to predict response to neoadjuvant therapy (NT) in rectal cancer (RC).
Authors: Kristen Carroll, Michael C. Burns, Ryan Jones, Masha Kocherginsky, Kirsten Bell Burdett, Guang-Yu Yang, Al Bowen Benson, Devalingam Mahalingam
Journal: Journal of Clinical Oncology (2020)

237 Background: NGS analysis has identified molecular alterations that have predictive and prognostic implications in advanced RC. However, its role in identifying predictive signatures of chemoradiotherapy response in RC remains largely unexplored. Neoadjuvant rectal cancer (NAR) score, a composite score available after resection, is a validated short-term surrogate endpoint for long-term outcomes. Herein, we identified gene alterations in early stage RC with NGS analysis and correlated mutations with tumor response using the NAR scoring system. Methods: Patients (pts) with stage I-III RC completing NT followed by resection (2011-2018) had their tumor prospectively sequenced by an ion torrent targeted 22 gene NGS panel ( AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, TP53). NAR scores were calculated based on clinical and pathologic staging data input, yielding 3 cohorts: low (score &lt; 8, pCR or near CR), intermediate (8-16), or high ( &gt; 16, poor or no response) NAR scores. Associations were drawn using Two-sided Fisher’s exact. Both unadjusted (p) and Benjamini &amp; Hochberg adjusted (BHp) p-values are shown. Results: 51 pts with RC were analyzed: median age 59 (24-81), male (59%), clinical stage I (6%), II (25%) and III (69%). Pathological mutations were found in 94% of pts, including TP53 (76%), KRAS (49%), PIK3CA (10%), NRAS (6%), FGFR3 (4%), MET (4%). Post NT 8 (16%) pts had low NAR scores, including 6 (12%) cases with pCR, 26 (51%) intermediate, and 17 (33%) high NAR scores. Gene alterations in FGFR3 (p =0.022, BHp = 0.15) and NRAS (p =0.026, BHp = 0.15) were associated with NAR score, while no differences were observed with mutations in TP53 or KRAS. Additionally, 17 (33%) pts had recurrences [13% of pts with low NAR scores, 31% intermediate, 47% high], with metastases primarily to lung (53%) and/or liver (35%). Conclusions: This study suggests that pts with RC who derived favorable responses to standard NT could have a targeted molecular profile, namely alterations in FGFR3 and NRAS. Conversely, pts that lack this profile may benefit from novel therapeutic approaches to improve NAR scores and long-term outcomes.