tbuckley/cabot-search huggingface dataset:
ERS clinical practice guidelines on treatment of sarcoidosis
Authors: Robert P. Baughman, Dominique Valeyre, Peter Korsten, Alexander G. Mathioudakis, Wim A. Wuyts, Athol Wells, Paola Rottoli, Hiliaro Nunes, Elyse E. Lower, Marc A. Judson, Dominique Israel-Biet, Jan C. Grutters, Marjolein Drent, Daniel A. Culver, Francesco Bonella, Katerina Antoniou, Filippo Martone, Bernd Quadder, Ginger Spitzer, Blin Nagavci, Thomy Tonia, David Rigau, Daniel R. Ouellette
Journal: European Respiratory Journal (2021)

Background The major reasons to treat sarcoidosis are to lower the morbidity and mortality risk or to improve quality of life (QoL). The indication for treatment varies depending on which manifestation is the cause of symptoms: lungs, heart, brain, skin or other manifestations. While glucocorticoids remain the first choice for initial treatment of symptomatic disease, prolonged use is associated with significant toxicity. Glucocorticoid-sparing alternatives are available. The presented treatment guidelines aim to provide guidance to physicians treating the very heterogenous sarcoidosis manifestations. Methods A European Respiratory Society Task Force committee composed of clinicians, methodologists and patients with experience in sarcoidosis developed recommendations based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology. The committee developed eight PICO (Patients, Intervention, Comparison, Outcomes) questions and these were used to make specific evidence-based recommendations. Results The Task Force committee delivered 12 recommendations for seven PICOs. These included treatment of pulmonary, cutaneous, cardiac and neurologic disease as well as fatigue. One PICO question regarding small-fibre neuropathy had insufficient evidence to support a recommendation. In addition to the recommendations, the committee provided information on how they use alternative treatments, when there was insufficient evidence to support a recommendation. Conclusions There are many treatments available to treat sarcoidosis. Given the diverse nature of the disease, treatment decisions require an assessment of organ involvement, risk for significant morbidity, and impact on QoL of the disease and treatment.
Association of pre-existing autoimmune diseases in melanoma patients receiving immune checkpoint inhibition with improved survival and increased toxicity.
Authors: Nicholas Gulati, Arda Celen, Paul Johannet, Amelia Sawyers, Min Jae Kim, Janice M. Mehnert, Jeffrey S. Weber, Michelle Krogsgaard, Iman Osman, Judy Zhong
Journal: Journal of Clinical Oncology (2021)

e21586 Background: Immune checkpoint inhibition (ICI) improves progression-free (PFS) and overall survival (OS) for patients with metastatic melanoma (MM), but induces immune-related adverse events (irAEs). Pre-existing autoimmune disease (pre-AI) is considered a relative contraindication due to concerns of inciting autoimmune flare. We here tested the impact of pre-AI on both the survival and irAEs in MM patients treated with ICI. Methods: We examined MM patients treated with ICI who were enrolled in a clinicopathological database at NYULH with protocol-driven prospective follow up. We compiled a comprehensive list of 23 autoimmune diseases and examined the presence of these diseases prior to ICI treatment. We tested the associations between pre-AI and PFS, OS, and irAEs both in univariate and multivariate models. Results: 74/485 (15.3%) patients, who received 718 lines of ICI treatment as either standard of care or in clinical trials, had pre-AI, most commonly asthma (n=42), inflammatory bowel disease (n=9), psoriasis (n=9), rheumatoid arthritis (n=7), and eczema (n=6). In patients receiving ICI as standard of care (n=535), pre-AI was associated with irAEs (P=0.05) as well as with significantly improved PFS (P=0.024) and OS (P=0.007), controlling for patients’ sex, age, stage, ECOG status, and treatment line (1st line versus 2nd or 3rd line). However, no associations were observed between pre-AI and PFS (P=0.2) or irAEs (P=0.54) in the clinical trial group. Conclusions: Our data demonstrate the disparate impact of pre-AI on response and irAEs in standard of care versus the highly controlled clinical trial settings, and underscore the importance of examining the complex interaction between autoimmune disease before and after initiation of ICI. Our data also challenge the notion that clinicians should avoid use of ICI in pre-AI patients. More mechanistic research is needed to understand how to uncouple ICI response from toxicity.
Extremity bone sarcoma: Evolution from primary amputation to limb salvage surgery (LSS).
Authors: Bhaskar N. Rao, Michael D. Neel, Hafeez Abdel-Hafeez, Sandra Murphy
Journal: Journal of Clinical Oncology (2021)

e22012 Background: Primary Extremity Bone Sarcomas (PEBS) were historically managed by upfront amputation. Early success rates utilizing neoadjuvant chemotherapy followed by LSS showed promise in halting disease progression and achieving local control. This prompted surgical oncologists to consider LSS in more patients. In anatomic locations for which no functional reconstruction exists, amputation is still considered the best option. Oncologic control, patient satisfaction and improved function are the primary goals of LSS. Three Dimensional CT and MRI have made for more accurate surgical planning, ensuring adequate margins and improved local control. Methods: Between January 1983 and December 2019 the senior author (BNR) has performed, or mentored over 590 LSS worldwide.Improvement in imaging modalities has been the most important advancement contributing to decreasing tumor margins. Initially bone scans determined the margins at 7cm. In the 1970s CT became the modality used to determine local tumor extent. The resection margins were reduced to 5 cm. The early 90’s saw MRI as the main imaging modality. Margins are now set at 1-2cm.LSS was initiated in the mid 80’s using the strict criteria of age &gt; 13, no metastasis, intramedullary extension less than 50%, and small extraosseus extent. Results: Of the 134 cases enrolled through 1990, the local control rate was 90%. Between July 1991 through December 2019, 388 patients enrolled in bone sarcoma protocols, 354 patients underwent LSS ( &gt; 95%). The primary site was the femur (171 cases, 43%) Histological Diagnosis was OS in 93%. Ages ranged from 3-25 years (median 10.8 years) The average length of tumor resection was 7cms(range 1-38cms). 5 patients presented with pathological fracture. All successfully underwent LSS without an increase in local recurrence. Intraoperative complications included, excessive hemorrhage defined as &gt; 10%of blood volume in 88 patients, 25%, Vascular injuries requiring repair in 9 patients, post operative neuropraxia in 28 patients. Mid and late term complications included, Superficial wound infection in 45 patients (19 requiring some surgical intervention), Deep wound problems were identified in 11 patients ( 3 required subsequent amputation), 9 patients had their prosthesis revised due to refractory infection, Local relapse in 5 patients , &lt; 1%. Long term implant related complications, loosening of the prosthesis in 16 , Stem fracture in 13, nonunion of the allograft in 3 patients. Conclusions: Disadvantages are the need for repeat surgeries consequent to either growth discrepancy, loosening, or implant fracture.LSS is feasible in over 95% of patients, complications are generally manageable. Successful oncologic results, satisfaction and function are readily obtained. Early rehabilitation is key to functional success.
Insurance coverage and care affordability in cancer survivors in 2016-2019.
Authors: Justin Michael Barnes, Eric Adjei Boakye, Mario Schootman, Evan Michael Graboyes, Nosayaba Osazuwa-Peters
Journal: Journal of Clinical Oncology (2021)

1520 Background: The Affordable Care Act (ACA) led to improvements in insurance coverage and care affordability in cancer patients. However, the uninsured rate for the general US reached its nadir in 2016 and has been increasing since. We aimed to quantify the changes in insurance coverage and rate of care unaffordability in cancer survivors from 2016 to 2019. Methods: We queried data from the Behavioral Risk Factor Surveillance System (2016-2019) for cancer survivors ages 18-64 years. Outcomes of interest were the percentage of cancer survivors reporting insurance coverage and the percentage reporting cost-driven lack of care in the previous 12 months. Survey-weighted linear probability models adjusted for covariates (age, sex, race/ethnicity, income, education, marital status, and state Medicaid expansion status) were utilized to estimate the average yearly change (AYC) in the outcomes across 2016-2019. Mediation analyses evaluated the mediating effect of insurance coverage changes on changes in cost-driven lack of care. Results: A total of 178,931 cancer survivors were identified among the survey respondents. The percentage of insured cancer survivors between 2016 and 2019 decreased from 92.4% to 90.4% (AYC: -0.54, 95% CI = -1.03 to -0.06, P =.026). This translates to an estimated 164,638 cancer survivors in the United States who lost insurance coverage in the study period. There were decreases in private insurance coverage (AYC: -1.66, 95% CI = -3.1 to -0.22, P =.024) but increases in Medicaid coverage (AYC: 1.14, 95% CI = 0.03 to 2.25, P =.043). The decreases in any coverage were largest in individuals with income &lt; 138% federal poverty level (FPL) (AYC: -1.14, 95% CI = -2.32 to 0.04, P =.059; compared to &gt; 250% FPL, P interaction =.03). Cost-driven lack of care in the preceding 12 months among cancer survivors increased from 17.9% in 2016 to 20% in 2019 (AYC: 0.67, 95% CI = 0.06 to 1.27, P =.03), which translates to an estimated 167,184 survivors in the US who skipped care due to costs. Changes in insurance coverage mediated 27.5% of the observed change in care unaffordability overall (p =.028) and 65.7% in individuals with income &lt; 138% FPL relative to &gt; 250% FPL (p =.045). Conclusions: Between 2016 and 2019, about 165,000 cancer survivors in the United States lost their insurance coverage and a similar number may have skipped needed care due to cost. Loss of insurance coverage was mostly among individuals with low socioeconomic status. Interventions to improve health insurance coverage among cancer survivors, such as the recent executive order to strengthen the ACA and further efforts promoting Medicaid expansion in additional states, may be important factors to mitigate these trends.
Plasma biomarker study of lenvatinib in gastroenteropancreatic neuroendocrine tumors reveals Ang2 and FGF2 as predictors of treatment response: Results from the international phase II TALENT trial (GETNE 1509).
Authors: Jaume Capdevila, Gabriela Jimenez-Valerio, Alba Martinez, Jorge Hernando, Toni Ibrahim, Nicola Fazio, Carlos Lopez, Alex Teule, Juan W. Valle, Salvatore Tafuto, Ana B. Custodio, Nicholas Simon Reed, Markus Raderer, Enrique Grande, Rocio Garcia-Carbonero, Paula Jiménez-Fonseca, Vicente Alonso, Oriol Casanovas
Journal: Journal of Clinical Oncology (2021)

4113 Background: Predictive biomarkers of response to antiangiogenics currently remain elusive, with several molecules discovered but not fully validated nor clinically applied. TALENT trial is a multicenter prospective phase II study of lenvatinib, a VEGFR1-3 and FGFR1-4 multikinase inhibitor (MKI), in advanced G1/G2 neuroendocrine tumors (NETs) from pancreatic (panNETs) and gastrointestinal (giNETs) origins, which has reported the highest overall response rate (ORR) by central radiology assessment with a MKI in this setting. Here we report the plasma biomarker study. Methods: Proangiogenic profiling of plasma samples from patients included in the trial were analyzed by multiplex ELISA (custom made Quantibody Array, RayBiotech). Quantitative determinations of VEGF-A, FGF2, FGF4, Ang2, IL8, PlGF, VEGF-C, VEGF-D and VEGFR2 were obtained from 85 samples of sufficient quality (out of 111 patients included in the study). Association and prediction of response were evaluated for each biomarker and correlated with PFS, OS and ORR in all patients and the different subgroups included in the trial. Results: While none of the factors were able to discriminate PFS or OS in the whole population, a significant association of high-Ang2 and low-FGF2 to ORR was observed. Subgroup analysis confirmed this association in the two cohorts of patients, giNETs (p = 0.003) and panNETs (p = 0.024). In the panNET cohort, prior targeted therapy was mandatory. Prior sunitinib exposure was observed in 8 patients. Of the factors studied, Ang2 and VEGFR2 were significantly decreased in plasma from sunitinib-pretreated patients (-73% p = 0.022 and -62% p = 0.042 respectively). Furthermore, in these sunitinib-pretreated patients Ang-2 and VEGFR2 levels associated to ORR (p = 0.029 and p = 0.029 respectively) and were able to discriminate PFS (log rank p = 0.027 and 0.007 respectively). ROC curve analysis defined Ang2 and VEGFR2 plasma levels with optimal predictive power to be 415pg/ml and 1770pg/ml respectively (p = 0.021). Conclusions: Plasma proangiogenic profiling of TALENT patient samples unraveled high-Ang2 and low-FGF2 as predictive biomarkers of response to lenvatinib in both cohorts. In antiangiogenic-pretreated patients, Ang2 and VEGFR2 levels significantly predict response to treatment in panNETs. Importantly, current studies with MKIs should confirm the value of these markers for advanced NETs not only to predict response, but also to stablish sequential treatment options for these patients.
Phase II study of panitumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable, <i>RAS</i> wild type colorectal cancer: OGSG 1602, survival update data.
Authors: Shingo Noura, Takeshi Kato, Tetsuji Terazawa, Masahiro Goto, Katsuya Ohta, Hironaga Satake, Yoshinori Kagawa, Hisato Kawakami, Hiroko Hasegawa, Kazuhiro Yanagihara, Tatsushi Shingai, Ken Nakata, Masahito Kotaka, Masayuki Hiraki, Ken Konishi, Shiro Nakae, Daisuke Sakai, Yukinori Kurokawa, Toshio Shimokawa, Taroh Satoh
Journal: Journal of Clinical Oncology (2021)

3558 Background: We previously reported the result of the phase II OGSG1602 study in which single agent of panitumumab (Pmab) demonstrated 76.5% and 50% of disease control rate (DCR), primary endpoint, and response rate (RR), respectively, in chemotherapy-naïve frail or elderly patietns (pts) with wild-type (wt) RAS unresectable colorectal cancer (CRC). Here, we reports the survival analysis including overall survival (OS) and progression free survival (PFS) in terms of sidedness and early tumor shrinkage (ETS). Methods: Thirty-six pts aged ≥76 years, or ≥65 considered unsuitable for intensive chemotherapy were enrolled and received Pmab 6 mg/kg intravenously every 2 weeks. Primary tumors located in the cecum to transverse colon were coded as right-sided tumors (RST), while tumors located from the splenic flexure to rectum were considered left-sided tumors (LST). Early tumor shrinkage (ETS) was determined as tumor reduction of 20% at week 8 compared to baseline. Results: Of total of 36 enrolled pts, 34 pts were included in the efficacy analysis, with pts with LST vs. RST being 26 vs. 8 cases, while pts who achieved ETS (ETS+) vs. those who did not achieve ETS (ETS-) being 15 vs. 19 cases. Among the evaluable 34 pts, the median PFS (mPFS) and median OS (mOS) were 6.0 months (95% Confidence Interval [CI]: 5.4-10.0) and 17.5 months (95%CI, 13.8-24.3), respectively, with the median follow-up of 17.0 months. For PFS, there were no significant differences between pts with LST vs. RST [6.6 months (95%CI, 5.4-11.5) vs. 4.9 months (95%CI, 1.9-NA), p = 0.120] but between pts with ETS+ vs. ETS- [10.4 months (95%CI, 7.4-NA) vs. months (95%CI, 2.1-7.9), p = 0.001]. Furthermore, OS was significantly different either in pts with LST vs. RST [19.3 months (95%CI, 14.2-NA) vs. 12.3 (95%CI, 9.9-NA), p = 0.043] or in pts with ETS+ vs. ETS- [ months (n = 15, 95%CI, 19.6-NA) vs. 10.1 months (n = 19, 95%CI, 6.8-21.8), p &lt; 0.001]. Conclusions: Pmab monotherapy showed the favolable OS in the frail or elderly pts with RAS wt, unresectable CRC. Our data also confirmed the prognostic value of sidedness as well as predictive value of ETS in this setting. Clinical trial information: UMIN000024528. [Table: see text]
A Wnt-Independent LGR4–EGFR Signaling Axis in Cancer Metastasis
Authors: Fei Yue, Weiyu Jiang, Amy T. Ku, Adelaide I.J. Young, Weijie Zhang, Eric P. Souto, Yankun Gao, Zihan Yu, Yi Wang, Chad J. Creighton, Chandandeep Nagi, Tao Wang, Susan G. Hilsenbeck, Xin-Hua Feng, Shixia Huang, Cristian Coarfa, Xiang H.-F. Zhang, Qingyun Liu, Xia Lin, Yi Li
Journal: Cancer Research (2021)

Abstract Leucine-rich repeat-containing G protein–coupled receptors 4, 5, and 6 (LGR4/5/6) play critical roles in development and cancer. The widely accepted mechanism is that these proteins, together with their R-spondin ligands, stabilize Wnt receptors, thus potentiating Wnt signaling. Here we show that LGR4 enhanced breast cancer cell metastasis even when Wnt signaling was deactivated pharmacologically or genetically. Furthermore, LGR4 mutants that cannot potentiate Wnt signaling nevertheless promoted breast cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Multiomic screening identified EGFR as a crucial mediator of LGR4 activity in cancer progression. Mechanistically, LGR4 interacted with EGFR and blocked EGFR ubiquitination and degradation, resulting in persistent EGFR activation. Together, these data uncover a Wnt-independent LGR4–EGFR signaling axis with broad implications for cancer progression and targeted therapy. Significance: This work demonstrates a Wnt-independent mechanism by which LGR4 promotes cancer metastasis. See related commentary by Stevens and Williams, p. 4397
Translational relevance of baseline NLR and LMR ratio in predicting response of EGFR-TKI.
Authors: Hrishi Varayathu, Rashi Yogendranath Tiwari, Shalaka Somayaji, Smruthy Ann Mathew, Beulah Elsa Thomas, Lalram Sangi, Renjan Thomas, Gautam Balaram, Mithua Ghosh, Satheesh Chiradoni Thungappa, Suhail Sayeed Mufti, Sriniivas Bj, Vinayak Munirathnam, Radheshyam Naik, Basavalinga Sadasivaiah Ajaikumar
Journal: Journal of Clinical Oncology (2021)

e15020 Background: Neutrophil-Lymphocyte Ratio (NLR) and Lymphocyte-Monocyte Ratio (LMR) have been under scrutiny for their potential as a prognostic tool in various cancers. While there have been conflicting opinions on their reliability, NLR has shown rather near accurate predictions in previous studies. Targeted tyrosine kinase inhibitors have shown good results in improving OS and PFS of patients with EGFR-mutated NSCLC but the prognostic indicators are limited. This study aims to decipher if baseline NLR and LMR ratios are valid tools to predict prognosis of patients with EGFR-mutated NSCLC. Methods: We analyzed 78 advanced NSCLC patients harboring Exon 19 Deletion and Exon 21 L858R mutation undergoing EGFR-TKI therapy. Baseline NLR and LMR were measured in peripheral blood within two weeks prior to the initiation of TKIs. Overall survival was used as an outcome measure for TKI therapy and it is defined as from the initiation of TKIs to death by any cause. The cut-off for NLR and LMR was calculated using an X-tile plot (version 3.6.1, Yale University, New Haven, CT, USA) by dividing marker data into three populations: low, middle, and high (i.e., two divisions), with randomized 1:1 “training” and “validation” cohorts. Results: Overall median survival of the study group was 31.5 months and median age was found to be 60 years. Gefitinib (35.9%) and afatinib (34.6%) were the most commonly prescribed followed by erlotinib (21.8%) and osimertinib (7.7%). With cut-points of 1.8 and 4.9 we analyzed three populations for baseline NLR as ≤1.8, 1.9-4.9 and &gt; 4.9. Similarly, for LMR cut-points of 3.49 and 5 were found and we analyzed patients with LMR of ≤3.49, 3.5-5 and &gt;5. There was a statistically significant overall median survival observed as per the obtained NLR as well as LMR cut-off as given in the table. Conclusions: A statistically significant co-relation was observed with baseline NLR and LMR ratio in predicting response to EGFR TKIs in NSCLC. Our study further strengthens the concept of using NLR and LMR as peripheral blood biomarkers for prognostic assessment in cancer patients undergoing treatment.[Table: see text]
Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity
Authors: Joseph L. Jilek, Kayla L. Frost, Kevyn A. Jacobus, Wenxi He, Erica L. Toth, Michael Goedken, Nathan J. Cherrington
Journal: Acta Pharmaceutica Sinica B (2021)

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions. Cisplatin (CDDP) elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion. Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis (NASH), however, associated changes to substrate toxicity is unknown. To test this, a methionine- and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics, transporter expression, and toxicity. NASH rats administered CDDP (6 mg/kg, i.p.) displayed 20% less nephrotoxicity than healthy rats. Likewise, CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min, renal secretion decreased from 6.23 to 2.80 mL/min, and renal CDDP accumulation decreased by 15%, relative to healthy rats. Renal copper transporter-1 expression decreased, and organic cation transporter-2 and ATPase copper transporting protein-7b increased slightly, reducing CDDP secretion. Hepatic CDDP accumulation increased 250% in NASH rats relative to healthy rats. Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats, although no drug-related toxicity was observed. These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance, which may alter nephrotoxicity.
The BET Inhibitor GS-626510 Converges with Idelalisib through the Inhibition of Tumor-Macrophage Crosstalk and Cytokine Production in Diffuse Large B-Cell Lymphoma
Authors: Juan G Valero, Aranzazu Chamorro-Jorganes, Katie Walker, Martina Guerrero-Hernandez, Vanina Rodriguez, Clara Recasens-Zorzo, Anna Esteve-Arenys, Eriong Lee-Verges, Alba Matas-Cespedes, Neus Serrat, Dolors Colomer, Armando Lopez-Guillermo, Stacey Tannheimer, Patricia Pérez-Galán, Gael Roue
Journal: Blood (2017)