tbuckley/cabot-search huggingface dataset:
Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer.
Authors: Patrick Neven, Hope S. Rugo, Sara M. Tolaney, Hiroji Iwata, Masakazu Toi, Matthew P. Goetz, Peter A. Kaufman, Susana Barriga, Yong Lin, George W. Sledge
Journal: Journal of Clinical Oncology (2018)

1002 Background: Abemaciclib is a selective inhibitor of CDK4 & 6 that is dosed on a continuous schedule and is approved for the treatment of HR+, HER2- advanced breast cancer (ABC) as monotherapy and in combination with fulvestrant (F). In the intent-to-treat (ITT) population in the MONARCH 2 study, abemaciclib in combination with F demonstrated improved progression-free survival (PFS) and objective response rate (ORR) compared to placebo (P) + F (16.4 vs 9.3 months; hazard ratio [HR] .553; 95% CI: .449, .681; p < .0000001; ORR in measurable disease 48.1% vs 21.3%; p < .001). Here, we compare the efficacy and safety of abemaciclib + F vs P + F in the pre/peri-menopausal subgroup. Methods: MONARCH 2 was a Phase 3 randomized, double-blind, placebo-controlled study of abemaciclib + F vs P + F in pts with HR+, HER2- ABC that progressed on ET. Key eligibility criteria were: pre/peri- and post-menopausal women with HR+, HER2- ABC (pre/peri-menopausal pts received a GnRH agonist); ECOG PS ≤ 1; progression on (neo)adjuvant ET, ≤12 months from end of adjuvant ET, or on first line ET for metastatic disease; ≤1 line of ET; no prior chemotherapy for metastatic disease. Pts received orally administered abemaciclib 150 mg twice daily + 500 mg F (per label) or P + F. Primary objective was investigator-assessed PFS. Secondary objectives included ORR, clinical benefit rate, disease control rate, duration of response, safety and tolerability. Results: 114 pre/peri-menopausal pts were randomized 2:1 to abemaciclib + F (N = 72) and P + F (N = 42) arms. 57 PFS events were observed. Median PFS was not reached for the abemaciclib + F arm and was 10.5 months for the P + F arm (HR, .446; 95% CI: .264, .754; p = .002). In pts with measurable disease (n = 79, 69.3%), ORR was significantly higher in the abemaciclib + F arm: 60.8% (3.9% complete response [CR]) vs 28.6% (0% CR; p = .006). The most frequent adverse events (any grade) for abemaciclib + F vs P + F were diarrhea (87.3% vs 23.8%), neutropenia (59.2% vs 7.1%) and leukopenia (43.7% vs 4.8%). Conclusions: Abemaciclib + F in combination with a GnRH agonist significantly improved PFS and ORR, and had a generally tolerable safety profile in pre/peri-menopausal women with HR+, HER2- ABC. Clinical trial information: NCT02107703.
First-line ribociclib (RIB) + letrozole (LET) in hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC): MONALEESA-2 biomarker analyses.
Authors: Gabriel N. Hortobagyi, Shani Paluch-Shimon, Katarina Petrakova, Cristian Villanueva, Arlene Chan, Arnd Nusch, Yoon Sim Yap, Lowell Hart, Anne Favret, Norbert Marschner, Gabe S. Sonke, Hege Oma Ohnstad, Carlos Arteaga, Fei Su, Wei He, Michelle Kristine Miller, Salomon M. Stemmer
Journal: Journal of Clinical Oncology (2018)

1022 Background: In MONALEESA-2, first-line RIB + LET improved investigator-assessed progression-free survival (PFS; primary endpoint) vs placebo (PBO) + LET in postmenopausal pts with HR+, HER2– ABC. Previous MONALEESA-2 biomarker analyses, involving immunohistochemistry, gene expression, and NGS of ctDNA, showed consistent RIB benefit. Here, we present additional MONALEESA-2 gene expression data. Methods: Tumor samples (n/N, 391/668) were evaluated for gene expression using the NanoString 230-gene nCounter® GX Human Cancer Reference panel. To assess correlations between gene expression level and PFS, pts were classified into low (L) and high (H) messenger RNA expression subgroups using a 10% cut-off for RB1 and median expression as the cut-off for other genes. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CI). Results: RIB + LET improved PFS in all pt subgroups (Table). Kaplan–Meier curves will be presented. Clinical trial information: NCT01958021. Conclusions: Benefit of RIB was consistent across gene expression subgroups; H vs L ESR1 and L vs H RTK expression trended towards greater RIB benefit. Genes implicated preclinically in mechanisms of resistance to CDK4/6 inhibitors require further investigation based on metastatic/liquid biopsies, and in larger clinical datasets. Gene(s) Expression level Events, n/N Hazard ratio; 95% CI RIB + LET PBO + LET CDK pathway and breast cancer ESR1 L 51/101 62/95 0.74; 0.51–1.07 H 34/96 58/99 0.39; 0.25–0.60 RB1 L 11/21 14/19 0.52; 0.23–1.16 H 74/176 106/175 0.55; 0.41–0.74 E2F1 L 31/105 45/91 0.56; 0.35–0.89 H 54/92 75/103 0.52; 0.37–0.75 Implicated in CDK4/6 inhibitor resistance CDK2 L 40/103 49/93 0.64; 0.42–0.98 H 45/94 71/101 0.48; 0.33–0.71 CCNE1 L 32/97 51/99 0.53; 0.34–0.83 H 53/100 69/95 0.54; 0.38–0.78 FGFR1 L 32/93 59/103 0.45; 0.29–0.69 H 53/104 61/91 0.63; 0.43–0.91 Involved in alternative pathways Cell cycle control L 32/99 47/97 0.66; 0.42–1.03 H 53/98 73/97 0.45; 0.31–0.64 PI3K pathway L 37/98 54/98 0.57; 0.37–0.86 H 48/99 66/96 0.54; 0.37–0.79 MAPK pathway L 42/99 61/97 0.55; 0.37–0.81 H 43/98 59/97 0.56; 0.37–0.83 RTKs L 39/103 59/93 0.41; 0.27–0.61 H 46/94 61/101 0.74; 0.50–1.08
Id1 is an essential transcriptional regulator of the hematopoietic microenvironment
Authors: Hyung Suh, Ming Ji, John Gooya, Kenneth Zheng, Kimberly Klarmann, Jonathan Keller
Journal: Cancer Research (2007)

1286   We previously found that Id1 mRNA is not expressed in hematopoietic stem cells (HSC), but is increased during the early stages of the myeloid development. Its expression is increased by C/EBPα, which is essential for granulocytic differentiation, suggesting Id1 might regulate myeloid development. Furthermore, over-expression of Id1 promotes increased myelopoiesis  in vivo . In this study, we examined Id1-/- mice to clarify the physiological role of Id1 in hematopoiesis. Granulocyte and monocyte counts were increased in the peripheral blood of Id1-/- mice, while B lymphocytes were decreased. Id1-/- bone marrow (BM) also showed increased percentages of myeloid cells, but total BM cellularity was decreased by 25% compared to Id1+/+ mice. Immunophenotypic analysis of BM progenitors showed decreased numbers of Granulocyte Monocyte Progenitors (lin-IL7Rα-cKit+Sca-1-CD34+ Fcγ RII/III+ cells) and more differentiated progenitors, while total HSC (lin-IL7Rα-cKit+Sca1+) numbers are preserved. In addition, the percentage of HSC and, committed progenitors (lin-IL7Rα-cKit+Sca1-) in S phase was increased in Id1-/- BM cells  in vivo  by BrdU staining. Serial transplantation experiments showed that self-renewal of HSC is preserved in the absence of Id1. Thus, though Id1 is not required for HSC self-renewal, Id1 deletion reduces the size of the myeloid compartment in BM and increases granulocytes in peripheral blood, suggesting accelerated myeloid differentiation. To evaluate if these defects were intrinsic to hematopoietic cells or the result of microenvironmental defects, we performed bone marrow HSC transplantation. Transplantation of Id1-/- BM cells into lethally irradiated Id1+/+ recipients exhibited normal tri-lineage reconstitution and normal BM cellularity. In contrast, transplantation of Id1+/+ BM cells to Id1-/- recipient mice reproduced the hematological features of Id1-/- mice including decreased BM cellularity, increased myelopoiesis, decreased B lymphopoiesis, suggesting the defective BM microenvironment of Id1-/- was responsible for the abnormalities in Id1-/- mice hematopoiesis. Microarray data indicated that Id1-/- BM cells have decreased expression of genes that are essential for BM microenvironment including CSF1, FGF1, TGF-α, EGF, α3 integrin, and α6 integrin. Based on these data, we propose that Id1 is essential to regulate normal hematopoiesis by maintaining proper BM microenvironment, and also provides negative feedback in myeloid differentiation to prevent accelerated granulocytic differentiation. Funded by NCI contract No. N01-CO-12400
Patterns of concordance with clinical algorithms for survivors of head and neck cancers.
Authors: Katherine Ramsey Gilmore, Guadalupe R. Palos, Patricia Chapman, Paula A. Lewis-Patterson, Weiqi Bi, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2018)

26 Background: Research indicates survivors of head and neck cancers (HNC) are at greater risk for recurrences and adverse late effects. HNC survivorship algorithms are available to provide consistent and optimal care to this at-risk group. Here, we describe practitioners’ concordance with algorithms aimed at survivors diagnosed with cancers of the oral cavity (OC) oropharynx (OP), and larynx/hypopharynx (LH). Methods: We reviewed medical records, treatment summaries, and survivorship care plans of patients seen in the HNC Survivorship Clinic from 09/01/2011 to 08/31/2014. The primary outcome was providers’ rate of concordance (&gt; 90%) with 3 HNC algorithms. Concordance rates (CRs) were measured and compared within and between groups. Results: 145 patients met the eligibility criteria. Demographics varied by cancer sub-type: 19.3% OC, 58.6% OP, and 22.1% LH. Most were white males with the mean age of 62.7 years at first visit during the study period. Table 1 indicates clinicians’ CRs ranged from 9.2% to 99.7%. Overall, CRs were highly consistent and met or exceeded the benchmark for H &amp; P, chest x-ray, and dysphagia and lymphedema assessment. Body image assessment had the lowest CRS. Wide variation in CRs existed within and between sites for: T4/TSH, head/neck CTs, xerostomia assessments. Conclusions: Our findings indicate providers’ practice did deviate from recommendations listed in the HNC algorithms. Increasing clinicians' awareness and education may help achieve optimal adherence to survivorship algorithms. [Table: see text]
Rich club disturbances of the human connectome from subjective cognitive decline to Alzheimer's disease
Authors: Tianyi Yan, Wenhui Wang, Liu Yang, Kewei Chen, Rong Chen, Ying Han
Journal: Theranostics (2018)

Alzheimer's disease (AD) has a preclinical phase that can last for decades prior to clinical dementia onset.Subjective cognitive decline (SCD) is regarded as the last preclinical AD stage prior to the development of amnestic mild cognitive decline (aMCI) and AD dementia (d-AD).The analysis of brain structural networks based on diffusion tensor imaging (DTI) has identified the so-called 'rich club', a set of cortical regions highly connected to each other, with other regions referred to as peripheral.It has been reported that rich club architecture is affected by regional atrophy and connectivity, which are reduced in patients with aMCI and d-AD. Methods:We recruited 62 normal controls, 47 SCD patients, 60 aMCI patients and 55 d-AD patients and collected DTI data to analyze rich-club organization.Results: We demonstrated that rich club organization was disrupted, with reduced structural connectivity among rich club nodes, in aMCI and d-AD patients but remained stable in SCD patients.In addition, SCD, aMCI and d-AD patients showed similar patterns of disrupted peripheral regions and reduced connectivity involving these regions, suggesting that peripheral regions might contribute to cognitive decline and that disruptions here could be regarded as an early marker of SCD.This organization could provide the fundamental structural architecture for complex cognitive functions and explain the low prevalence of cognitive problems in SCD patients.Conclusions: These findings reveal a disrupted pattern of the AD connectome that starts in peripheral regions and then hierarchically propagates to rich club regions, when patients show clinical symptoms.This pattern provides evidence that disruptions in rich club organization are a key factor in the progression of AD that can dynamically reflect the progression of AD, thus representing a potential biomarker for early diagnosis.
A phase Ib trial of copanlisib and tratuzumab in pretreated recurrent or metastatic HER2-positive breast cancer “PantHER”.
Authors: Niamh M. Keegan, Janice Maria Walshe, Sinead Toomey, Giuseppe Gullo, M. John Kennedy, Kyran Noel Bulger, John McCaffrey, Catherine Margaret Kelly, John Crown, Keith Egan, Jennifer Kerr, Ausra Teiserskiene, Andrés Hernando, Imelda Parker, Ray McDermott, Maccon M. Keane, William Grogan, Oscar S. Breathnach, Patrick G. Morris, Bryan Hennessy
Journal: Journal of Clinical Oncology (2018)

1036 Background: PI3K pathway activation is implicated in resistance to trastuzumab (T) therapy in breast cancer (BC). Copanlisib (C) is a pan-class I PI3K inhibitor with particular activity against PI3Kα, the isoform encoded by the PIK3CA gene. PIK3CA mutation may predict response to PI3K inhibition. Methods: The maximum tolerated dose (MTD) and safety of C + T were evaluated in an open label, single arm, adaptive multicenter phase Ib dose escalation clinical trial in patients (pts) with HER-2 positive BC. Eligible pts had disease progression following at least one line of (T) or TDM-1 based therapy in the metastatic setting. Pts were treated with T (4mg/kg loading dose then 2mg/kg weekly) given with C intravenously on Day 1, 8 + 15 of 28 day cycle at one of two dose levels (DL) according to a modified 3+3 (6+6) design. Cycle 1 safety data were used to determine dose limiting toxicities (DLTs). Disease assessments were made every 8 weeks. PIK3CA mutation status was determined in formalin-fixed paraffin-embedded (FFPE) primary tumor blocks by standard sequencing and in serial samples of plasma circulating tumor DNA (ctDNA) during treatment by droplet digital PCR. Results: Twelve pts were treated with C + T, 6 on DL1 (45mg) and 6 on DL2 (60mg). Median age was 53yrs. Pts had 15 to 85 months of prior therapy in the metastatic setting with a median of 4 prior lines. There were no DLTs. The MTD and recommended dose for phase II is 60mg. Eleven SAEs were reported. Of these, 36% (n = 4) were infections requiring hospitalization and all resolved with no changes in dose. Grade(G) 3 lung infection and G3 abdominal pain SAEs were reported possibly related to C. All others were considered unlikely or not related to C. G3 liver enzyme rise was reported in 1 pt with a single episode of G4 rise in GGT. G3 hypertension was reported in 33% (n = 4) pts. Best response was stable disease in 9/12 pts and 6 pts continued treatment ≥16 weeks. PIK3CA mutation was positive in 6/12 (50%) of tumors. Concordance between PIK3CA mutation in tissue and plasma pre-treatment was 80% with evidence of dynamic change in quantity of mutation during treatment. Conclusions: C+T is a safe, well tolerated combination. Efficacy of C+T will be assessed in a phase 2 study at the MTD of 60mg. Clinical trial information: NCT02705859.
Using electronic medical records system to advance cancer survivorship programs.
Authors: Megan Lanigan, Theresa M. Lee, Lisa Torp, Beth Rudge, Kit Yu Lu
Journal: Journal of Clinical Oncology (2018)

65 Background: Survivorship care is now being increasingly recognized as an important part of cancer care. The Commission on Cancer (CoC) Standard 3.3 now recommends 100% compliance in the delivery of Survivorship Care Plans (SCP) by 2019 to eligible survivors. However, there are no systematic ways of ensuring compliance of Care Plan delivery and assessing patient eligibility. There are also no standardized methods for documentation or data collection to ensure appropriate consolidation of information from the electronic medical record (EMR) to a SCP, to assess for patient eligibility for survivorship follow up, or to appropriately report on timely delivery and follow-up with Survivorship Programs. Methods: Our survivorship team worked closely with the Cancer Registry Program, nurse navigators, and Information Technology team to optimize our institution owned EPIC electronic medical records system to populate and consolidate information automatically into patient specific care plans. By having electronic care plans, we are able to deliver plans to all members of the care team and to the patients. We also created discrete methods of flagging eligible survivors and automated data reporting and collection to ensure compliance and timeliness of care plan delivery. Results: By optimizing our electronic medical records system and our workflow process for Care Plan delivery, we were able to increase our delivery compliance rate to 100%. We are able to track patients through their care delivery and appropriately refer to our survivorship program and track care plan delivery. Conclusions: The CoC has implemented new standards to encourage appropriate survivorship care delivery and proper communication for ongoing survivorship care and follow up. With these new standards comes the challenge of developing and implementing a system for creating, delivering and evaluating the delivery of SCP. For our team to provide quality survivorship care that is measurable, we have developed data analysis and reports through our EMR with assistance from our IT department. These improvements utilizing our IT and EMR more efficiently has provided us with the ability to achieve 100% care plan delivery compliance.
<i>Notes from the Field:</i> Verona Integron-Encoded Metallo-Beta-Lactamase–Producing <i>Pseudomonas aeruginosa</i> Outbreak in a Long-Term Acute Care Hospital — Orange County, Florida, 2017
Authors: Danielle Rankin, Luz Caicedo, Nychie Dotson, Paige Gable, Alvina Chu
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
Role of adding ovarian function suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy: The ASTRRA study.
Authors: Woo Chul Noh, jong Won Lee, Seok Jin Nam, Seho Park, Seock-Ah Im, Eun Sook Lee, Yongsik Jung, Jung Han Yoon, Sung Soo Kang, Soo-Jung Lee, Kyong Hwa Park, Joon Jeong, Se-heon Cho, Sung Yong Kim, hee Jeong Kim, Chanheun Park, Se-Hwan Han, Wonshik Han, Min Hee Hur, Hyun-Ah Kim
Journal: Journal of Clinical Oncology (2018)

502 Background: The role of adding ovarian function suppression (OFS) to tamoxifen (T) for premenopausal patients with breast cancer after completing (neo) adjuvant chemotherapy is uncertain. The prospective randomized phase III trial was conducted to evaluate the efficacy of adding OFS to T in patients with hormone receptor-positive breast cancer who remain in premenopausal status or resume ovarian function after chemotherapy (NCT00912548). The primary and key secondary endpoints were to compare the 5-year disease-free survival and overall survival, respectively, between patients who received T and those who received T and OFS. Methods: We enrolled 1483 premenopausal women (aged ¡Â45 years) with estrogen receptor-positive breast cancer who were treated with definitive surgery after completing neoadjuvant or adjuvant chemotherapy. Ovarian function was assessed every 6 months for 2 years since enrollment based on follicular-stimulating hormone levels and menstruation history. If ovarian function was confirmed to be premenopausal at each visit, the patient was randomized to receive 5 years of T (T-only group) or 5 years of T plus 2 years of OFS by monthly goserelin (T + OFS group). A total of 1282 patients was randomly assigned. Disease-free survival was defined as the time from enrollment to the detection of recurrence of breast cancer, contralateral breast cancer, secondary malignancy, or death by any cause. Results: After a median follow-up of 63 months, the estimated disease-free survival rate at 5 years was 91.1% in the T + OFS group and 87.5% in the T-only group (hazard ratio 0.686; 95% confidence interval [CI], 0.483 to 0.972; P = 0.033). The estimated overall survival rate after 5 years was 99.4% in the T + OFS group and 97.8% in the T-only group (hazard ratio 0.310; 95% CI, 0.102 to 0.941; P = 0.029). Conclusions: Ovarian function needs to be monitored for at least 24 months after completing chemotherapy to establish eligibility for OFS. Adding 2 years of OFS to T significantly improved disease-free survival as compared to T alone in those who remained premenopausal or resumed ovarian function after chemotherapy. Clinical trial information: NCT00912548.
Modified ketogenic diet in lymphoma: A case series in the Veteran Affairs Pittsburgh Healthcare System.
Authors: Jocelyn Tan-Shalaby, Roby Antony Thomas, Jennifer Carrick, Andrew D. Liman, Vida Almario Passero, Arisha Patel, Jenna Shields
Journal: Journal of Clinical Oncology (2018)

e24222 Background: Cancer cells preferentially use glucose due to mitochondrial dysfunction. Ketogenic diets preferentially feed normal cells while starving cancer. There are no human studies on ketogenic diets in lymphomas or leukemia. Methods: Three lymphoma patients began the modified ketogenic diet. We provided dietary advice, limited daily carbohydrate to 20-40 grams, omitted sweets and starches. Data on their history, dietary course and clinical outcomes are presented. Results: Case 1: 52 year old male with mycosis fungoides was on UVB light and topical steroid treatment for a year. Pruritic erythema covered 90% of his body, including the scalp, legs, arms, chest and entire back. Frontal scalp, medial eyebrows had patchy alopecia plus he had eyeball pain and daytime sweating. Weight was 255 lbs. Four months later he lost 22 lbs (232 lb), and eyeball pain was gone. Arm and back erythema faded. 7 months later, his back was erythema free. 15 months later, at 206 lb (49 lb wt. loss) his eyebrows normalized, with mild erythema left over parts of his face. Case 2. 80 y.o male with CLL/SLL progressed on Bendamustine + Rituximab BR and transformed into prolymphocytic lymphoma. He lost 31 lb. (17% of baseline), had bilateral leg edema, pleural effusions and increasing adenopathy on imaging scans. We held chemotherapy and he started the diet. A week later he lost 12 more lbs. but was more energetic and edema resolved. Concerned about the weight loss, he added low glycemic fruits to his diet. Weight improved and 2 months later he resumed chemotherapy, recovering to baseline weight by 1 year. Two years later he is disease free on maintenance Rituximab. Case 3. 73 y/o male with MALT gastric lymphoma and Stage 3 mantle cell lymphoma had a partial response after 6 cycles of BR chemotherapy. Weighing 216 lb, BMI 28.6, he began the diet at cycle 4. Six months after chemotherapy he lost 22 lbs (11%) and PET CT scans were cancer free. He is disease free 2 years later. Conclusions: Ketogenic diets in human lymphomas appears well tolerated and can improve symptoms, quality of life, and possibly limit tumors. Ketogenic diets may reverse the weight loss seen in terminal cancer patients with cachexia.