tbuckley/cabot-search huggingface dataset:
CT and PET radiomic features associated with major pathologic response to neoadjuvant immunotherapy in early-stage non-small cell lung cancer (NSCLC).
Authors: Erica C. Nakajima, Jeffrey P. Leal, Wei Fu, Hao Wang, Jamie E. Chaft, Matthew David Hellmann, Martin Pomper, Patrick M. Forde
Journal: Journal of Clinical Oncology (2020)

9031 Background: An early biomarker of response to immunotherapy (IO) is needed urgently to identify the patients (pts) who will derive benefit. We reported the first clinical trial of neoadjuvant IO (nIO) in resectable non-small cell lung cancer (NSCLC) (NCT02259621). In this study, we investigated whether there was an association between MPR and radiomic features (RF) in [ 18 F]-fluorodeoxyglucose ([ 18 F]-FDG) PET and standard CT images obtained at baseline and after nIO in early stage NSCLC tumors. Methods: Prior to receiving neoadjuvant nivolumab or nivolumab/ipilimumab, patients with Stage I-IIIA NSCLC underwent two [ 18 F]-FDG PET-CTs and/or plain CTs: a baseline scan at enrollment (PRE), and after nIO (POST). After neoadjuvant treatment, tumors were resected and evaluated for MPR. Volumes of interest (VOIs) were drawn around primary tumors on the scans. Using our novel radiomic software, Imager-4D, VOIs were evaluated for 20 RFs assessing [ 18 F]-FDG standard uptake value (SUV) or Hounsfield unit (HU) heterogeneity and spatial distribution in PET and CT images respectively. The baseline, post-treatment, and percent change in RFs before and after nIO were compared between tumors with and without MPR. Wilcoxon test was used for the comparisons. Results: The PRE and POST scans of 24 pts were analyzed. All pts had PRE and POST CTs performed, and 17 pts had PRE and POST [ 18 F]-FDG PET-CT scans. 7 of 24 (29%) had MPR. In the CT scan analysis, HU-based RFs of voxel count, total volume, energy, entropy, homogeneity, contrast, and dissimilarity in POST CT scans each significantly association with MPR. In the PET scan analysis, SUV mean and voxel count RFs in the POST scans, and the percent change in the cluster shade RF between PRE and POST scans were significantly associated with MPR. Conclusions: Collectively, we identified a significant increase in heterogeneity in the POST CT images of NSCLC tumors that had MPR. This association may reflect increased T cell infiltration or tumor necrosis. In contrast, most [ 18 F]-FDG-based RFs did not distinguish MPR vs non-MPR tumors, although the sample size was limited. We will further investigate these HU-based RFs as non-invasive markers of response to IO in conjunction with pathologic markers of IO response and in a larger patient cohort.
Amino acid mixture (enterade) as a new approach to reducing cancer therapy-induced gastrointestinal toxicity: A retrospective study.
Authors: Aman Chauhan, Reema Anil Patel, Laura Luque, Holly Chitwood, Fariha Siddiqui, Zachary Tarter, Katherine Mitchell, James Cloud, Rachel C. Miller, Lowell Brian Anthony
Journal: Journal of Clinical Oncology (2020)

e24107 Background: Gastrointestinal toxicity is a common side effect of cancer therapy. Pre-clinical studies using a proprietary mixture of amino acids, demonstrated a reduction in mucositis and gastrointestinal toxicity following irradiation via tightening of the mucosal barrier, increasing proliferation of crypt cells, increasing villous height and increasing absorption of fluid, electrolytes and nutrients. A novel 5-amino acid mixture “enterade” was previously evaluated in a Phase II clinical trial for anti-diarrheal effects in post bone marrow transplant patients at Dana Farber Cancer Institute (NCT02919670). Signs of anti-diarrheal efficacy were found in treatment-compliant patients.Enterade is currently being tested in two prospective Phase II studies (NCT03722511 and NCT04073017) in neuroendocrine tumor patients with quality of life limiting diarrhea. We conducted a pilot study to evaluate early antidiarrheal signals in oncologic treatment-induced diarrhea. Methods: An IRB-approved retrospective chart review was conducted at Markey Cancer Center between Sept 2019 and Dec 2019. Medical records were retrospectively reviewed for all solid tumor patients who received enterade for chemotherapy or immunotherapy-induced diarrhea. Patients were instructed to consume one 8-oz bottle of enterade twice a day for at least one week in addition to standard of care antidiarrheal medications. Results: A total of 46 patients were offered enterade. Antidiarrheal efficacy data was available on 17 patients. 11 were female and the mean age of the cohort was 64 years. Six out of 17 patients had a previous history of bowel resection. Four patients had immune checkpoint induced colitis. Three patients developed diarrhea from TKI use and rest were on cytotoxic chemotherapy at the time of the diarrheal episode. Eighty-eight percent (15/17) of patients reported a reduction in diarrhea frequency after consuming enterade. On average, patients noticed an improvement in diarrhea frequency after 3.6 days of enterade consumption, with 86% (13/15) of responders reporting at least 50% reduction in diarrhea frequency. Conclusions: Patient-reported diarrheal improvement after enterade consumption is consistent with pre-clinical data. Results suggest the amino acid mixture may alleviate symptoms of cancer therapy-induced gastrointestinal toxicity (i.e. diarrhea). A prospective clinical trial is warranted to substantiate the observed improvement in chemotherapy and immunotherapy induced diarrhea.
Comparison of contact versus non-contact measurements of axial length
Authors: Chen-li Feng, Li-yang Wang, Fei Yuan
Journal: BMJ (2012)

To compare the measurements of axial length by A-scan ultrasound and IOLMaster.For a total of 138 eyes,axial length was measured with IOLMaster followed by contact A-scan ultrasound.Though a great correlation existed between two measurements,the axial length was a little longer with IOLMaster than with A-scan ultrasound.And the difference was statistically significant (P ＜ 0.01).The mean difference of two methods was (-0.198 ± 0.146) mm.With the elongation of axial length,the difference of two methods also increased.For cataract patients with axial length ＞ 28 mm,the control range of crror from IOLMaster for axial length was much lower than that from A-scan.Thus IOLMaster is a simple,fast,reliable and non-contact measurement method of axial length.

Key words: 
Ultrasonography; Interferometry
Factors influencing disease control in metastatic lung cancer with intracranial metastasis post gamma-knife radiotherapy.
Authors: Laura Tam, Mark B. Pinkham, Kenneth John O'Byrne, Rahul Ladwa
Journal: Journal of Clinical Oncology (2020)

e21602 Background: Traditionally, disease control of brain metastases (BM) has dictated the prognosis of those with metastatic lung cancer. Immune check-point inhibitors (ICI) have shown intracranial response but data on the magnitude of such effect in combination with radiation is still evolving. We report the time to progression of intracranial and systemic disease post gamma-knife radiation (GK) and associations with the use of ICI in this cohort. Methods: Patients with metastatic lung cancer with BM treated with GK between 2015 and 2019 were retrospectively analysed in a single institution at the Princess Alexandra Hospital, Queensland. The primary endpoint was time from first GK to death. Results: 104 patients were eligible. Median age was 63 years. BM was seen in 46.7% at diagnosis (versus relapsed in brain). Solitary BM was seen in 37.1% patients. 7.7% had prior whole-brain radiation (WBRT) prior to GK. 45.7% received ICI either at the time of GK or as the next line of treatment immediately post GK. 56.2% received ICI at any time during the study period. Oncogenic driver mutations were seen in 13 cases [EGFR mutant (9.5%), ALK mutation (2.5%)]. 15.2% patients had a high-PDL1 (≥50%) level. Time from GK to death was: 14 (9.7-18.3) months for all patients. Incidence of progressive BM was 46.7%. Time to intracranial PD was 5 months. Systemic PD was seen post GK in 44.8% patients. Survival was improved in those patients with the presence of a driver mutation (p = 0.043) on univariate analysis. Factors which did not impact survival included: the number of BM (solitary vs multiple; p = 0.837), PD-L1 status (PD-L1 &lt; 50% vs ≥50%; p = 0.186), use of ICI (used vs not used; p = 0.307) and previous WBRT (treated vs not treated; p = 0.251). Failure of BM requiring GK on ICI was not associated with a worse outcome (p = 0.707). Conclusions: The presence of driver mutations was associated with prolonged overall survival in select patients undergoing GK for BM. High PDL-1 expressivity and timing of ICI relative to GK do not appear to positively influence outcome in this retrospective study.
Survival impact of multidisciplinary thoracic oncology care in a regional healthcare system.
Authors: Raymond U. Osarogiagbon, Nicholas Ryan Faris, Matthew Smeltzer, Anna Derrick, Philip Edward Lammers, Shailesh R. Satpute, William Walsh, Rameses Sroufe, Todd Robbins, Keith Tokin, Rob Optican, Angela Fulford, Laura McHugh, Jeffrey Wright, Anurag Mehrotra, Thomas Callihan, Meredith Ray
Journal: Journal of Clinical Oncology (2020)

2004 Background: Much-advocated, the value and impact of multidisciplinary care and planning (MDC) needs greater evidence. We compared non-small cell lung cancer (NSCLC) patient characteristics, treatment patterns and survival in a large community healthcare system spanning 3 US states with some of the highest lung cancer incidence and mortality rates. Methods: We identified MDC patients in the Tumor Registry NSCLC data from 2011-2017. Because the MDC program was located in metropolitan Memphis, we separated non-MDC patients by location of care resulting in 3 cohorts: MDC, non-MDC metropolitan care and non-MDC regional care. Using National Comprehensive Cancer Network guidelines, we categorized treatment by stage as ‘preferred’, ‘appropriate’ (allowable under certain circumstances). We compared demographic and clinical characteristics across cohorts using chi-squared tests and compared survival using Cox regression with Bonferroni adjustment. We repeated survival analysis with propensity matched cohorts. Results: Of 6259 patients, 14% received MDC, 56% metro care and 30% regional care; MDC had the highest rates of African Americans (34% v 28% v 22%), stage I-IIIB (63 v 40 v 50), urban residents (81 v 78 v 20), stage-preferred treatment rates (66 v 57 v 48), stage-appropriate treatment rates (78 v 70 v 63;), and lowest non-treatment rates (6 v 21 v 28). All p&lt;0.001. Compared to MDC, the hazard for death was higher in metro (1.4, 95% confidence interval 1.3-1.6) and regional (1.7, 1.5-1.9); hazards were higher in regional care v metro (1.2, 1.1-1.3); all p&lt;0.001 after adjustment. Results were similar for MDC comparisons after propensity matching with and without adjusting for preferred treatment. No differences in regional and metro cohorts. Conclusions: In this large community-based healthcare system, receipt of MDC for NSCLC was associated with significantly higher rates of guideline-concordant care and survival, providing strong evidence for recommending rigorous implementation of MDC. [Table: see text]
Phase I/II trial assessing hydroxychloroquine and itraconazole in women with advanced platinum-resistant epithelial ovarian cancer (EOC) (HYDRA-01).
Authors: Ainhoa Madariaga, Stefano Marastoni, Ilaria Colombo, Victoria Mandilaras, Michael Cabanero, Jeffrey Bruce, Swati Garg, Lisa Wang, Sarbjot Gill, Neesha C. Dhani, Valerie Bowering, Xuan Li, Amit M. Oza, Anthony M. Joshua, Stephanie Lheureux
Journal: Journal of Clinical Oncology (2020)

6049 Background: Autophagy is a mechanism of resistance to platinum chemotherapy. Itraconazole (Itr), an antifungal agent, can alter cholesterol-trafficking, leading to accumulation of cholesterol in endosomes/lysosomes and resulting in cancer cell death. Itr is also involved in regulation of angiogenesis, mTOR and Hedgehog pathways. In preclinical studies the Itr effect can be enhanced by combining it with the autophagy inhibitor hydroxychloroquine (H). Drug repurposing studies with Itr have shown a signal of activity in prostate, lung and basal cell carcinoma. Methods: A rolling-6 phase I design was used to enroll patients (pts) with platinum-resistant/refractory EOC. Pts received Itr 300mg twice daily (BID) with H as per dose escalation schedule (range 200mg BID- 600mg BID), continuously in a 28-day cycle. Primary objective was establishment of MTD; secondary objective was objective response rate, progression free survival (PFS). Pre- and on-treatment biopsies were mandatory to evaluate exploratory objectives assessing effect on apoptosis/proliferation, angiogenesis, cholesterol metabolism and mechanism of cytotoxicity. RNAseq and IHC was performed in the sequential biopsies. Results: 11 pts were enrolled, 9 evaluable for efficacy. Histology was high 91% and low-grade serous 9%. Median lines of prior therapy was 7. RP2D was Itr 300mg BID and H 600mg BID. 1 DLT was seen in dose-level 2 was grade 3 hypertension. Other grade ≥3 related toxicity were grade 3 hypokalemia and grade 4 QTc prolongation (1 pt, dose-level 3). No objective responses were observed and 1 pt had stable disease. Median PFS was 1.6 months (1-1.7). Pre- and on-treatment biopsy was available for 10 pts. Increase in autophagy related protein, LC3, P62 and lysosomal marker, LAMP1, expression by IHC was identified in 3 pts. RNAseq revealed no differences between pre and on treatment samples in cholesterol homeostasis, angiogenesis, lysosomal-autophagy, PI3K-mTOR pathways. Conclusions: The combination of Itr and H was feasible but did not show antitumour activity in this heavily pre-treated platinum resistant EOC population. Increase of IHC expression in autophagy related proteins was detected in 30% of pts but did not correlate with patient benefit. Clinical trial information: NCT03081702. [Table: see text]
全科医生在中毒抢救中应该注意的问题
Authors: 刘凤奎
Journal: BMJ (2007)

在临床工作中遇到急性中毒患者时,有些社区卫生服务中心或社区卫生服务站不给予任何抢救措施,直接找车转上级医院.看起来好像是对患者负责,在社区中心医院一点也没浪费时间,但实际上却增加了患者对毒物的吸收,延误了抢救时间。
Collaborative meta-analysis of randomized trails of antiplatelet therapy for prevention of death, myocardial infarctions, and stroke in high risk patients
Authors: 刘靖, 徐成斌
Journal: BMJ (2002)

研究目的：
确定闭塞性血管事件高危患者的抗血小板治疗效果。


研究设计：
协作汇总分析（系统性综述）。


纳入标准：
1997年9月前结束的研究。研究设计为在高危患者（急性或既往血管疾病或某些其他易感情况）中进行抗血小板药物与对照药物比较或不同抗血小板药物间比较的随机试验。试验需采取随机化方法，受试者预先不知道将被分配进行何种治疗，而且比较不能混杂，即对于研究对象来说仅仅是抗血小板药物不同。


研究回顾：
共287项研究，其中抗血小板治疗与对照比较试验共纳入135 000人，不同抗血小板药物间比较试验共纳入77 000人。


主要结果的测量指标：
严重血管事件，包括非致命性心肌梗死，非致命性卒中或血管性死亡。


结果：
在高危患者中，抗血小板治疗使所有严重血管事件减少1/4，非致命性心肌梗死减少1/3，非致命性卒中减少1/4，血管性死亡减少1/6（对其他原因的死亡无明显有害作用）。陈旧性心肌梗死患者每1000人治疗2年可减少严重血管事件危险的绝对值为36（标准误为5）人；急性心肌梗死患者每1000人治疗1个月可减少严重血管事件危险的绝对值为38（标准误为5）人；陈旧性卒中或暂时缺血性卒中患者每1000人治疗2年可减少严重血管事件危险的绝对值为36（标准误为6）人；急性卒中每1000人治疗3周可减少严重血管事件危险的绝对值为9（标准误3）人；其他高危患者（稳定心绞痛、外周动脉疾病，房颤）每1000人治疗2年，可减少严重血管事件危险的绝对值为22（标准误为3）人。在每一类高危情况中，绝对收益大大超过了主要颅外出血的绝对危险。阿司匹林是研究最多的抗血小板药，每日75 ～ 150 mg至少与高剂量同样有效。低于75 mg剂量效果不确定。氯吡格雷同阿司匹林比较，使严重血管事件下降10%（标准误为4%），与其类似物噻氯匹定相似（12%，标准误为7%）。与单用阿司匹林比较，双嘧达莫加阿司匹林并未使血管事件进一步下降。冠状动脉急性闭塞的高危患者，短期应用静脉Ⅱb/Ⅲa拮抗剂加阿司匹林，每治疗1000人进一步减少20（标准误为4）人的血管事件（P< 0.0001），但却增加23例的颅外大出血事件（但少有致命性）。


结论：
阿司匹林（或其他口服抗血小板药）对大多数闭塞性血管事件高危患者具有保护作用，这包括急性心肌梗死或缺血性卒中、不稳定或稳定性心绞痛、陈旧性心肌梗死、卒中或脑缺血、外周动脉疾病或房颤。小剂量阿司匹林(75~150mg／日）是有效的长期使用的抗血小板药物，但在急性情况下通常需要至少150 mg的负荷剂量。在某些临床情况下，在阿司匹林基础上加用第二种抗血小板药物可以产生附加效益，但这一治疗策略还需进一步研究。
Mortality within 30 days of receiving checkpoint inhibitor immunotherapy: An Australian multicenter review.
Authors: James Fletcher, Katherine Kang, Gabriella Smallwood, Jasotha Sanmugarajah, Megan Lyle
Journal: Journal of Clinical Oncology (2020)

e19182 Background: Mortality within 30 days of chemotherapy is recognised as an important quality assurance measure. There is limited data regarding mortality within 30 days of immunotherapy and whether the same standards should apply. In contrast to chemotherapy, immunotherapy has a favourable toxicity profile and a higher chance of durable responses. We assess 3 years of data from two regional cancer centres in Queensland, Australia. Methods: Retrospective review of patients treated with checkpoint inhibitor immunotherapy at Cairns Hospital and Gold Cold University Hospital between June 2016 and June 2019. Results: 533 patients received immunotherapy and 59 (11.1%) died within 30 days of treatment. 25 patients died within 30 days of their first treatment (4.7%). Anti-PD-L1/PD-1 was more common than anti-CTLA-4 and combination treatment (84.7% v 1.7% v 13.6%). Median age was 65 years (range 37 – 87). Most patients were treated for non-small cell lung cancer (51%) and melanoma (36%). Poor prognostic features were prevalent: ECOG 3-4 (30%), brain metastases (34%), 3 sites of metastases (59%), and raised LDH (80%). Grade 3+ toxicity was uncommon (3.4%) and there were no treatment-related mortalities. Most patients died due to progressive disease. 67% died in hospital and 25% received acute treatment within 48 hours of their death. Most patients were known to palliative care (85%). Resuscitation plans were documented in 55% before their final treatment. Discussion regarding very poor prognosis was documented in 44%. Conclusions: Thirty-day mortality rates were similar to published data relating to chemotherapy and mortality within 30 days of initiating therapy was low. While there were few significant immune-related toxicities, a quarter of patients received acute treatment within 48 hours of their death. Most patients had documented resuscitation plans and were known to palliative care.
An open-label, single-arm, phase I study to assess the safety, efficacy, and biomarker effects of OMT-110 in patients with refractory colorectal cancer.
Authors: Soobong Park, Haejun Lee, Keun-Yeong Jeong, Jeong-Heum Baek, Chong-Hwan Chang
Journal: Journal of Clinical Oncology (2020)

e16027 Background: A metabolism modulatory anticancer durg candidate, OMT-110, has been applied for phase I clinical trial to evaluate the effect of OMT-110 on safety, efficacy, and biomarker in patients with refractory colorectal cancer resistant to standard therapies. FDG PET-CT has been suggested to be a resonable biomarker for a metabolism modulator and tested as a possible biomarker for OMT-110 in the clinical trial. Methods: The study was composed of 4 cohorts with a specified dose of 12.5, 25, 50, and 100 mg, and each cycle consisted of daily subcutaneous injections for 3 consecutive weeks and had a resting period of 1 week. 3 subjects were enrolled in each cohort in a total of 12 patients. FDG-PET/CT was utilized as a biomarker and the SUV max was evaluated according to European Organisation for Research and Treatment of Cancer (EORTC) criteria. Results: None of the subjects permanently discontinued or reduced the dose of the investigational drug due to dose-limiting toxicity. Serious drug adverse reactions that resulted in permanent discontinuation of investigational drugs were not reported. Biomarker evaluation using FDG-PET/CT revealed that the tumor responses of 9 from total 9 subjects who completed FDG-PET/CT evaluation by Cycle 2 (8 weeks) were stable metabolic disease (SMD) or higher . In particular, four subjects showed a clear tendency for a decrease in glucose transporting and were evaluated by partial metabolic response (PMR). The result was compatible with the response of Chest CT and APCT according to RECIST. Conclusions: In the study, the results of FDG/PET-CT show OMT-110 modulates the cancer-specific metabolism and thus reduces glucose transportation. Based on the study outcome, FDG PET-CT is possibly considered as a biomarker of OMT-110 and further study is warranted.
Safety and efficacy of optimized tandem CD19/CD20 CAR-engineered T cells in patients with relapsed/refractory non-Hodgkin lymphoma.
Authors: Yajing Zhang
Journal: Journal of Clinical Oncology (2020)

3034 Background: Chimeric antigen receptor T (CAR T) cells targeting CD19 have been used to achieve breakthroughs in the treatment of hematological malignancies, however, a high recurrence rate is the main obstacle to durable remission following CAR T cell therapy. Methods: As an open-label and single-arm phase I/IIa trial (ClinicalTrials.gov number, NCT03097770), we screened 99 patients with r/r B-NHL—including DLBCL, PMBCL, CLL/SLL, MCL, TFL and FL—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue, and a total of 87 patients received an infusion of one dose tandem CD19/CD20 CAR-engineered T cells on day 0 in the range of 0.5×10 6 -10×10 6 cells per kilogram of body weight after conditioning chemotherapy. The primary objective was to evaluate the safety and tolerability of CAR T cells. Efficacy, progression-free survival (PFS) and overall survival (OS) were evaluated as secondary objectives. Our clinical trials is registered with ClinicalTrials.gov, NCT03097770. Safety was assessed by CTCAE Version 5.0, and clinical response by PET-CT referred to standard international criteria. The trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Results: Between May 11, 2017, and Jan 31, 2020, 99 patients were enrolled and 87 received tandem CD19/CD20 CAR-engineered T cells across phases I/IIa. As of the cutoff date, 74 assessable patients were followed up for a median of 13.5 months (IQR 33.2 - 3.3), 62 (84%) had an objective response, and 55 (74%) had a complete response. The median progression-free survival and overall survival were all not reached. Cytokine release syndrome (CRS) occurred in 62 patients (71%), with 61% grade 1 or 2 and 10% grade 3 or more. CAR-T-cell-related encephalopathy syndrome (CRES) of grade 3 occurred in 2 patients (2%) . Three treatment-related deaths (2 in pulmonary infection and 1 in deposition of CART cells in pulmonary alveoli). Conclusions: In this study, optimized tandem CD19/CD20 CAR-engineered T cells induced a potent and durable anti-tumour response with controllable CRS and CRES. Clinical trial information: NCT03097770 .
Association of higher EGFR mutation in the primary lesions with lymph node metastasis in early lung adenocarcinoma.
Authors: Yi Zhang, Jinjin Wang, Yuwei Yuan
Journal: Journal of Clinical Oncology (2020)

e21039 Background: Prognosis of early stage lung adenocarcinoma after surgery are usually affected by whether the patients had lymph node metastasis along with the primary lesions. The pathological stage of operable lung adenocarcinoma without or with lymph node metastasis were ⅠA/B or ⅡB/ⅢA, respectively, which related to different clinical outcomes, especially 5 years survivors (90% vs 50%). Due to the high tumor heterogeneity, it is difficult to trace which genes lead to tumor metastasis. We hypothesis that the genetic mutations in the smaller tumor might discover the key genetic changes associated with metastasis. Methods: 47 NSCLC patients with the primary lesion diameter less than or equal to 3cm were enrolled for genotyping with multiple cancer-related genes. Among them, 20 were lymph node metastasis and 27 were non-metastasis. Fisher test was used to analyze the difference between the two primary tumors. Results: EGFR amplification in all patients with lymph node metastasis is higher than the non-metastasis group (0.250 vs 0.037, P = 0.043), shown in the following table. This tendency was also found when the tumor diameter thresholds were configurated as &lt; 2.5cm and &lt; 2cm, even more prominently in the latter, (0.400 vs 0, P = 0.020). The CNV value of EGFR increased while the tumor diameter threshold value decreased. The difference of EGFR VAF between the two groups showed the same pattern. The metastatic patients had higher VAF values than the non-metastatic patients (each P-value was lower than 0.05). Conclusions: Based on the above results, it is speculated that EGFR mutations plays an important role in tumor early metastasis, and the genetic mutations in the smaller tumor might discover the key genetic changes associated with metastasis more notably. [Table: see text]