tbuckley/cabot-search huggingface dataset:
Residual breast tissue after mastectomy in non high risk and BRCA mutated patients.
Authors: Georg Pfeiler, Alex Farr, Ramona Woitek, Thomas Helbich, Daphne Gschwantler-Kaulich, Christian F. Singer, Maria Bernathova
Journal: Journal of Clinical Oncology (2015)

1061 Background: Skin sparing mastectomy (SSM) and nipple sparing mastectomy (NSM) and immediate reconstruction by an implant are widely used in patients with breast cancer and in high risk patients for prophylaxis. Surgical procedure is guided by oncological aspects on the one hand – meaning cutaneous/subcutaneous envelope as thin as possible – and by cosmetic aspects on the other hand – meaning envelope as thick as possible. Pre-operative MRI might help the surgeon to choose the right thickness of this envelope. In this retrospective analysis we investigated the presence of residual breast tissue and the thickness of the envelope after SSM and NSM. Methods: Patients treated with SSM or NSM for prophylaxis or after breast cancer at a single university hospital, who had at least one post-operative MRI, were included. MRI’s were retrospectively analysed by two independent radiologists. Analyses included (a) the detection of residual breast tissue (yes/no) and (b) the maximum thickness of the envelope directly above the implant. Results: 39 patients of which 19 had bilateral SSM/NSM were included. 14 patients with BRCA 1/2 mutation had prophylactic bilateral SSM/NSM. Residual breast tissue could be detected in all 58 reconstructed breasts. The medium thickness of the envelope was 11.2mm (1-35mm). In patients with bilateral SSM/NSM, a strong correlation between the thickness of left and right breast envelope could be observed (r = 0.79, p < 0.05). Conclusions: Thickness of the envelope of the reconstructed breast does not appear to be the major determining factor of residual breast tissue.
Contribution of Expiratory Muscle Pressure to Dynamic Intrinsic Positive End-Expiratory Pressure
Authors: SPYROS G. ZAKYNTHINOS, THEODOROS VASSILAKOPOULOS, EPAMINONDAS ZAKYNTHINOS, ANTONIS MAVROMMATIS, CHARIS ROUSSOS
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

In spontaneously breathing (SB) patients expiratory muscle contraction leads to an overestimation of dynamic intrinsic PEEP (PEEPi,dyn). To quantify this overestimation, PEEPi,dyn measured with the esophageal balloon technique was corrected for the increase in Pga over the course of expiration (Pga,exp rise), for the whole decay of Pga during inspiration (Pga,total decay) or for the part of Pga decay restricted between the onset of inspiratory effort and the point of zero flow (Pga,zf decay). Corrections were compared with the reference PEEPi,dyn (PEEPi,dyn ref ), calculated by using the Campbell diagram. In 15 ventilator-dependent, SB, and actively expiring patients, we found that the difference PEEPi,dyn − Pga,total decay (mean ± SD, 5.7 ± 1.9 cm H2O) was quite similar to PEEPi,dyn ref (5.3 ± 1.9 cm H2O). Their mean difference was 0.37 cm H2O with limits of agreement − 0.09 to 0.83 cm H2O, indicating strong agreement between these methods. PEEPi,dyn − Pga,exp rise (6.0 ± 2.1 cm H2O) was also similar to PEEPi,dyn ref. Their mean difference was 0.72 cm H2O with limits of agreement − 1.69 to 3.13 cm H2O, indicating good agreement. In contrast, mean difference of PEEPi,dyn − Pga,zf decay and PEEPi,dyn ref was 3.14 cm H2O with limits of agreement − 0.46 to 6.74 cm H2O, indicating lack of agreement. The error in measurement due to the subtraction of Pga,zf decay from PEEPi,dyn (i.e., [PEEPi,dyn − Pga,zf decay] − PEEPi,dyn ref ) was proportional to the intensity of expiratory muscle contraction, as expressed by the Pga,exp rise (r = 0.903, p < 0.001). We conclude that in actively expiring patients an adequate correction of PEEPi,dyn for the overestimation caused by expiratory muscle contraction can be made by subtracting either Pga,total decay or Pga,exp rise from PEEPi,dyn, the former achieving the best performance.
Metastatic pattern of late metastases of gastrointestinal stromal tumors and the contribution radiation therapy for disease control.
Authors: Peter Hohenberger, Franka Menge, Jens Jakob, Ulrich Ronellenfitsch, Monika Mathew, Alexander Marx, Bernd Kasper, Peter Reichardt, Eva Wardelmann
Journal: Journal of Clinical Oncology (2014)

10554 Background: Metastases to the liver and the peritoneum are the typical locations of tumor spread in GIST. Effective 2nd and 3rd line therapies beyond imatinib lead to advanced GIST as a chronic disease. Newly arising metastases after 4 years of being stable on TKIs is a rare event. We were interested to analyze the pattern of late metastases and evaluated the effects of radiation therapy to control bone and soft tissue lesions. Methods: 731 pts with biopsy proven GIST were treated and followed-up since 2004 with a median follow-up 43.6 months (range, 1-274 mos); data were prospectively documented. There were 394 females (53.9%). 101 (13.8%) pts. presented with M1 disease initially. Of the remaining 630 pts, 358 pts (56.8%) developed tumor recurrence. Results: Median time to disease recurrence was 22 months, (range, 2-144) and 312/358 pts (87%) developed metastases within the abdomen: liver n=96, peritoneal n=97, liver+peritoneal n=78, locoregional n=10, locoreg.+hep/per n=21. In 35 pts, extraabdominal sites were found (biopsy 29 pts): bone n=19, multiple sites n=12; soft tissue (STS) n=9, lung/pleura n=7, spleen n=1, brain n=1. All of these locations occurred after at least liver or peritoneal metastases with a median RFS of 58 months (range, 27-105 months). 26 pts had at least two lines of therapy prior to ‘atypical’ metastases. The median OS of this cohort is 118 months (range, 40-264 months) and 11 pts are still alive. 4/9 pts with STS and 21 sites of pts with bone metastases underwent radiation therapy of 45- 56 Gy, all in parallel to continued TKI therapy. Only one patient showed PD after RT at 6 months. The average duration of local control is 22 months. No unusual mutational pattern was detected in the primary tumors. Interestingly, in 7 pts a 2ndary exon 13 V654A mutation could be found. Conclusions: Extraabdominal metasteses of GIST are a rare and late event in the course of disease and occurs only after long-lasting therapy with TKIs. These ‘atypical’ metastases do not indicate rapid disease progression and may be controlled by radiation therapy if located in the bones or soft tissues. Whether continued TKI therapy contributes to the effective use of RT warrants further exploration.
Use of telemedicine in the delivery of survivorship care plans among breast cancer survivors: Lessons learned at Kaiser Permanente East Bay.
Authors: Pamela Kim Washington, Heather Tews, Dan-Thanh Nguyen, Leeina Wade, Trang Phan, Mala N. Reddy, Janet Lai, Nicole M Barnett, Jennifer Greer, Veronica Shim
Journal: Journal of Clinical Oncology (2017)

77 Background: Beginning in 2015, the National Accreditation Program for Breast Centers (NAPBC) requires accredited facilities to provide Survivorship Care Plans (SCP) to breast cancer patients treated with curative intent. Here we describe lessons learned with the use of telemedicine in the delivery of SCPs at Kaiser Permanente East Bay. Methods: SCP implementation followed a two-step process: patients who are diagnosed and complete treatment in 2016 are given a SCP at their last surgical or medical oncology appointment (YTD, n=8); 2) patients diagnosed in 2015 who completed treatment in 2015-2016 were contacted by a physician assistant and offered an appointment by telephone or in-person to deliver the care plan (n=152). Both clinic and telemedicine appointments consist of a detailed review of treatment received, post-treatment follow-up care, discussion of health education resources, and provision of referrals as appropriate. Patients also have the opportunity to ask questions about treatment and follow-up care. Results: Among patients diagnosed in 2015 who were offered a TAV or in-person visit, 44.0% preferred a telephone appointment. Actual appointment duration ranged from 10 to 30 minutes. Lack of co-payment and fees associated with transportation as well as loss of income due to taking time off work were the primary factors cited choosing telemedicine over in-person clinic appointments. Interestingly, no differences in member satisfaction scores for in-person vs. telephone visits were observed. Conclusions: Findings suggest telemedicine may be effective in the delivery of SCPs. Similar to rural settings, use of telemedicine in urban settings has a unique capacity to increase service to breast cancer patients.
Evaluating outcomes of pancreatic cancer patients with cacehxia.
Authors: Andrew Eugene Hendifar, Carlyn Rose Co Tan, Patrick Yaffee, Arsen Osipov, Richard Tuli, Christie Y Jeon
Journal: Journal of Clinical Oncology (2014)

e15208 Background: Although cachexia is a common complication in pancreatic cancer patients and a risk factor for poor outcomes, physicians do not necessarily diagnose and treat it. In a nationally representative cancer database, we investigated the extent of diagnosed cachexia and its treatment in pancreatic cancer patients. We also evaluated if treatment with cachexia drugs (i.e. megestrol and dronabinol) are associated with improved outcomes in pancreatic cancer patients. Methods: We employed data on patients with primary pancreatic adenocarcinoma represented in the linked Surveillance, Epidemiology and End Results tumor registry and Medicare claims database between 2007 and 2009. The study sample comprised of 8619 patients who were continually enrolled in Medicare Parts A, B and D, for whom diagnostic codes and prescription drug data were available. Cachexia was defined as ICD-9 coded diagnosis of cachexia, anorexia, wasting, or weight loss following cancer diagnosis, and/or prescription for megestrol or dronabinol. We performed multivariable Cox Regression, adjusting for age, sex, race, stage, grade, tumor size, chemotherapy, resection, diabetes, obesity and dyslipidemia to investigate the association between cachexia and overall survival, incorporating cachexia diagnosis and its treatment as time-dependent covariates. Results: Cachexia was diagnosed and/or treated in 3022 (35%) of study population, in whom 1697 were diagnosed with cachexia, and 1600 and 259 were treated with megestrol and dronabinol, respectively. Those diagnosed or treated with cachexia showed higher hazard of death across all stages of pancreatic cancer (HR =1.57, 95%CI 1.50, 1.65) Once diagnosed with cachexia use of megestrol (HR = 1.54, 95% 1.37, 1.73) and dronabinol (HR = 1.57, 95%CI 1.25, 1.96) were significantly associated with mortality. Conclusions: Pancreatic cancer cachexia is diagnosed and treated in a minority of patients. Use of existing cachexia drugs are associated with worse outcomes in pancreatic cancer patients with cachexia and likely indicates severity of disease.
Copenhagen prospective personalized oncology (CoPPO): Sequencing and array-based pipeline for selection of patients to phase 1 studies.
Authors: Ida Elisabeth Viller Tuxen, Eric Santoni-Rugiu, Lars Joenson, Jonas Vikesaa, Morten Mau-Soerensen, Finn Cilius Nielsen, Ulrik Niels Lassen
Journal: Journal of Clinical Oncology (2014)

11097 Background: Advanced genomics technology can be used to characterize genomic alterations (GA) that potentially drive tumor growth. We have established a sequencing and array based pipeline to identify GA to select patients (pts) who might benefit from novel targeted treatments and to enrich the population in Phase 1 trials with pts that harbor specific targets. Methods: Pts with advanced solid tumors referred to a dedicated Phase 1 Unit were offered mapping of GA to identify pts who could benefit from a personalized treatment. Two ultrasound-guided biopsies were obtained and stored in RNAlater for DNA and RNA purification. A third biopsy for histology was paraffin embedded. SNP-array from tumor and whole exome sequencing (WES) from DNA (tumor and blood) were performed using sequence capture and Illumina sequencing to call tumor specific mutations. Expression levels of therapeutic targets were revealed by expression Array and RNA-seq from tumor RNA. Results were reviewed by a tumor board. Patients with specific genetic profiles that could be targeted with marketed drugs or drugs in development, were, if possible, offered individualized treatment. Results: From May 2013 to December 2013, 30 heavily pretreated patients with solid tumors were included. In 28 patients (93%) a dedicated biopsy was obtained. An actionable target was identified in 15 patients (53%) and 6 patients (21%) were offered treatment according to the findings of either mutations or RNA expression levels of oncogenes. Median time from biopsy to result was 38 days. We were able to define a hypothetic driver for tumor growth in 80% of the cases. Conclusions: Establishing sequencing and array-based pipeline for enrichment of pts to phase 1 trials is feasible.
PR and Ki67 in primary tumors and metastatic sites as biomarkers for benefit from endocrine therapy (ET) in metastatic breast cancer (mBC).
Authors: Cristiano Ferrario, Alberto Farolfi, Roberta Maltoni, Elisa Carretta, Elisabetta Melegari, Elisabetta Pietri, Andrea Rocca, Oriana Nanni, Dino Amadori
Journal: Journal of Clinical Oncology (2013)

e11521 Background: Commonly used biomarkers (ER, PR, HER2, Ki67) are thought to identify BC subtypes with different sensitivity to ET, but data on this are scarce for the metastatic setting, where changes in receptor status between primary tumor (T) and matched metastases (M) are reported. We investigate PR and Ki67 on T and M as predictors of clinical benefit from 1st line ET in mBC. Methods: We identified mBC patients (pts) treated in our Center with 1st line ET (2002-11), excluding those receiving concomitant chemotherapy (CT) or trastuzumab or pretreated with &gt;2 lines of CT. PR and Ki67 were scored as IHC percentage of positive cells, with a cut-off of 20% for high vs low. Clinical benefit was evaluated by time-to-progression (TTP). Results: We identified 137 pts, median age 58 (29-85), only 28% with visceral metastases. ER was &gt;50% in 94%, HER2+ in 17.5%. With 93% receiving an aromatase inhibitor, median TTP was 14 months (median follow-up 43 months). In 34 pts with Ki67 available from T and M a strong correlation between the 2 was shown (Spearman: 0.69, p&lt;.0001), confirming little variation. A shorter median TTP (10 vs 17 months, n=113; Wilcoxon p=0.006) was seen in pts with Ki67 &gt;20% on T (with a similar trend on M, n=58; p=0.06). In 48 pts with PR scored on T and M only a weak trend for correlation was found, with a discordant classification (≤ or &gt;20%) in 44%. More than the score on T (n=118), PR on M (n=64) was a strong predictor of median TTP: 12 months for PR ≤20% vs 22 months for PR &gt;20% (p=0.02). Pts with PR≤20% + Ki67&gt;20% on M had a median TTP of only 4 months, vs 21 months for PR&gt;20% + Ki67≤20%, vs 14 months for either PR&gt;20% or Ki67≤20% (p=0.006). In a multivariate Cox analysis with clinical data and biomarkers from T, visceral disease and HER2 positivity were significantly associated with the risk of progression (HR 2.22 and 2.07, respectively). With biomarkers from M, the risk of progression correlated with relapse ≤5 vs &gt;5 years from surgery (HR 3.48) and PR ≤20% (HR 2.47, p=0.01). Conclusions: In an ER-high population, PR &gt;20% on M identifies pts with a long TTP on ET. Ki67 on T or M can also contribute in estimating the expected benefit, but an independent prognostic role could not be fully confirmed in this small cohort.
Humanized mice (humice) carrying patient-derived xenograft (PDX) as a platform to develop immunotherapy in bladder cancer (BCa).
Authors: Chong-xian Pan, Wei Shi, Ai-Hong Ma, Hongyong Zhang, Primo Lara, James G. Keck, Karolina Palucka, Susan D. Airhart, Ralph deVere White
Journal: Journal of Clinical Oncology (2017)

381 Background: Immunotherapy with anti-programmed cell death 1 (PD1) or PD ligand 1 (PD-L1) antibody has emerged as a promising therapeutic modality, but has a response rate of approximately 20% in BCa. There are various drawbacks associated with current animal models. The objective of this study is to establish and characterize humice carrying PDXs in which both the immune cells and BCa cells are derived from humans. Methods: NOD-scid IL2Rgamma null or NSG, mice received CD34+ hematopoietic progenitor cells (HPC) cells i.v. after whole body radiation. PDXs were established through direct implantation of human BCa clinical specimens into NSG mice. Immune cell subpopulations were analyzed through flow cytometry analysis. Humice carrying HLA-unmatched PDXs were treated with an anti-PD1 antibody pemborlizumab (pembro) or in combination with a BKT/ITK inhibitor ibrutinib to determine the anti-tumor efficacy and toxicity. Results: PDXs retained the morphology fidelity and 92-97% of genetic alterations of parental patient cancers. Of the first 8 PDXs tested, 3 had high PD-L1 ( &gt; 10 FPKM) as determined by RNA-seq which was further confirmed with flow cytometry analysis. Major human immune cell sub-populations were reconstituted in humice. No xenograft versus host disease was observed before pembro treatment. In humice with HPC donor 6466, pembro significantly inhibited tumor growth (p = 0.0016 at Day 29) of PDX BL293, but had no effect in another PDX BL440 with the same HPC donor 6466, or with the same PDX BL293 but with a different HPC donor 912. In another set of humice (HPC donor 710) carrying PDX BL293, pembro alone inhibited tumor growth. However, addition of ibrutinib did not potentiate the efficacy of pembro, but increased toxicity. Tumor regression with pembro treatment was associated with decrease of CD4+PD1+, CD8+PD1+ cells at peripheral blood and increased CD45+ and CD8+ cells in PDXs. Conclusions: Humice carrying PDXs reconstitute with human immune system, and can potentially be used to screen for effective immunotherapeutic agents or combinations, and to study resistant mechanisms.
Phase I dose escalation study of recombinant interleukin-21 (rIL-21; BMS-982470) in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced or metastatic solid tumors.
Authors: Laura Quan Man Chow, Michael S. Gordon, Theodore F. Logan, Scott J. Antonia, Shailender Bhatia, John A. Thompson, Julie R. Brahmer, Gretchen Solberg, Rachel Bittner, David Fontana, Joseph Grosso, Lewis J. Cohen, Christoph Matthias Ahlers, Jon M. Wigginton, Charles G. Drake
Journal: Journal of Clinical Oncology (2013)

TPS3112 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2. Nivolumab, a PD-1 receptor blocking antibody, has shown durable antitumor activity in pts with various solid tumors in two phase I clinical trials. The cytokine rIL-21 has also shown antitumor activity in selected solid tumors. We hypothesized that combining rIL-21-induced stimulation of T-cell and NK-cell function in conjunction with T-cell checkpoint blockade using nivolumab could enhance biologic activity resulting in improved clinical outcomes, as compared with either agent alone. We describe a novel phase I study investigating the biologic activity and clinical outcomes of the combination in pts with advanced solid tumors. Methods: This ongoing study (N=160) includes a dose escalation phase (Part 1) using a 3 + 3 design followed by an expansion phase (Part 2). In Part 1 (N=60), successive pt cohorts with advanced solid tumors are being treated with escalating doses of rIL-21 (10, 30, 50, 75, or 100 µg/kg IV) on two distinct schedules (Arms A and B) in combination with fixed-dose nivolumab (3 mg/kg q 2 weeks) in 6 week cycles. Arm A administers rIL-21 on a weekly schedule, given on day 1 in weeks 1–4 of the 6 week cycle. Arm B administers rIL-21 at 3x per week during weeks 1 and 3 of the 6 week cycle. In Part 2, pts with renal cell carcinoma (N=50) or non-small cell lung carcinoma (N=50) will each be randomized to treatment at the maximum tolerated dose (MTD) or maximum administered dose, if no MTD is determined, for Arm A or Arm B. Therapy for pts who are stable or responding in Parts 1 and 2 may be continued for up to 2 years or until treatment discontinuation criteria are met. Primary objectives are to evaluate the safety of rIL-21 + nivolumab, and to define the MTD of the 2 schedules. Secondary and exploratory objectives include a preliminary assessment of the antitumor activity, pharmacokinetics, immunoregulatory activity (peripheral blood, tumor) and immunogenicity of this combination. Clinical trial information: NCT01629758.
Pazopanib (PZP) in germ cell tumors (GCT) after chemotherapy (CT) failure: Final results of the open label, single-group, phase II Pazotest trial.
Authors: Andrea Necchi, Salvatore Lo Vullo, Patrizia Giannatempo, Daniele Raggi, Giuseppina Calareso, Elena Togliardi, Flavio Crippa, Marzia Pennati, Nadia Zaffaroni, Federica Perrone, Maurizio Colecchia, Nicola Nicolai, Luigi Mariani, Roberto Salvioni
Journal: Journal of Clinical Oncology (2017)

414 Background: Therapeutic options for patients (pts) with chemoresistant GCT are limited and prognosis is poor. PZP is a potent and selective tyrosine kinase inhibitor (TKI) with distinct antiangiogenic activity. Methods: In Pazotest trial (NCT01743482), pts were given PZP 800 mg/day until disease progression (PD) or unacceptable toxicity. Eligibility included failure of ≥ 2 platinum-based CT, including high-dose (HD)-CT. Baseline serum tumor markers (STM), computed tomography and FDG-PET were repeated after 4 wks and q8 weeks thereafter. The primary endpoint was PFS (H0: 3-m PFS ≤ 10%, H1: ≥ 25%, α = 5%/β = 20%). PD was defined as rising STM, increasing size of nonteratomatous masses (RECIST v1.1), or the appearance of new lesions. Translational analyses included circulating IL8 levels and next generation sequencing of pre-PZP tissue from extreme responders. Results: 43 pts were enrolled from 05/2013 to 07/2016. 35 pts (81.4%) had nonseminoma, 6 (14%) primary mediastinal GCT. The number of failed CT regimen was: 2 (11.6%), 3 (51.2%), &gt; 3 (37.2%). 53.5% had failed HDCT. 39 pts had elevated STM: 56.4% AFP, 43.6% HCG. Grade 3-4 adverse events were seen in 4 pts (increased AST/ALT). 26/39 pts (66.7%) had STM reduction (38.5% &gt; 50% from baseline) after 4 wks. RECIST results: 1 partial response, 20 stable disease, 16 PD (6 not evaluable). 12 (27.9%) had a decreased FDG uptake. Median follow-up was 29.6 months. 3-m PFS was 12.8% (95%CI: 5.7-28.9), median PFS was 2.5 m (IQR: 1.0-3.0). 24-m OS was 14.2% (95%CI: 6.0-33.7). In pts with &gt; 50% STM decline, 24-m OS was 24.1% (95%CI: 8.3-69.6). Univariably, STM was associated with OS (HCG vs AFP: HR: 2.73, 95%CI: 1.24-6.02, p = 0.042). Baseline and +4wks IL8 levels did not predict for PFS/OS. In 2 responding pts, new mutations were found ( FLT3, G846V and RAD50 E448Q classified as damaging; TSC2, R197M and TNF A16V classified as benign). Conclusions: PZP was well tolerated and showed predictable activity, with early but short-living STM decline. Long term survival was obtained in a significant proportion of pts. Based on the present results, PZP may be investigated in earlier disease stages as an optimal bridging therapy preceding salvage curative treatment. Clinical trial information: NCT01743482.