tbuckley/cabot-search huggingface dataset:
Sensor-controlled scalp cooling for chemotherapy-induced alopecia: Safety and effectiveness in primary breast cancer patients exposed to anthracyclines and/or taxanes in the neoadjuvant or adjuvant setting.
Authors: Christian M. Kurbacher, Susanne Herz, A. Tabea Kurbacher, Gabriele Kolberg, Nele Kettelhoit, Jutta A. Kurbacher
Journal: Journal of Clinical Oncology (2018)

e22196 Background: This retrospective analysis sought to obtain detailed information on both effectiveness and safety of sensor-controlled scalp cooling (SCSC) to prevent chemotherapy-induced alopecia (CIA) using the Paxman system (Paxman, Huddersfield, UK) in patients (pts) with primary breast cancer (PBC) exposed to neoadjuvant (NACT) or adjuvant Ctx (ACT) with anthracyclines (A), taxanes (T), or both (A+T) in the clinical routine. Methods: 86 pts were analyzed: NACT, 47 (54.6%); ACT, 39 (45.4%); dose-dense (dd) Ctx, 38 (44.2%); non-dd Ctx 48 (55.8%); premenopausal, 48 (55.8%); postmenopausal, 38 (44.2%). Ctx was as follows: A→T, 38 (44.2%), T→A, 23 (26.7%), T, 25 (29.1%). Pts were underwent SCSC during each Ctx cycle. CIA was quantified according to the Dean score (DS) determined 3 wks after the last cycle. Data were analyzed regarding SCSC completion rate, quality of hair preservation (success: DS 0-2, failure: DS 3-4), reasons of SCSC discontinuation, and safety. Moreover, the following parameters were investigated in regard to the success of SCSC: menopausal status, NACT vs ACT, dd Ctx vs non-dd Ctx, Ctx regimen. Results: Success rate was 64.0% with 35 pts (40.7%) experiencing complete hair preservation (DS 0), and 20 (23.3%) showing partial response to SCSC (DS 1-2). 27 pts (31.4%) stopped SCSC prematurely with CIA being the reason in 21 pts (24.4%). Local discomfort and pain were reported by 3 pts (3.5%) each. Effectiveness of SCSC did not differ for most analyzed subgroups. The relative risk (RR) to experience CIA was 1.23 (CI: 0.87-1.74) for post- vs premenopausal pts, 1.07 (CI: 0.78-1.46) for ACT vs NACT, 1.28 (CI: 0.91-1.80) for dd Ctx vs non-dd Ctx, and 1.56 (0.98-2.36) for A+T vs T. However, the SCSC success rate for A→T (47.4%) was significantly lower (p = 0.016), compared to T→A (73.9%) or T (80.0%). Conclusions: SCSC was safe and effective in order to prevent CIA in a real-world population of pts with PBC. All therapeutic subgroups benefited from SCSC. A+T-based Ctx per se is not a contraindication for SCSC. However, the success rate is significantly higher when the taxane precedes the anthracycline.
患者の年齢と脆弱性に従う多発性骨髄腫の個別化治療: 欧州骨髄腫ネットワーク(EMN)の報告
Authors: Palumbo Antonio, Bringhen Sara, Ludwig Heinz, A Dimopoulos Meletios, Blade Joan, V Mateos Maria, Rosinol Laura, Boccadoro Mario, Cavo Michele, Lokhorst Henk, Zweegman Sonja, Terpos Evangelos, Davies Faith, Driessen Christoph, Gimsing Peter, Gramatzki Martin, Hajek Roman, E Johnsen Hans, DA Costa Fernando Leal, Sezer Orhan, Spencer Andrew, Beksac Meral, Morgan Gareth, Einsele Hermann, Miguel Jesus F. San, Sonneveld Pieter
Journal: Blood (2011)
P05.22 Growth deceleration of meningioma associates with progression of calcification: evaluation with CT Hounsfields units
Authors: S Nakasu, T Ohnishi, S Kitahara, H Ohwaki, K Matsumura
Journal: Neuro-Oncology (2018)

Predicting a growth speed in meningiomas is very important to plan a treatment not only in asymptomatic tumors but also symptomatic ones. Although calcification may be an important sign of slow growth in meningiomas, the developmental process and relation to a tumor growth pattern have not been elucidated. Between 2006 and 2017, CT scans were performed in 145 meningiomas in 136 patients (19 symptomatic tumors) in our hospital. We investigated evolutional changes of calcification in meningiomas using a CT scan by Hounsfield units. The results were compared with clinical features and tumor growth patterns. Tumor growth was evaluated with serial CT or MRI studies. In 145 meningiomas, 94 showed calcification in various degrees. Tumors in females had calcified components more frequently (p<0.0001). They showed higher mean Hounsfield unit (mHU) (median 57.5) than those in males (median 38.0) (p<0.0001). In 54 tumors, mHU was measured at least twice at a interval more than a year apart. The median annual increase in mHU was 2.22 units. Tumors in females showed greater mHU increase than those in males (p=0.002). Tumor doubling time (Td) and annual volume change (AVC) were calculated in 85 tumors. We found significant correlation between Td and mHU (R=0.58, p<0.0001). Tumors in females showed significantly slower growth than those in males. Tumors in the younger age group (less than 65 y.o.) showed faster growth than those in the older age group (p=0.007). Multivariate analysis showed mHU was the only significant factor for Td (p<0.0001). AVC was only related to the initial tumor size. Growth curve patterns (exponential or decelerating) were evaluated in 51 tumors. The pattern had a significant relation to existence of calcification (p=0.0078). Tumors of decelerated growth showed calcification more frequently than tumors of exponential growth (p=0.044). The tumors of exponential growth showed less mHU and less mHU increase than those of decelerated growth (p=0.029). ROC analysis showed mHU 46.9 is a cut-off point (specificity 1.0, sensitivity 0.68) for exponential and non-exponential growth. Calcified tumors gradually increased mHU with deceleration of their growth. Non-calcified meningiomas were likely to grow exponentially. Meningiomas in females had calcification more frequently, increased mHU more rapidly, and showed slower growth than those in males. mHU that correlated with Td may be a good quantitative indicator for growth speed. and pattern.
Dose escalating study of crenolanib besylate in advanced GIST patients with PDGFRA D842V activating mutations.
Authors: Margaret von Mehren, Eric Daniel Tetzlaff, Meghan Macaraeg, Jeremy Davis, Vartika Agarwal, Abhijit Ramachandran, Michael C. Heinrich
Journal: Journal of Clinical Oncology (2016)

11010 Background: PDGFRA D842V mutated GIST is resistant to all available TKIs with a median PFS of ≤ 2.8m and a median OS 14.7m. Crenolanib is a unique type I inhibitor of PDGFRα, with in vitro activity against PDGFRA D842V (cellular IC50 9 nM). We here report a phase I/II study evaluating safety, PKs, and antitumor efficacy of crenolanib in advanced GIST with PDGFRA D842V mutations. Methods: Crenolanib was administered at four dosing regimens including 200 mg QD, 340 mg QD, 140 mg BID and 72 mg/m2/TID. Pts who had progressed on prior TKIs were eligible so long as they had measurable disease. As most pts had undergone prior gastrectomies, PK analysis was performed to assess adequate crenolanib absorption. Results: 20 pts (12 males, 8 females, median age 61) were enrolled. 16/20 had progressed after prior imatinib (15), sunitinib (7), dasatinib (5), sorafenib (4), nilotinib (2), and regorafenib (2). 16/20 pts had undergone prior partial (14) or total (2) gastrectomy. Only 4 out of 20 pts were FDG-avid by a baseline PET scan (PDGFR GIST is typically PET negative). Crenolanib was administered at 200mg QD to the first 9 pts. 4/9 pts were subsequently escalated to 340mg QD. PK demonstrated t1/2 of 8.6 hrs, suggesting a BID or TID schedule would be more optimal to maintain adequate trough crenolanib levels. The next 7 pts were given crenolanib on a 140 BID schedule. 4/7 pts were escalated to an individualized BSA dosing of 72 mg/m2/TID. 4 additional pts were also treated at the 72 mg/m2/TID schedule. 2/16 pts achieved a PR while 3/16 pts achieved SD; clinical benefit rate was 31% (5/16 pts).7 pts stayed on crenolanib for over 6 m and 1 pt each for 1yr and 2yrs. Grade 3/4 AEs included reversible LFT elevations (3 pts) and anemia (3 pts). 1 pt each with pre-existing ascites and pleural effusion developed worsening fluid accumulation in the context of disease progression. Despite prior gastrectomy, crenolanib reached clinically relevant concentration. Conclusions: Crenolanib is the first and only TKI to show activity in PDGFRA D842V mutant GIST. Crenolanib was well-tolerated when given to pts on a chronic basis. A randomized placebo-controlled study of crenolanib in advanced D842V GIST is currently being initiated. NCT01243346 Clinical trial information: NCT01243346.
CD13-HDAC5 signaling axis promotes hepatocecullar carcinoma and sorafenib resistance by activating NF-KB.
Authors: Xin-Rong Yang, Bo Hu, Zhou Jian, Jia Fan
Journal: Journal of Clinical Oncology (2018)

e16144 Background: CD13 is a novel marker for liver cancer stem cells (CSC) that is responsible for therapy resistance in hepatocellular carcinoma (HCC). However, functional characterization of CD13 and therapeutic utility of targeting it in HCC remained elusive. Methods: CD13 expressions were evaluated various types of clinical samples including a tissue microarray containing 403 HCC patients. The effects of CD13 modulation on proliferation, cell cycle, invasion and xenograft tumor growth were determined. CD13 regulatory mechanism was dertermined by LC-MS/MS mass spectrometry, co-immunoprecipitation and gene expression profiling. The anticancer effect of targeting CD13 by ubenimex, a clinical used CD13 inhibitor, was examined in both sorafenib-sensitive and resistant HCC cells and patient-derived xenografts (PDX). Results: CD13 expression was higher in metastatic HCC samples, with its overexpression independently associated with poor survival and increased recurrence after resection. CD13 could positively regulate HCC cell proliferation, invasiveness and sorafenib resistance. Mechanistically, CD13 interacts with HDAC5 to deacetylate NF-κB p65 subunit to prevent it from degradation, which promote HCC progression and chemotherapy resistance. Ubenimex greatly suppress the tumor growth of HCC PDX models and showed synergetic effect with HDAC5 inhibitor. Surprisingly, targeting CD13 effectively restored the sensitivity of HCC cells towards sorafenib in both sorafenib-resistant cell lines and PDX models. Consistently, patients with lower CD13 expression exhibited better prognosis to sorafenib treatment. Conclusions: CD13 is a prognostic indicator as well as an effective predictor for sorafenib response in HCC. Moreover, targeting CD13 is a promising strategy for treating HCC and reversing sorafenib resistance.
A Nonpump Function of Sodium Iodide Symporter in Thyroid Cancer via Cross-talk with PTEN Signaling
Authors: Fang Feng, Lamis Yehia, Ying Ni, Yi Seok Chang, Sissy Meihua Jhiang, Charis Eng
Journal: Cancer Research (2018)

The sodium iodide symporter (NIS) is a classical iodide pump typically localized within the cell plasma membrane in thyroid cells, where NIS expression is believed to ensure success of mainstay radioiodide therapy in thyroid cancers. Although radioiodide uptake is generally reduced in thyroid cancer tissue, intracellular nonmembranous NIS has been reported to increase, suggesting that NIS serves a pump-independent function. Thyroid cancer is one of the major component cancers of Cowden syndrome, a subset of which is caused by germline mutations in PTEN In this study, we explored the noncanonical tumorigenic role of NIS in thyroid cancer cells in relation to PTEN signaling. PTEN knockdown in thyroid cancer cell lines stabilized intracellular NIS protein by promoting an interaction with NIS-LARG (leukemia-associated RhoA guanine exchange factor). Increased protein levels of cytoplasmic NIS enhanced RhoA activation and resulted in a promigration tumorigenic phenotype. Inhibition of NIS glycosylation through activation of the PI3K/AKT/mTOR signaling pathway contributed to mislocalization of NIS in the cytoplasm, facilitating its nonpump tumorigenic function through an interaction with LARG, which predominantly localized in the cytoplasm. Moreover, PTEN or PI3K/AKT/mTOR signaling could affect DPAGT1, a glycosylating enzyme involved in the initial step of N-linked glycosylation, to inhibit glycosylation of NIS. In summary, our results elucidate a pump-independent, protumorigenic role for NIS in thyroid cancer via its cross-talk with PTEN signaling.Significance: A novel pump-independent protumorigenic role of nonmembranous NIS challenges the presumption that radioiodine treatment of thyroid cancer is ineffective when transmembrane NIS is not expressed. Cancer Res; 78(21); 6121-33. ©2018 AACR.
A phase 2A open-label, multicenter trial of the safety and efficacy of LYC-55716, a first-in-class oral, small-molecule RORγ agonist to treat select solid tumors.
Authors: Karen Kelly, Melissa Lynne Johnson, Devalingam Mahalingam, Stephen V. Liu, Hope Elizabeth Uronis, Christina Wu, Laura Carter, Xiao Hu, Garry Alan Weems, H. Jeffrey Wilkins, Linda R. Duska
Journal: Journal of Clinical Oncology (2018)

TPS2617 Background: LYC-55716 is a first-in-class, oral, small-molecule agonist of the retinoic acid receptor–related orphan receptor γ (RORγ) under development as a novel immuno-oncology agent for solid tumors. Preclinical evidence suggests that LYC-55716 alters immune cell anti-tumor effector functions and immunosuppressive mechanisms, leading to reduced tumor growth and enhanced survival. In the Phase 1 portion of an ongoing Phase 1/2A trial, LYC-55716 was well tolerated with no dose-limiting toxicities. Evidence of pharmacodynamic target engagement was demonstrated and disease stabilization with tumor reduction was noted in patients after failure of PD-1 therapy. The Phase 2A trial (NCT02929862) is underway in patients with advanced non–small cell lung, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers. Methods: The Phase 2A portion of the trial will enroll ~70 adult patients who will receive 28-day treatment cycles of LYC-55716 administered twice daily. The primary endpoint is to determine the objective response rate (ORR). Secondary endpoints will include duration of response, progression-free survival, overall survival, safety, and pharmacokinetics. As an exploratory endpoint, immune-related biomarkers will be assessed in blood samples from all patients, taken at screening and every 2-4 weeks through treatment cycle 4, and in tissue biopsy samples of selected patients, taken at screening and 4-12 weeks after beginning cycle 1. Immune markers of interest will be evaluated using a NanoString platform and immunohistochemistry. Results will be analyzed using descriptive and summary statistics. Clinical trial information: NCT02929862.
5-FU based chemotherapy with bevacizumab in synchronous metastatic colorectal cancer patients with bleeding primary tumor.
Authors: Birgit Gruenberger, Patrick Starlinger, Elisabeth Messinger, Lukas Oehlberger, Sabine Weibrecht, Jan Philipp Jonas, Barbara Weitmayr, Thomas Gruenberger
Journal: Journal of Clinical Oncology (2016)

e23208 Background: The benefit of systemic chemotherapie (5-FU based) in combination with Bevacizumab (Bev) in patients (pts) with metastatic colorectal cancer (mCRC) is well proven. Nevertheless, an anti-VEGF therapy for patients with an intact primary is still controversial. As bleeding is a well-known side effect during treatment with an anti-VEGF therapy Bevacizumab is not recommended in patients with active bleeding. Bev was reported to significantly decrease tumor perfusion, vascular volume and microvascular density. The primary aim of this analysis is to evaluate the safety and efficacy of Bev in patients with clinical bleeding colorectal primary. Methods: mCRC patients enrolled from January 2010 to December 2015 were identified from a prospective multi-site Austrian registry. Patients with an intact primary tumor and synchronous metastases who were treated with first line chemotherapy (5-FU based) with Bev were studied. Results: Out of 207 patients with synchronous mCRC 89 had the primary tumor in situ. 67 of these pts received a 5-FU based chemotherapy with Bev. 41 presented at first visit with an iron deficiency anemia with clinical bleeding signs. 57% described having noticed a stool abnormality. A minority of pts presented with a subileus, one required a gastric tube for decompression. In all patients bleeding stopped after the first treatment cycle, and bowel habits improved within a month. 40% (28/67) pts underwent a potential curative surgery of metastases and primary during follow-up. Pathological responses were similar in metastases and primary tumor with major size reductions in initial initial primaries. Two patients had to undergo emergency surgery due to perforation at a diverticulum, no perforation at the primary was recorded. Conclusions: In routine clinical practice Bev seems safe in patients with a clinical bleeding primary. These study findings indicate that VEGF blockade has a direct and rapid antivascular effect on primary colorectal cancer.
Reducing chronic breast cancer related lymphedema utilizing a program of prospective surveillance with bioimpedance spectroscopy (BIS).
Authors: Pat W. Whitworth, Chirag Shah, Frank Vicini, Andrea Cooper
Journal: Journal of Clinical Oncology (2017)

10117 Background: Breast cancer related lymphedema (BCRL) represents a major side effect that can significantly impact quality of life. Current guidelines support prospective surveillance to allow for early diagnosis and treatment of BCRL at a subclinical, reversible stage. This current large, single institution experience evaluated the use of bioimpedance spectroscopy (BIS) to monitor patients for the development and treatment of BCRL. Methods: From April 2010 through Nov 2016, 596 patients (79.6% with high-risk features) were evaluated with BIS.Patients received a pre-operative baseline L-Dex measurement and post-operatively at regular intervals. Elevated L-Dex scores were defined as an increase of ≥10 points above baseline (considered subclinical BCRL). Intervention then consisted of applying an over the counter (OTC) sleeve for 4 weeks followed by re-evaluation. The need for complete decongestive physiotherapy (CDP) represented a surrogate for the development of clinically significant, chronic BCRL. Results: Median follow-up for all patients was 17 months. Seventy-three patients (12%) developed an elevated L-Dex score with axillary lymph node dissection (ALND) (p &lt; 0.001), taxanes (p = 0.008), and (regional nodal irradiation (RNI) (p &lt; 0.001) associated. At last follow-up, only 18 patients (3%) had unresolved clinically significant BCRL requiring CDP. Mastectomy (p = 0.02), ALND (p &lt; 0.001), taxanes (p = 0.05), and RNI (p &lt; 0.001) were associated with requiring CDP. Conclusions: Our results demonstrate that prospective monitoring using BIS, with intervention (using a simple OTC sleeve for 4 weeks) triggered by a ≥10-point L-Dex elevation, resulted in only a 3% rate of chronic, clinically significant BCRL. These results are lower than reported in contemporary studies and validate recent guidelines supporting prospective screening and intervention for BCRL.
Preliminary interim results of the first-in-human, dose-finding PROCLAIM-CX-072 trial of the PD-L1 Probody therapeutic (Pb-Tx) CX-072 in combination with ipilimumab (ipi) in patients (pts) with advanced solid tumors.
Authors: Rachel E. Sanborn, Catharina Wilhelmina Menke, Karen A. Autio, Hendrik-Tobias Arkenau, Javier Garcia Corbacho, Patricia LoRusso, Elizabeth Ruth Plummer, Nataliya Volodymyrivna Uboha, Morganna Louise Freeman, Jerzy Wydmanski, Vanessa Huels, Beiyao Zheng, Matthias Will, Rachel W. Humphrey, Fiona Thistlethwaite, Elisabeth G.E. de Vries, Anthony B. El-Khoueiry
Journal: Journal of Clinical Oncology (2018)

3072 Background: CX-072 is a Pb-Tx directed against programmed cell death ligand 1 (PD-L1), designed to be preferentially activated by tumor-associated proteases but not in healthy tissue. Preclinically, the combination of a PD-1 Pb-Tx with an anti–CTLA-4 antibody showed comparable efficacy but improved safety compared to the non–Pb-Tx combination control. This dose-escalation cohort of CX-072 + ipi in pts with advanced solid tumors was designed to examine the safety and tolerability of combination therapy. Preliminary safety and antitumor activity are reported. Methods: In this ongoing phase 1-2 study (NCT03013491), pts receive CX-072 + ipi in a concomitant dosing schedule (study Part B1). Eligible pts are PD-1, PD-L1, and CTLA-4 inhibitor naive. Planned doses are CX-072 0.3-30 mg/kg IV every 21 days + ipi 3 mg/kg or 10 mg/kg IV every 21 days for 4 cycles, followed by CX-072 monotherapy every 14 days. Results: As of data cut (Nov 30, 2017), part B1 enrolled 9 pts. Median age was 44 years (range, 28-70); 6 pts (67%) were male. Median number of prior anticancer treatments was 4 (range, 2-18). At the time of data cut, 6 pts remained on treatment. Median number of doses of CX-072 (0.3 and 1 mg/ kg) and ipi (3 mg/kg) was 2 (range, 2-10) and 2 (range, 2-4), respectively. 1 DLT (grade 3 dyspnea, 0.3 mg/kg CX-072 + 3 mg/kg ipi) was observed. MTD has not been reached and dose escalation continues. Grade 1-2 treatment-related adverse events (TRAEs) occurred in 6 pts (67%). 4 grade 3 TRAEs were experienced by 2 pts (22%) and included colitis, pneumonitis, and AST and ALT increases (0.3 mg/kg CX-072 + 3 mg/kg ipi). At cutoff, 1 of 4 evaluable pts showed target lesion reduction of 31% from baseline (0.3 mg/kg CX-072, anal SCC, MSI stable, and intermediate tumor mutation burden). As of Dec 4, this patient had a confirmed PR with 56% reduction in target lesion. Conclusions: Preliminary data for CX-072 + ipi show a manageable safety profile and signals of antitumor activity. The study is ongoing, and all cohorts through 10 mg/kg CX-072, the dose selected for monotherapy cohort expansion, are now enrolled. Escalation of ipi dose to 10 mg/kg is pending. Clinical trial information: NCT03013491.