tbuckley/cabot-search huggingface dataset:
The solved and unresolved issues of melanoma staging: A comparison of American Joint Committee on Cancer (AJCC) 7th versus 8th edition.
Authors: Shirin Bajaj, Anthony Collado, Una Moran, Douglas MacArthur Donnelly, Paul Johannet, Richard L. Shapiro, Russell S. Berman, Jeffrey S. Weber, Judy Zhong, Iman Osman
Journal: Journal of Clinical Oncology (2019)

9578 Background: The recently revised (AJCC) Staging Manual, 8th edition, introduced changes including removal of mitotic index and addition of the IIID substage. There is active debate on the utility of this revision, especially, without the inclusion of a novel prognostic biomarker, during an era of major therapeutic shifts and amidst accrual of adjuvant clinical trials for high-risk resected primary melanoma. We examined whether re-staging primary melanoma patients using the new AJCC 8 system yielded improved prognostication as compared to AJCC 7. Methods: We compared the impact of changes in staging criteria in stage I-III melanoma patients who were prospectively enrolled in a NYU clinicopathological database between January 2010 and December 2016 with active protocol-driven follow up (FU). We assessed primary tumor category (T) and nodal status (N) according to both AJCC 7 and 8. Progression free survival (PFS) and overall survival (OS) curves were generated for both editions and then stratified by substage. We analyzed discordance using Cox Regression Models. Results: 1,379 patients (56% male, mean thickness 1.6, median FU 34.8 months) were included in the analyses. All but one patient remained in the same ‘major’ stage using AJCC 7 and 8 (stage I- 998; II- 224, 225; III- 157, 156) whereas 44% of stage III substage classifications were discordant comparing AJCC 7 to 8. Despite removing mitoses as a criterion for Stage I, there was no significant change between editions in PFS/OS when evaluating major and substages of stage I. Stage IIC patients had worse PFS/OS than stage IIIA patients in AJCC 8 (PFS p = 0.04, OS p = 0.02). AJCC 8, which implemented four rather than three substages, had improved PFS prognostication (c-index = 0.59 vs 0.66, p = 0.05 for AJCC 7 vs 8). Conclusions: Our results reinforce the added value of AJCC 8 compared to 7, as removing an operator dependent variable is more practical for stage I, and increased influence of thickness/ulceration and the addition of a new substage is more prognostically informative for stage III. Nevertheless, the poor prognosis of stage IIC patients, despite nodal negative disease, continues to be an unaddressed gap within our current staging framework.
Complexities in cardiovascular rhythmicity: perspectives on circadian normality, ageing and disease
Authors: Oliver Monfredi, Edward G Lakatta
Journal: Cardiovascular Research (2019)

Biological rhythms exist in organisms at all levels of complexity, in most organs and at myriad time scales. Our own biological rhythms are driven by energy emitted by the sun, interacting via our retinas with brain stem centres, which then send out complex messages designed to synchronize the behaviour of peripheral non-light sensing organs, to ensure optimal physiological responsiveness and performance of the organism based on the time of day. Peripheral organs themselves have autonomous rhythmic behaviours that can act independently from central nervous system control but is entrainable. Dysregulation of biological rhythms either through environment or disease has far-reaching consequences on health that we are only now beginning to appreciate. In this review, we focus on cardiovascular rhythms in health, with ageing and under disease conditions.
Efficacy and safety of conversion therapy using chemotherapy plus anti-angiogenic therapy in unresectable gastric cancer.
Authors: Lu chuan Chen
Journal: Journal of Clinical Oncology (2019)

e15510 Background: Conversion therapy has been a promising option for patients with unresectable gastric cancer (GC) (including Phase IV gastric cancer, N3, lymph node fusion and local progression patients). We aimed to investigate the efficacy and safety of S1/oxaliplatin chemotherapy plus apatinib, a novel inhibitor of VEGFR-2, in the conversion therapy for unresectable GC. Methods: This was a single-center, single-arm, open-label study. unresectable GC patients with unresectable factors were eligible for this study. Apatinib (500mg, qd) was administrated continuously, oxaliplatin (130mg/m 2 ) on day 1, and S1 (&lt;1.25m 2 , 40mg*2/d; 1.25-1.5m 2 , 50mg*2/d; &gt;1.5m 2 , 60mg*2/d) on day 1-14 every 3 weeks. Treatment was given for 4-6 cycles preoperatively, but the last cycle did not include apatinib. The primary objective included R0 resection rate and safety profile of preoperative treatment. Results: Total 17 patients were enrolled, the median age was 57 (55.12±10.08) years old. The histological types were mainly signet ring cell carcinoma 10 (58.82%), poorly differentiated adenocarcinoma 5 (29.41%), and moderately differentiated adenocarcinoma 2 (11.76%). Among the 17 patients eligible for preoperative efficacy evaluation, 13 achieved partial response (PR), 3 achieved stable disease (SD), and 1 had progressive disease (PD), the overall response rate (ORR) was 76.5% and disease control rate was 94.1%. Of the 13 pts with PR, 1 refused consents for surgery, 12 patients underwent surgery and 9(75%) achieved R0 resection. During preoperative treatment, the incidence of adverse events (AEs) was 76.5%. The common hematologic AEs were neutropenia (64.7%), leukopenia (64.7%) and hemoglobin decrease (11.8%), and nonhematologic AEs included hyperbilirubinemia (11.8%), hand-foot syndrome (17.6%), oral mucositis (29.4%), fatigue (70.6%), proteinuria (5.9%). Conclusions: Combination of apatinib with S1/oxaliplatin chemotherapy could induce a sufficient conversion rate and achieve a relative high R0 resection rate for initially unresectable GC, with tolerable safety profile. Clinical trial information: ChiCTR-ONC-17010430 trial.
Impact of comorbidity and age on treatment choice among men with localized prostate cancer.
Authors: Paul F Pinsky, Dudith Pierre-Victor, Iman K. Martin, Eric Miller, Worta J. McCaskill-Stevens, Robert L. Grubb
Journal: Journal of Clinical Oncology (2019)

e16585 Background: Prostate cancer (PCa) is the most commonly diagnosed cancer among men in the United States. A substantial proportion of PCa patients has at least one comorbidity. Comorbidities have a meaningful impact on cancer treatment choice. The objective of this study was to investigate the effect of comorbidity, as well as age, on treatment choice among men with localized PCa. Methods: From the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, men with localized PCa diagnosed from 1994-2014 were selected (N = 10, 281). Comorbidity score was determined based on a modified Charlson index. Treatment was classified as curative, either radical prostatectomy (RP) or radiation therapy with curative intent (RT), or non-curative (all other modalities). We used multivariate logistic regression to assess the association of treatment choice with age and comorbidity score (including their interaction), controlling for D’Amico risk group, demographics and diagnosis year. Results: About half (48.3%) of patients had comorbidity score ≥ 1. Most men received curative treatment (75.2%); RT (55.2%) was more common than RP (44.8%). The likelihood of curative treatment decreased with increasing age; odds ratios (OR) for curative treatment were 0.63 (95%CI: 0.52-0.76), 0.36 (95%CI: 0.30-0.43) and 0.13 (95%CI: 0.11-0.16) for men aged 65-69, 70-74 and 75+, respectively, compared to men aged 55-64. Men with a comorbidity score of 2+ (OR = 0.84; 95%CI: 0.74-0.96) were less likely to receive curative treatment than men with a score of 0. Within curative treatment, older age was strongly associated with RT. Compared to men aged 55-64 years, men aged 65-69 years (OR = 2.0; 95% CI: 1.72-2.3), 70-74 years (OR = 5.3; 95% CI: 4.5-6.3), and 75+ years (OR = 25.0; 95% CI: 17-33) were more likely to receive RT than RP. Men with a comorbidity score of 1 (OR = 1.16; 95%CI: 1.03-1.30) or 2+ (OR = 1.92; 95%CI: 1.6-2.3) were also more likely to receive RT. The interaction between age and comorbidity score was not significant. Conclusions: In this cohort, age was a strong independent predictor of treatment choice for localized PCa. Although comorbidity was not a strong predictor of curative treatment, it was associated with receipt of RT.
A randomized controlled trial of the conventional technique versus the no-touch isolation technique for primary tumor resection in patients with colon cancer: Primary analysis of Japan Clinical Oncology Group study JCOG1006.
Authors: Yasumasa Takii, Junki Mizusawa, Yukihide Kanemitsu, Koji Komori, Manabu Shiozawa, Masayuki Ohue, Yoji Nishimura, Satoshi Ikeda, Nobuhiro Takiguchi, Takaya Kobatake, Hideyuki Ike, Toshihiko Sato, Naohiro Tomita, Mitsuyoshi Ota, Tadahiko Masaki
Journal: Journal of Clinical Oncology (2019)

3515 Background: The no-touch isolation technique (NTIT) aims to reduce cancer cells flowing from the primary tumor site to the liver and other organs by first ligation of blood vessels that feed the primary tumor. The efficacy of NTIT has not been proved in previous studies. To acquire the answer of an unsolved problem more than 60 years, we conducted a phase III trial to confirm the superiority of NTIT in patients with cT3/T4 colon cancer. This is the primary analysis of the disease-free survival (DFS) as the primary endpoint. Methods: Eligibility criteria included histologically proven colon cancer; tumor located in the cecum, ascending, transverse, descending, sigmoid or rectosigmoid colon; clinical T3 or T4, N0-2, M0; patients age 20-80 years. Patients were randomized preoperatively to either conventional technique (CoT) arm or NTIT arm. Operation was performed in open surgery. Patients with pathological stage III received adjuvant chemotherapy with capecitabine. The primary endpoint was DFS. Planned sample size was 850 to detect a hazard ratio (HR) of 0.732 in DFS with one-sided alpha of 5% and power of 80%. Results: A total of 853 patients were randomized (CoT: 427, NTIT: 426) between January 2011 and November 2015. The 3-year DFS were 77.3% and 76.2% in the CoT arm and NTIT arm,respectively. The HR was 1.029(95% CI 0.800-1.324); thus the superiority of NTIT was not confirmed (p = 0.59). The 3-year overall survival (OS), 3-year recurrence-free survival (RFS) and 3-year liver-recurrence-free survival (LRFS) are shown in the Table. Conclusions: The superiority of NTIT to CoT was not confirmed. NTIT does not improve the DFS or OS, RFS, LRFS in the patents with stage II and III colon cancer. Clinical trial information: UMIN000004957. [Table: see text]
Pembrolizumab (pembro) with paclitaxel (taxol) or capecitabine (cape) as early treatment of metastatic triple-negative breast cancer (mTNBC).
Authors: David B. Page, Brie Chun, Joanna Pucilowska, Isaac Kim, Katherine Sanchez, William L Redmond, Zhaoyu Sun, Yaping Wu, Alicia Feryn, Maritza Martel, Christina DiLauro Abaya, Dottie Wadell, Staci L. Mellinger, Nicole Moxon, Walter John Urba, Philomena McAndrew, Maryliza El-Masry, Reva K. Basho, Alison Katherine Conlin, Heather L. McArthur
Journal: Journal of Clinical Oncology (2019)

1015 Background: Atezolizumab (anti-PD-L1) plus nab-paclitaxel was shown to improve outcomes in mTBNC in a phase III clinical trial. Subjects were required to be &gt; 12 months from curative-intent therapy in this trial. It remains unknown whether non-taxane chemo + anti-PD-1/L1 will be beneficial in mTNBC, or whether this approach is effective in rapidly-progressing patients ( &lt; 12 mo from curative-intent therapy). Methods: mTNBC patients were enrolled in a phase Ib study of anti-PD-1 (pembro, 200mg IV q3w) plus physician’s choice chemo (cape: n = 14, 2000mg BID, 7d on/7d off; or taxol: n = 14, 80mg/m2 q1w). Primary/secondary objectives were to evaluate safety/tolerability (primary) and RECIST1.1 response (w12). The exploratory objective was to explore for differences in immunomodulation according to chemo choice. Mixed effects models were employed to compare the longitudinal effects of chemo on peripheral immune cells (flow cytometry) and T-cell diversity (Immunoseq assay). Results: Enrollment of the trial is complete (n = 28), with 100% of evaluable patients tolerating therapy (n = 22) as of 2/1/2019. Cape ORR was 43% (5 PR, 1 CR, 2 SD) with median PFS = 155d. Taxol ORR was 25% (1 CR, 1 PR, 3 SD) with median PFS = 99d. Subjects enrolled &lt; 12 months from curative-intent therapy had numerically lower response (ORR = 27%, 1 CR, 2 PR, 3 SD) than subjects without rapid progression (ORR = 45%, 1 CR, 4 PR, 2 SD). No significant differences in immunomodulation were observed according to chemo type, however both cape &amp; taxol were associated with declines in T-cell quantity (CD4 p &lt; .02, CD8 p &lt; .04) and Immunoseq T-cell fraction over time. Conclusions: Pembro plus cape or taxol is safe with encouraging efficacy, however activity may be lower in the setting of rapid progression following curative-intent chemo. Cape+pembro efficacy is favorable with no measurable differences in immunomodulation, and therefore cape may be preferred as a chemo backbone in selected patients. Both cape and taxol are associated with iatrogenic declines in T-cell quantity, which may explain the observed dropoff in anti-PD-1/L1 activity in later lines. Clinical trial information: NCT02734290.
Phase 1/1b multicenter trial of TPST-1120, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist as a single agent (SA) or in combination in patients with advanced solid tumors.
Authors: Ginna Laport, John D. Powderly, Saurin Chokshi, Jason J. Luke, Johanna C. Bendell, Amanda Enstrom, Chan C Whiting, Thomas Walter Dubensky
Journal: Journal of Clinical Oncology (2019)

TPS2665 Background: Tumor cells initially favor glucose metabolism via aerobic glycolysis. As tumors rapidly proliferate and metastasize, glucose stores are depleted and facilitated by a hypoxic tumor microenvironment (TME) and metabolic reprogramming shifts intracellular metabolism(IcM) towards fatty acid oxidation (FAO). Fatty acids support metabolism of suppressive immune cells in the TME in addition to tumor growth. PPARα is a ligand-activated nuclear transcription factor which regulates lipid metabolism and FAO. TPST-1120 is a first in class, oral selective PPARα antagonist that blocks transcription of PPARα target genes leading to an intracellular metabolism shift from FAO to glycolysis. Reduction of fatty acids in the TME leads to direct killing of tumor cells dependent on FAO, skews macrophages from immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells. TPST-1120 also restores thrombospondin-1, a known natural inhibitor of angiogenesis, to homeostatic levels within the TME. TPST-1120 has an IC 50 of 0.04 nM with &gt; 35 fold selectivity over other PPAR isoforms. Preclinical studies in multiple tumor models show efficacy of TPST-1120 as a SA and in combination(combo) with an anti-PD1 monoclonal antibody (mAb) and chemotherapy. Methods: We have initiated a phase 1/1b multicenter, open label Dose Escalation (DEs) and Dose Expansion (DEx) trial to evaluate TPST-1120 as a SA and in combo with nivolumab, an anti-PD1 mAb; docetaxel, a chemotherapeutic agent and cetuximab, an anti-EGFR mAb. Objectives: 1) evaluate safety and tolerability of continuous dosing of TPST-1120 2) identify a recommended phase 2 dose (RP2D) and 3) evaluate efficacy. Eligibility: 1) patients with select advanced solid tumors who have failed 1 and up to 5 prior therapies. This phase 1/1b adaptive design has 4 DEs arms, 1 SA arm and 3 combination arms in which TPST-1120 is combined with nivolumab, docetaxel or cetuximab. The RP2D of TPST-1120 to proceed to DEx will be determined by safety and biomarkers during DEs. The DEx arms have 8 histology-specific cohorts, 4 SA arms and 4 combo arms and will follow a 2-stage expansion design. Biomarker analyses include gene expression profiling of PPARα-associated genes, tumor markers of immune modulation and serum lipid profiling. The total sample size is up to 338 pts. This trial is accruing at U.S sites. Clinical trial information: NCT03829436.
Case 45-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Peter F. Weller, Gail Moskowitz
Journal: New England Journal of Medicine (1987)

Presentation of CaseA 16-year-old girl was admitted to the hospital because of hepatic and pulmonary masses.She was well until two months earlier, when she began to experience abdominal pain of two types. One was localized in the epigastrium and at times radiated to the right side of the chest and the right shoulder and lasted for two or three minutes; in addition, she had episodes of crampy, nonradiating pain in the epigastrium that persisted for five minutes. Neither pain was influenced by activity or by intake of food. Six weeks before entry intermittent pain developed in the lower . . .
Eflapegrastim, a novel, long-acting GCSF for reducing chemotherapy-induced neutropenia: Integrated results from two phase III trials in breast cancer patients.
Authors: Lee S. Schwartzberg, Gajanan Bhat, Jayaram S. Bharadwaj, Osama Hlalah, Alvaro Restrepo, Inderjit Mehmi, Shanta Chawla, Patrick Wayne Cobb
Journal: Journal of Clinical Oncology (2019)

61 Background: Eflapegrastim (E) is a novel, long-acting GCSF comprised of recombinant human GCSF covalently linked to human IgG4 Fc fragment via a PEG linker (MW, 72 kDa). E showed increased potency vs pegfilgrastim (P) in preclinical and Phase I and II trials. Two identically designed Phase III pivotal trials (NCT02643420, NCT02953340) were conducted globally with a fixed dose of 13.2 mg E containing 3.6 mg GCSF to evaluate E vs P (6 mg) in pts receiving chemotherapy for early-stage breast cancer. Methods: Each open-label trial randomized pts 1:1 to a single subcutaneous dose of E 13.2 mg/0.6 mL or P 6 mg/0.6 mL on Day 2 of each of four 21-day cycles following Day 1 adj/neoadj docetaxel 75 mg/m 2 + cyclophosphamide 600mg/m 2 (TC) . The primary endpoint was to demonstrate E non-inferiority (NI) to P as measured by mean duration of severe neutropenia (DSN) in Cycle 1. Results: A total 643 intent-to-treat pts (314 E/329 P) with median age 60 yrs (24–88) were enrolled. Cycle 1 mean (SD) DSN was 0.24 (0.581) vs 0.36 (0.789) days for E and P, confirming NI (p&lt;.0001) and suggesting statistical superiority (p&lt;.029). DSN NI was also shown across cycles 2–4. Among subgroups, including elderly (≥65 yrs) and overweight (&gt;75kg) pts, DSN was reduced for E vs P. In Cycle 1, E showed an absolute risk reduction for severe neutropenia of 6.5% vs P (27.1% relative risk reduction, p&lt;.043). Neutropenic complications (hospitalization and/or anti-infective use) were 2.9% and 4.0% for E and P (p=ns) in Cycle 1. Incidence of FN was low for both E and P, 1.6% vs 1.8% in Cycle 1 and 3.2% vs 3.0% overall. ANC profiles showed sustained increased levels for E vs P in the recovery phase across all cycles. Safety profiles including events of special interest, irrespective of grade, were mostly similar for E and P. The most common ≥ Grade 3 adverse events were hematologic due to chemotherapy. Conclusions: These integrated pivotal trial results confirm a similar safety profile and non-inferiority in reducing neutropenic risk for E at a lower GCSF dose vs P. The data also suggests the potential for increased potency of E to deliver improved clinical benefit, a possibility that warrants further clinical trials. Clinical trial information: NCT02643420 and NCT02953340.
Frameshift mutations (Fsindel) complement tumor mutation burden (TMB) in predicting survival after immune checkpoint inhibitors (ICI) in a pancancer analysis.
Authors: Vaia Florou, Wungki Park, Peter Joel Hosein, Breelyn A. Wilky, Jonathan C. Trent, Gilberto Lopes
Journal: Journal of Clinical Oncology (2019)

2617 Background: ICI benefit certain patients (pts) with various malignancies and discovering biomarkers for response is an active research field. Recently, higher TMB (top 20% in each histology) based on nonsynonymous single nucleotide variants from MSK-IMPACT was shown to correlate with superior survival in a pancancer cohort. Fsindels may generate more immunogenic neoantigens and robust T cell infiltrates, thus predicting better responses to ICI. We previously demonstrated the clinical implication of fsindel in lung cancer pts on ICI. However, its value in other solid cancers has not been evaluated. Methods: Comprehensive genomic profiling (CGP) of the tumors was performed by FoundationOne to derive fsindel and TMB as previously described. Pts with advanced solid cancers who received ICI and had CGP available were included. We categorized pts into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). Also, they were categorized into TMB high (top 20%) and TMB low (bottom 80%) within their own histology. Progression free survival (PFS) and overall survival (OS) were compared. Results: One hundred thirty-one pts excluding lung cancer were included. There were 11 histology groups: 14 soft tissue sarcomas, 19 GU, 23 GI, 23 skin, 10 HEENT, 10 RCC, 9 GYO, 6 pancreas, 5 mucosal melanoma, 4 breast, and 8 others. 74 pts received pembrolizumab, 25 nivolumab, 29 ipilimumab/nivolumab, and 3 atezolizumab. All pts had metastatic disease, mean age was 61 years and 55 (42%) were women. Among the 131 pts, 74 were FS- and 57 FS+. The presence of fsindel (FS+) was significantly correlated with overall response (p = 0.032) and clinical benefit rates (p = 0.025). TMB-high did not show any significant difference in PFS (p = 0.1) or OS (p = 0.28) when compared to the TMB low. However, in a combined model of TMB and fsindel, TMB high and FS+ patients had significantly better PFS compared to patients who had either TMB high or FS+ or neither (TMB low and FS-) (p = 0.021). Conclusions: Combined model of TMB high and fsindel (+) correlated with superior PFS in advanced solid cancer pts on ICI, in concordance with previous report for lung cancer. Validation in a larger cohort is underway.
Massive haemoptysis and ventilatory failure in pregnancy
Authors: William G Flight, Ivan Tang, Alison Gates, Joanna Snowball, John M Wrightson, Lucy Mackillop, Stephen J Chapman
Journal: Thorax (2019)

<h3>SUMMARY</h3> Telomerase reverse transcriptase (TERT) expression is indispensable for tumor immortality. Non-invasive methods of imaging TERT can, therefore, report on tumor proliferation and response to therapy. Here, we show that TERT expression is associated with elevated levels of the redox metabolite NADH in multiple cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanistically, TERT acts via the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme for NADH biosynthesis. Importantly, deuterium magnetic resonance spectroscopy (<sup>2</sup>H-MRS), which is a novel, clinically translatable metabolic imaging modality, can be leveraged for imaging TERT-linked NADH in preclinical tumor models <i>in vivo</i>. Since NADH is essential for pyruvate flux to lactate, <sup>2</sup>H-MRS following administration of <sup>2</sup>H-labeled pyruvate non-invasively visualizes TERT expression and reports on early response to therapy. Collectively, our study provides insights into the mechanisms of TERT-linked metabolic reprogramming and, importantly, establishes <sup>2</sup>H-MRS as a pan-cancer strategy for imaging tumor immortality.