tbuckley/cabot-search huggingface dataset:
Trastuzumab + fluoropyrimidine maintenance in the frontline setting for non-progressing advanced HER-2 positive gastroesophageal adenocarcinoma.
Authors: Ahmed Abdelhakeem, Jane Elizabeth Rogers, Xuemei Wang, Irene Thomas, Mariela A. Blum-Murphy, Allison Trail, Meina Zhao, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2020)

291 Background: In untreated patients with HER2 positive advanced gastroesophageal adenocarcinoma (AGEA), trastuzumab plus active cytotoxic combination is the standard of care. Our objective was to assess the role of maintenance therapy (trastuzumab + fluoropyrimidine) in the absence of cancer progression. Methods: We retrospectively analyzed HER2 positive AGEA patients (between August 2008 and October 2018) who received first-line trastuzumab-based therapy followed by maintenance therapy. The primary objectives were to assess the time to maintenance failure (TTMF), the first progression-free survival (PFS), and overall survival (OS). Results: Of 70 patients analyzed, 80% were men with a median age of 60.5 years. Primary tumor commonly involved the gastroesophageal junction (65.7%). More than 1 sites of metastases were frequent (88.6%). The best response was complete in 17%, partial in 70%, and stable in 11.4%. The median follow-up time for survivors was 2.1 years (range, 0.6 to 9.2). The median TTMF was 0.7 years (95% CI; 0.4 to 1.1 years). One-year TTMF-free rate was 41%. The median PFS was 1.3 years (95% CI, 0.8-1.6). The median OS was 3.2 years (95% CI, 2.3 years–4.5 years), with a 3-year survival rate of 55% (95% CI, 40%-67%). Conclusions: Our results showed that the OS of this unique population of HER2 positive AGEA patients who qualify for maintenance therapy is excellent. The contribution of the maintenance therapy can be clarified only by prospective investigations.
Utilization of somatic comprehensive genomic profiling (CGP) to identify patients (pts) with pancreatic cancer (PC) that harbor germline DNA damage repair (DDR) gene alterations.
Authors: Matthew Lasowski, Samantha Stachowiak, Igli Arapi, Kulwinder Dua, Abdul H. Khan, William Adrian Hall, Beth Erickson, Susan Tsai, Kathleen K. Christians, Douglas B. Evans, Raul Urrutia, Paul S. Ritch, Mandana Kamgar, James P. Thomas, Ben George
Journal: Journal of Clinical Oncology (2020)

760 Background: Somatic and germline DDR gene alterations in PC have been postulated to positively predict response to DNA damaging cytotoxic agents. Due to the relatively high prevalence of germline DDR gene alterations, germline testing is recommended in all pts with PC. We examined whether somatic CGP can be used to reliably identify PC pts that merit germline testing. Methods: We retrospectively reviewed the electronic medical records of PC pts who underwent both somatic CGP (utilizing the Foundation One assay) and germline testing. DDR gene mutations were categorized as somatic-pathogenic, somatic-variant of uncertain significance (VUS), germline-pathogenic and germline-VUS. For somatic testing, DNA was extracted from formalin fixed paraffin embedded (FFPE) clinical specimens and CGP was done on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of &gt; 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Germline genetic testing was performed on submitted blood or saliva samples, utilizing commercial assays; next generation or Sanger sequencing of all coding regions and adjacent intronic nucleotides were performed. Results: Ninety-three pts had somatic CGP data, 51 (55%) pts had both somatic CGP and germline data available. Among the 51 pts with both germline and somatic data available, DDR gene alterations that were somatic-pathogenic, germline-pathogenic, somatic-VUS and germline-VUS were present in 7 (13.7%), 7 (13.7%), 23 (45.1%) and 16 (31.4%) pts, respectively. Of the 7 pts with somatic-pathogenic alterations, 5 (71%) had a concordant germline alteration and of the 7 pts with germline-pathogenic alterations, 5 (71%) had a concordant somatic alteration. Of the 23 pts with somatic-VUSs, 12 (52%) had a concordant germline VUS and of the 16 pts with germline-VUSs, 12 (75%) had a concordant somatic VUS. Conclusions: Both somatic and germline DDR gene alterations are common in PC pts. Despite the relatively high concordance rate between somatic and germline pathogenic DDR gene alterations, somatic CGP will miss approximately one fourth of the germline DDR gene alterations.
Molecular landscape and prognostic value of HER2 low-expression on metastatic colorectal cancer.
Authors: Masataka Yagisawa, Kentaro Sawada, Yoshiaki Nakamura, Takahiro Ishii, Yohei Kubota, Hiromichi Nakajima, Tomoko Jogo, Akinori Sasaki, Saori Mishima, Daisuke Kotani, Akihito Kawazoe, Yasutoshi Kuboki, Kohei Shitara, Takashi Kojima, Toshihiko Doi, Atsushi Ohtsu, Satoshi Fujii, Takayuki Yoshino, Hiroya Taniguchi
Journal: Journal of Clinical Oncology (2020)

229 Background: HER2 dual blockade showed the promise in clinical trials in patients (pts) with HER2-positive (HER2-Pos) metastatic colorectal cancer (mCRC). A phase I/II study of a novel anti-HER2 antibody-drug conjugate (HER2-ADC) showed promising activities across different cancer subtypes including HER2-Pos mCRC, and also showed a hint of activity for low-expressing (HER2-L) mCRC, regardless of RAS mutation. However, molecular landscape and prognostic value of HER2-L on mCRC are unclear. Methods: The eligibility included pts with mCRC who had undergone surgical resection of primary tumor. Using the specimen, HER2 expression was evaluated by immunohistochemistry (IHC) and FISH. Definition of HER2 positivity was as follows; HER2-Pos as IHC 3+ or IHC 2+/FISH positive: HER2-L as IHC 2+/FISH negative or IHC 1+: Negative (HER2-Neg) as IHC 0+. NGS tests were also done. Results: Between 2005 and 2015, a total of 370 pts were analyzed; 60% were male, with a median age of 64 y/o. Fifteen pts (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg were identified. Proportion of left-sided primary tumor was similar among groups ranging from 72% to 78%. No difference was observed in terms of major clinicopathological characteristics. The proportion of co-altered RAS mutations in HER2-L was significantly higher than HER2-Pos ( p = 0.037) and similar to HER2-Neg (27% in HER2-Pos vs. 62% in HER2-L vs. 56% in HER2-Neg). As of median follow-up of 24.8 months, median overall survival (mOS) in HER2-L was significantly better than that in HER2- Pos ( p = 0.029, 18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 pts harboring RAS wild-type who received an anti-EGFR monoclonal antibody therapy, median progression-free survival (mPFS) in HER2-L tended to be better than that in HER2- Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.5 in HER2-Neg ( p = 0.099). Conclusions: Since HER2-L mCRC had the high prevalence of co-altered RAS mutations but showed a better prognosis and might benefit more from an anti-EGFR therapy than HES2-Pos, the HER2-L mCRC seems to have a different biological behavior from HER2-Pos in terms of molecular landscape and prognostic value on mCRC.
Outcomes of appendiceal adenocarcinomas compared to right and left-sided colorectal adenocarcinomas: An analysis from the National Cancer Database (NCDB).
Authors: Kanika Gupta Nair, Wei Wei, Michael Cruise, Katherine Tullio, Bassam N. Estfan
Journal: Journal of Clinical Oncology (2020)

42 Background: Appendiceal carcinomas (AC) account for 1-2% of colorectal cancers (CRC) and are generally treated like other CRC. However, there is limited data to guide treatment. While AC originate on the right side of the colon, it is unclear if they behave like as right-sided CRC (R-CRC). We seek to learn how AC differ from right versus left-sided CRC (L-CRC). Methods: We identified histologically confirmed cases of appendiceal and colorectal adenocarcinomas with information about stage and overall survival (OS) diagnosed between 2004 and 2016 from the National Cancer Database. Kaplan-Meier method and log-rank test were used to estimate and compare OS. Results: 833,939 patients met our inclusion criteria: 15,138 (1.8%) AC, 447,551 (53.7%) L-CRC, 308,794 (37.0%) R-CRC, and 62,456 (7.5%) transverse CRC (T-CRC). Median age at diagnosis of all patients was 68 years (range:18-90); AC was lowest at 61 years for stage I-III disease and 58 years for stage IV disease. Stage IV AC was more common in females 3628/5739 (63.22%). AC had the best OS among site groups in stage I-III. Median OS for stage I-III AC was 128.8 months (95% CI: 117.9-139.0), with 5-year OS rate of 0.69 (95% CI: 0.67-0.70); L-CRC median OS was 111.6 months (95% CI: 110.9-112.4), with 5-year OS rate of 0.681 (95% CI: 0.680-0.683); R-CRC median OS was 88.5 months (95% CI: 87.8-89.1), with 5-year OS rate of 0.613 (95% CI: 0.611-0.615); and T-CRC median OS was 86.2 months (95% CI: 84.7-87.6), with 5-year OS rate of 0.608 (95% CI: 0.604-0.613) (p &lt;0.0001) (Table). Similar difference was observed in stage IV patients (Table). Conclusions: Patients with AC had significantly better OS for stages I-III and stage IV compared to patients with L-CRC, R-CRC, and T-CRC, though outcomes were more similar to L-CRC. The difference is more evidence for patients with stage IV disease. T-CRC had similar OS to R-CRC, as anticipated. [Table: see text]
Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): Final results of the phase II AVETUX trial (AIO-KRK-0216).
Authors: Alexander Stein, Mascha Binder, Eray Goekkurt, Sylvie Lorenzen, Jorge Riera-Knorrenschild, Reinhard Depenbusch, Thomas Jens Ettrich, Steffen Doerfel, Salah-Eddin Al-Batran, Meinolf Karthaus, Uwe Pelzer, Donjete Simnica, Lisa Waberer, Axel Hinke, Carsten Bokemeyer, Susanna Hegewisch-Becker
Journal: Journal of Clinical Oncology (2020)

96 Background: Single agent PD-1/L1 inhibition is efficacious in MCRC patients (pts) with high microsatellite instability (MSI-H). For the vast majority of MCRC pts with MS stable (MSS) phenotype the role of immunotherapy remains undetermined. Methods: The single arm phase II AVETUX trial combined mFOLFOX6 and cetuximab with avelumab (10mg/kg day 1 from cycle 2 onwards) in RAS/BRAF wildtype (local lab) MCRC pts. Primary endpoint was 12 month progression-free survival rate. Secondary endpoints included overall response rate (ORR), tolerability, overall survival and translational research evaluating tissue including PD-L1 expression (tumour/immune cells) and serial ctDNA. Efficacy analyses were done by intention to treat (ITT). Results: Overall 43 pts were enrolled. Median age was 61 (range 29-82), 14 pts (33%) were female and 39 (91%) left sided. 30 pts (70%) had liver mets and 17 (40%) liver mets only. 2 pts were MSI-H, one MSI-low and 40 MSS. Besides immediate and otherwise unexplained fever in 4 pts treatment was well tolerated and avelumab was not associated with unexpected adverse events to standard FOLFOX/cetuximab. Central tissue review found 4 pts to be ineligible due to low frequent KRAS or BRAF mutation (15-31%). Thus, ITT included 39 pts. The ORR was 79.5%, including 6 complete (CR) and 25 partial responses (PR). Further 5 stable diseases were noted, thus disease control rate was 92.3%; 2 pts had progression and 1 was not evaluable. Early tumor shrinkage (ETS) rate (≥20% after 8 weeks) was 79.5% (1 CR, 27 PR and 3 SD with ≥20% - &lt; 30%). In MSI-H pts 1 PR and 1 SD and in the 3 low RAS mut pts 2 PR were noted. Panel sequencing was feasible with 153 mutations detected, showing an immediate ctDNA drop within 4 weeks of treatment, mirroring the high rate of early tumor response. Notably, the 4 pts with fever had a high T cell infiltration in the tumor. Final data including the primary endpoint and translational data will be presented at the meeting. Conclusions: The AVETUX regimen was feasible producing a high rate of responses in MSS pts mainly occurring within the first 8 weeks. The noted ORR/ETS of 79.5% warrants further evaluation in a randomized trial. Clinical trial information: NCT03174405.
The MAPPE score predicts survival in those treated with yttrium-90 selective internal radiotherapy in hepatocellular carcinoma
Authors: Michael Christopher Wallace, Shaun Samuelson, Tiffany Khoo, Jacob Ooi, Jonathan Tibballs, John Ferguson, David B. Preen, Mathew Knuiman, George Garas, Gerry C. MacQuillan, Leon A. Adams, Gary P. Jeffrey
Journal: Hepatology (2019)
More Meta-analytical Explorations on Adolescent Sexual Health Interventions Are Needed—Reply
Authors: Laura Widman, Reina Evans, Sophia Choukas-Bradley
Journal: JAMA Pediatrics (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Clinical outcome of initially unresectable pancreatic cancer patients: Conversion surgery after modified FOLFIRINOX or gemcitabine nab-paclitaxel.
Authors: Yuta Ushida, Yosuke Inoue, Hiromichi Ito, Yoshihiro Ono, Takafumi Sato, Yu Takahashi
Journal: Journal of Clinical Oncology (2020)

725 Background: Although pancreatic cancer (PC) is unfavorable clinical entity, the prognosis of resectable PC has been improving due to perioperative chemotherapy. Meanwhile, the prognosis of unresectable (UR) PC remains poor. In highly selected patients, however, conversion surgery (CS) has been performed with good outcome. Indication criteria of CS remain unestablished because the number of patients who underwent CS was very small in each institution. Methods: From 2014 to 2018, 485 consecutive patients with UR-PC who received modified FOLFIRINOX (mFFX) / Gemcitabine Nab-Paclitaxel (GnP) chemotherapy were reviewed. Among them, patients with disease control for more than 8 months were enrolled and divided into two groups; patients who underwent CS (CS group) and patients who did not undergo CS (non-CS group). We compared clinical characteristics and survival outcomes between groups. Our surgical indications were as follows: 1) Decreasing trend in CA19-9, 2) With response for chemotherapy in image, 3) Disease control more than 8 months, 4) Decision in Cancer board as for metastatic cases. Results: In UR-PC patients, 358 patients had distant metastasis (MPC) and 127 patients had locally advanced (LA) PC. The overall survival (OS), progression free survival (PFS) and conversion rate of LAPC were significantly better than MPC (OS; 21 vs. 13 months, PFS; 12 vs. 7 months, Conversion rate; 16 vs. 5 %, p &lt; 0.001). Chemotherapy regimen (mFFX/GnP) had no significant difference in survival outcome. Between CS group (n = 39) with non-CS group (n = 160), age, sex, body mass index, location of lesion, CEA, CA19-9, regimen of chemotherapy and histology had no significant differences. The median survival time of CS group was significantly better than that of non-CS group (OS; NA vs. 21 months, p &lt; 0.001, PFS; 24 vs. 14 months, p = 0.01). In CS group, median operative duration was 509 minutes, blood loss was 735 ml, hospital stay was 26 days, and there was no 90-days mortality case. Conclusions: In our retrospective study, CS for UR-PC can be safely performed, and among carefully selected patients, reasonable short and long term outcomes can be obtained without acceptable morbidity rate.
Clinical outcome associated with neoadjuvant chemoradiation and orthotopic liver transplantation versus definitive chemoradiation in 49 patients with unresectable, hilar, or extrahepatic cholangiocarcinoma.
Authors: Brady S. Laughlin, Molly M. Petersen, Jonathan Ben Ashman, William G. Rule, Mitesh J. Borad, Bashar A. Aqel, Mohamad Bassam Sonbol, Tanios S. Bekaii-Saab, Daniel H. Ahn, Nathan Y. Yu, Todd DeWees, Terence Tai Weng Sio
Journal: Journal of Clinical Oncology (2020)

494 Background: Our aim was to compare survival between patients receiving neoadjuvant chemoradiation and orthotopic liver transplantation (OLT group) versus definitive chemoradiation (CRT group) for extrahepatic or hilar cholangiocarcinoma. Methods: 49 patients (20 in OLT group vs. 29 in CRT group) with unresectable hilar/extrahepatic cholangiocarcinoma were treated at Mayo Clinic Arizona between Feb. 1998–Sep. 2019. Treatment included external beam radiation therapy (median 4500cGy) and boost (median 900cGy) with either continuous 5-flurouracil (dose range 180–225 mg/m2) or capecitabine (dose range 825–1000 mg/m2 BID) prior to or without OLT. Radiation boosts were delivered with EBRT or bile duct brachytherapy. Patients were between 27.9–84.3 years (median 64.3) at diagnosis. 18 patients had previous diagnosis of PSC. Results: Between Feb. 1998–Sep. 2019, 31(63%) of 49 patients died by the end of follow-up. Of patients treated with neoadjuvant therapy and OLT, 7(35%) of 20 patients died. 24(86%) of 28 patients treated with definitive therapy died. The OLT cohort were younger (mean age 56.5 vs. 69.0 years), more likely to have PSC and UC (65% vs. 17%), and had a lower CA 19-9 (median 43 vs. 535)(P &lt; 0.003). From the end date of radiation, median overall survival was 76.8 months vs. 15.6 months for the OLT and CRT groups, respectively. Survival rates at 3 and 5 years were 78% and 69% in the OLT group compared to 19% and 6% in the CRT group (HR 7.73; 3.04-19.65:(P &lt; 0.0001)). Progression-free survival (89% vs. 30% at 3 years), and distant metastasis-free survival (88% vs. 66% at 3 years) favored OLT versus CRT alone (HR 5.74;1.12-29.34:(P &lt; 0.02)). Univariate analysis demonstrated that the method of treatment (OLT vs. CRT) was the only variable associated with better clinical outcomes. Conclusions: In patients with unresectable extrahepatic/hilar cholangiocarcinoma, survival was higher in those who underwent chemoradiation and OLT. Patients who received definitive chemoradiation in the absence of OLT were expected to have worse overall, progression-free, and metastasis-free survival.
Gene polymorphisms of CCL3, CCL4, CCL5, and CCR5 network in metastatic colorectal cancer patients treated with regorafenib.
Authors: Mitsukuni Suenaga, Wu Zhang, Tetsuo Mashima, Marta Schirripa, Shu Cao, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Afsaneh Barzi, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

199 Background: We previously reported that genetic variant in the CCL5/CCR5 pathway predict efficacy of regorafenib in metastatic colorectal cancer patients (mCRC). CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with longer overall survival (OS) and severe skin toxicity due to low VEGF-A production via endothelial progenitor cell (EPC). CCL4 rs1634517 G allele and CCL3 rs1130371 C allele correlated with longer Progression-free survival (PFS) and OS. We investigated the biological role of CCL4 and CCL3 gene polymorphisms. Methods: We analyzed genomic DNA extracted from 79 samples of a Japanese cohort receiving regorafenib. Single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Blood samples were obtained from 57 patients at baseline (BL), day 21 and progressive disease (PD), and serum CCR5, CCR5 ligands (CCL3, CCL4, CCL5) and VEGF-A levels were measured using ELISA. PFS and OS were analyzed using Kaplan-Meier curves and log-rank test. Results: Increased CCL3 levels at PD were associated with longer OS than decreased (12.6 vs 4.8 mos, P = 0.003). Patients with decreased CCL4 levels at day 21 had a trend toward longer PFS and tumor shrinkage. Positive correlation was observed between CCL3 and CCR5 throughout the treatment independent of other ligands (change at day 21: r = 0.426, P = 0.009). There was no significant correlation of CCL3 and CCL4 levels with VEGF-A levels. Patients with the G/G variant in CCL3 rs1130371 had increased CCL3, CCR5 and CCL5 levels at day 21 than any A allele. Similarly, patients with the C/C variant had increased CCL3, CCR5 and CCL5 levels at day 21 compared with those with any A allele. In contrast, both CCL5 rs2280789 G allele and CCL5 rs3817655 T allele were associated with increased CCL3 levels and decreased CCL4 levels at day 21 (P = 0.006, P = 0.043; P = 0.006, P = 0.043). Conclusions: Positive correlation of CCL3, CCR5 and CCL5 impact similarly on CCL3 and CCL4 SNPs, while different manner between CCL3 and CCL4 was found in CCL5 SNPs. This suggests an alternative mechanism of action in the network of CCR5 and the ligands except CCL5-VEGF-A signaling via EPC in mCRC patients receiving regorafenib.
Evolving Populations in Biofilms Contain More Persistent Plasmids
Authors: Thibault Stalder, Brandon Cornwell, Jared Lacroix, Bethel Kohler, Seth Dixon, Hirokazu Yano, Ben Kerr, Larry J Forney, Eva M Top
Journal: Molecular Biology and Evolution (2020)

Abstract Bacterial plasmids substantially contribute to the rapid spread of antibiotic resistance, which is a crisis in healthcare today. Coevolution of plasmids and their hosts promotes this spread of resistance by ameliorating the cost of plasmid carriage. However, our knowledge of plasmid–bacteria coevolution is solely based on studies done in well-mixed liquid cultures, even though biofilms represent the main way of bacterial life on Earth and are responsible for most infections. The spatial structure and the heterogeneity provided by biofilms are known to lead to increased genetic diversity as compared with well-mixed liquids. Therefore, we expect that growth in this complex environment could affect the evolutionary trajectories of plasmid–host dyads. We experimentally evolved Shewanella oneidensis MR-1 with plasmid pBP136Gm in biofilms and chemostats and sequenced the genomes of clones and populations. Biofilm populations not only maintained a higher diversity of mutations than chemostat populations but contained a few clones with markedly more persistent plasmids that evolved via multiple distinct trajectories. These included the acquisition of a putative toxin–antitoxin transposon by the plasmid and chromosomal mutations. Some of these genetic changes resulted in loss of plasmid transferability or decrease in plasmid cost. Growth in chemostats led to a higher proportion of variants with decreased plasmid persistence, a phenomenon not detected in biofilms. We suggest that the presence of more stable plasmid–host dyads in biofilms reflects higher genetic diversity and possibly unknown selection pressures. Overall, this study underscores the importance of the mode of growth in the evolution of antibiotic-resistant bacteria.