tbuckley/cabot-search huggingface dataset:
Systematic improvement of SBRT dose gradients.
Authors: Patrick James Gagnon, Sheri Weintraub, Amanda Scott, Deborah Schofield, Tushar Kumar, Therese M. Mulvey
Journal: Journal of Clinical Oncology (2012)

154 Background: Stereotactic body radiation therapy (SBRT) offers excellent local control for early stage lung cancer. SBRT utilizes high fractional doses of radiation in 5 or fewer treatments. Normal tissue risk is substantial necessitating steep dose gradients and conformal plans. The Radiation Therapy Oncology Group (RTOG) has established quality metrics for conformality and dose gradients for SBRT. The conformality ratio is the prescription isodose volume to the planning target volume (PTV). Dose falloff is represented by the ratio of the 50% prescription isodose volume to PTV volume (R50%). We evaluated our approach and identified a systematic method to improve our SBRT plans in a community cancer center setting. Methods: 26 lung nodules were treated with SBRT over 30 months at our institution. RTOG 0915 benchmarks were evaluated. Conformality ratios were excellent in all cases. Dose falloff was measured by the R50% and the 7 cases with the largest R50% were re-planned systematically. The technique included creation of a customized ring structure: PTV volume was multiplied by the maximum allowable ratio to establish an ideal 50% isodose volume and a 2 cm ring structure was created around this: the 50 IDV Ring. Intensity modulated radiation therapy (IMRT) optimization specified a max dose to the 50 IDV Ring of 50% of the prescription. Beam geometry and IMRT objectives were held constant from the initial plan. Results: Conformality ratios were maintained and were excellent in all cases. The 50 IDV Ring resulted in R50% improvements in 5 of 7 cases, 4 of which had at least a 15% improvement (15%, 20.6%, 19.2%, and 20.4%) and 1 of which had a 3.3% improvement. Two cases resulted in 1.8% and 0.5% increases in the ratio representing a small deterioration in dose falloff. Conclusions: A strategically designed ring structure can have an impact on dose falloff around a target volume resulting in improvements in dose gradients for SBRT plans. Whether this benchmark is clinically significant is uncertain but it does provide a useful metric for comparison and quality assurance of SBRT plans. A systematic approach to SBRT planning may help provide the highest possible therapeutic ratio in the setting of optimal beam geometry.
Translational investigations of gastrointestinal malignancies using spheroid cultures.
Authors: Evie Carchman, Susan Payne, Cheri Pasch, Kristina Matkowskyj, Sam Joseph Lubner, Michael F. Bassetti, Noelle K. LoConte, Daniel Mulkerin, Dustin A. Deming
Journal: Journal of Clinical Oncology (2016)

620 Background: Spheroid cultures are now being used to investigate the biology of multiple types of cancer. This technique allows for a cost-effective, efficient and reliable means to culture tissues of interest. Recent investigations have demonstrated that spheroids maintain high mutational concordance with the cancers they are derived. We sought to determine if spheroid techniques could be utilized to perform translational investigations into subtypes of gastrointestinal malignancies. Methods: Transgenic mice carrying conditional mutations in key genes known to have important roles in colorectal cancer (CRC) tumorigenesis and progression were treated with a Cre-expressing adenovirus to initiate tumorigenesis. The mutant genes of interest included Apc, Trp53, KRAS, Pik3ca, and/or BRAF. Biopsies of these cancers were obtained with the murine endoscope and the tissue processed for spheroid culture. In addition, transgenic E6 and E7 mice were treated with DMBA and the resulting anal squamous cell carcinomas were harvested for spheroid culture. Cultured spheroids were imaged to characterize growth rate and changes in architecture. In addition, studies assessing response to therapeutics were performed and correlated with in vivo response. Human operative specimens were also obtained for culturing. Results: Multiple lines of murine CRC spheroids were able to be generated with a greater than 90% efficiency rate. These cultures maintained phenotypic characteristics of the cancers from which they were derived. Bright field imaging pre- and post-treatment was able to be utilized for quantification of treatment response. The median relative change in spheroid diameter was compared across treatment groups and correlated with response in vivo. Heterogeneity in the response of individual spheroids to treatment strategies was detected with this method. Murine squamous cell anal carcinoma was spheroid lines were generated similarly. Human CRC and anal cancers were also generated with high efficiency. Conclusions: Spheroid cultures from CRC and anal cancers can be generated with high efficiency and hold great promise for furthering treatment options for patients with cancer.
Amino Acid Substitution At Peptide-Binding Pockets of HLA Class I Molecules Adversely Impacts Hematopoietic Cell Transplantation Outcomes
Authors: Joseph Pidala, Tao Wang, Michael D Haagenson, Stephen Spellman, Medhat Askar, Minoo Battiwalla, Lee Ann Baxter-Lowe, Menachem Bitan, Marcelo Fernandez-Vina, Manish Gandhi, Ann A. Jakubowski, Martin Maiers, Susana R. Marino, Steven GE Marsh, Machteld Oudshoorn, Jeanne Palmer, Vinod K. Prasad, Vijay Reddy, Olle Ringden, Wael Saber, Stella Santarone, Kirk R. Schultz, Michelle Setterholm, Elizabeth Trachtenberg, Vicky Turner, Ann Woolfrey, Stephanie J. Lee, Claudio Anasetti
Journal: Blood (2012)
Hypoplastic MDS Is a Distinct Clinico-Pathological Entity with Somatic Mutations Frequent in Patients with Prior Aplastic Anaemia with Favorable Clinical Outcome
Authors: Alesia Abigael Hunt, Anjum Bashir Khan, Victoria T Potter, Donal McLornan, Kavita Raj, Hugues de Lavallade, Antonio Pagliuca, Alexander E Smith, Judith C Marsh, Austin Kulasekararaj, Ghulam J Mufti
Journal: Blood (2014)
A multicenter randomized phase II study of NPC-1C (N) in combination with gemcitabine (G) and nab-paclitaxel (A) versus G and A alone in patients with metastatic or locally advanced pancreatic cancer (PC) previously treated with folfirinox (F).
Authors: Austin G. Duffy, Muhammad Shaalan Beg, Tim F. Greten, Melony A. Beatson, Sharon Mavroukakis, Sandip Pravin Patel, Michael A. Morse, Philip M. Arlen
Journal: Journal of Clinical Oncology (2015)

TPS499 Background: PC carries a poor prognosis. F has improved overall survival (OS) compared to G leading to its use as a 1st line treatment for patients (pts) with advanced PC. Similarly, the combination of G and A has demonstrated OS benefit. No data exists for G/A in the 2nd line setting. Many oncologists continue to sequence F treatment followed upon disease progression by G/A for pts with advanced PC with good performance status. N is a chimeric monoclonal IgG1 antibody recognizing an aberrantly glycosylated MUC5AC specific to GI tumors. Its mechanism of action is through ADCC. An IHC based companion diagnostic assay is utilized to select pts whose tumors express the target (approx. 65-70%). A prior study administering N to pts with advanced PC refractory to chemotherapy was well tolerated with disease stabilization and prolongation of OS. Furthermore 2 of 5 pts receiving the combination of G+N following progression on F remain alive at 10 and 12 months respectively. Methods: The primary objective of this phase 2.5 study is to determine if the combination of N and G plus A can improve the OS for pts who have PC over G plus A alone in the post F setting. The trial is a 2-arm randomized 1:1 multi-institution trial of N plus G and A vs. G and A. Eligible pts would be expected to have an estimated 4.5 to 4.8 month median OS with G alone, but this may be enhanced somewhat with the addition of A. The goal is to determine if the use of N along with G and A will result in pts having an increased median OS of 8 months vs. an estimated 5 months without N. Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods. All pts must have tissue positive for the MUC5AC variant (≥20% by IHC). Because N has been established to be safe when given with G alone but not with the combination of G and A, stopping rules for safety will be adhered to for the first 6 pts randomized to G/A plus N. Enrollment to the study has commenced. Correlative studies will utilize both PBMCs and serum for immune monitoring. Frequency, phenotype and function of different immune cells (including CD8+ T cells, CD4+ T cells, Tregs and MDSCs) will be analyzed. Clinical trial information: NCT01834235.
A randomized controlled trial (RCT) of 2 dose ratios for conversion from parenteral to oral methadone in patients with cancer pain.
Authors: Jesus Gonzalez-Barboteo, Josep Porta-Sales, Maria Nabal-Vicuña, Leyre Diez-Porres, Jaume Canal, Alberto Alonso-Babarro, Yolanda Vilches, Silvia Llorens, Mireia Sanllorente, Silvia Perez-Pujol, Eduardo Bruera
Journal: Journal of Clinical Oncology (2016)

206 Background: Methadone (M) is frequently used for severe cancer pain using the parenteral and oral route. The most commonly used dose ratio (DR) parenteral: oral is 1:2. However, methadone is highly bioavailable and a lower ratio might result in similar analgesia with less toxicity. The main objective of this RCT is to compare success and side effects with 2 ratios of parenteral to oral M: 1:2 vs 1:1.2 in hospitalized patients with cancer pain. Methods: Inpatients with cancer pain well controlled with parenteral M requiring rotation to the oral route. Double blind RCT. Outcomes included pain intensity (BPI), opioid toxicity (CTCAE), and M dose. Success was defined as good pain control with no toxicity at 72hs. Results: 39/44 randomized patients were evaluable (89%): 21 in DR 1:2 and 18 in DR 1:1.2. 71% male, median age 65. No significant difference between DR1:2 and DR1:1.2 in frequency of neuropathic pain (64 Vs 68%), Papscore A/B (100 Vs 91%), CAGE + (23 Vs 18%). Median M dose pre/post was 24.5mg±13.5 y 49 mg±27.3 for DR 1:2, Vs 23.3mg±9.4 (p: NS) y 28mg±11.3 (p &lt; 0.01) for DR 1:1.2. The DR1:2 group developed more cumulative toxicity at dasy 1, 2 and 3 (p &lt; 0.015, p &lt; 0.006 y p &lt; 0.001 respectively). Pain intensity pre/ post was: 1.58±1.3 and 0.87±1.0, ns for DR 1:2, Vs 1.13±0.7 (p:NS) and 1.07±0.9 (p:NS) for DR 1:1.2. Success was observed in 12 pts in DR1:2 Vs 18 in DR 1:1.2, p &lt; 0.001. Side effects related to M were observed in 33/46 pts in DR 1:2 (mainly neurotoxicity symptoms) Vs 1/6 in DR 1:1.2. Conclusions: DR 1:1.2 when changing from parenteral to oral M resulted in lower toxicity and no difference in analgesia. More conservative dose adjustment during M route change should be considered. Granted by Spanish Ministry of Health EC10-133. EUDRACT Number: 2010-024092-39. Clinical trial information: 2010-024092-39.
Benefits of cover makeup for survivors.
Authors: Takako Wakeda, Yuji Heike
Journal: Journal of Clinical Oncology (2016)

259 Background: Cancer therapy causes various appearance changes, such as chemotherapy-induced alopecia and skin pigmentation. These events decrease cancer survivors’ QoL (quality of life), and sometimes deprive them of social life and work opportunities. Even though wigs are commonly accessible to care hair loss, the way has not been established to care visual changes in skin. Our previous interview survey revealed that visual changes in skin depressed cancer survivors and their daily life were also interrupted, e.g., “I cannot go swimming with this wound” and “I don’t like to see anyone due to the pigmented face.” Therefore, we decided to try to adapt cover makeup technique for survivors in order to increase their QoL and recover their confident. This study was performed to examine whether “cover makeup” on the skin appearance changes could contribute to the patient with cancer’s QoL. Methods: Cover makeup was supplied for the cancer survivors, including a special cream that matched each individual’s skin color. The QoL values (Skindex-16 and visual analog scale) were compared before and 2–3 months after the first makeup instruction. The participants used cover makeup in this follow-up period freely. Results: Almost all visible changes in skin were completely concealed with cover makeup among 43 participants (breast, 23; thyroid, 11; stomach, five; leukemia, two; others, two), including only two male patients. Skindex-16 and visual analog scale values improved in all participants, regardless of the diagnosis, cause or site of skin problems. Conclusions: Using subjective scales, this study showed that cover makeup can improve patients with cancer’s QoL. Appearance changes caused by life-saving treatments tend to be dismissed but more attention should be paid to appearance care to enable patients with cancer to experience better QoL. Our results suggest that cover makeup is helpful and important for survivors’ daily living. Clinical trial information: UMIN000011652.
末梢動脈疾患に対する最先端治療戦略 7 重症下肢虚血に対する創傷治療
Authors: 木村勇亮, 大浦紀彦, 梶谷彩奈, 多田朋子, 菅浩隆, 多久嶋亮彦, 波利井清紀
Journal: Circulation (2014)
Palliative care consultation for patients enrolled in cancer clinical trials.
Authors: Ryan David Nipp, Elizabeth Powell, Beverly Moy
Journal: Journal of Clinical Oncology (2015)

139 Background: Cancer clinical trials often enroll patients with advanced cancer, yet trial participation should not preclude the appropriate use of palliative care (PC) services for these patients. We sought to describe rates and correlates of PC consultation in clinical trial patients and identify factors associated with use of PC. Methods: We prospectively collected data on patient characteristics and rates of PC consultation among all patients enrolled in cancer clinical trials at Massachusetts General Hospital in 2014. We used multiple logistic regression with purposeful selection of covariates to identify factors associated with PC consultation. Results: Of 1,218 clinical trial patients (mean age = 58 years; 643 (53%) female), 781 (64%) were married and 851 (70%) had metastatic disease. All cancer types were represented, but hematologic cancers (21%) were most common. Of those who had tumor genotype testing, 340 (62%) had a somatic mutation. Overall, 177 (15%) received PC consultation. Of those with metastatic disease, 149 (18%) received a PC consult. Metastatic disease, being unmarried, and absence of a somatic tumor mutation correlated with receipt of a PC consult. Conclusions: We found that a minority of cancer clinical trial patients receive PC consultation. Having metastatic disease and being unmarried correlated with receipt of PC consultation, thus highlighting a population likely needing additional supportive care. Presence of a somatic mutation was inversely associated with receiving PC consultation, suggesting that disease biology may impact patients’ supportive care needs or presence of these mutations influences clinician decisions about the need for PC services. These data help identify the factors associated with appropriate use of PC, and add to our understanding about the use of these services in cancer clinical trial patients. [Table: see text]
One-off sigmoidoscopy screening cuts bowel cancer risk for 17 years, UK study finds
Authors: Susan Mayor
Journal: BMJ (2017)

One-off screening sigmoidoscopy reduces the risk of developing bowel cancer by nearly a third, and this risk protection lasts at least 17 years, a large randomised trial in the UK has shown.1

The UK Flexible Sigmoidoscopy Screening Trial randomly allocated 170 432 men and women aged 55-64 (mean age 60) to flexible sigmoidoscopy screening or to a control group, who were not offered screening. All participants had previously indicated in a questionnaire that they would probably attend for screening if invited. None of the participants …
Analysis of putative resistance mechanisms in recent treatments targeting the androgen receptor in castration-resistant prostate cancer (CRPC).
Authors: Paul Thelen, Eiko Walleck, Felix Bremmer, Lutz Trojan, Arne Strauß
Journal: Journal of Clinical Oncology (2013)

130 Background: Recent breakthrough therapies targeting androgen receptor signalling in CRPC involve multifunctional androgen receptor (AR) blockade and exhaustive androgen deprivation. Nevertheless, limitations to an enduring effectiveness of new drugs are anticipated in resistance mechanisms occurring under such treatments. Here we specify the origin of CYP17A1 up-regulation under abiraterone acetate treatment in CRPC cell models. Methods: CRPC cell models VCaP and LNCaP as well as AR-negative PC-3- and non-neoplastic epithelial BPH-1-cells were treated with various concentrations of abiraterone hydrolyzed from abiraterone acetate (AA, Janssen-Cilag, Germany). Functional analyses by RNA interference were done with AR- and CYP17A1-siRNA. Expression of androgen regulated genes and CYP17A1, AKR1C3 was quantitated by real time PCR. Protein analyses were performed by western blots and PSA secretion was assessed by ELISA kits. Results: AA treatments (5 to 25 µM) of AR positive CRPC cell models led to decreased expression of androgen regulated genes such as PSA. In these cells diminished expression of androgen regulated genes was accompanied by an up-regulation of CYP17A1 expression (&gt;2-fold at 25µM AA) within short treatments of 24 hours. No such effects became evident in AR-negative PC-3 cells. AR directed siRNA (siAR) used in VCaP cells significantly reduced mRNA expression and AR protein abundance. Such interference with AR signalling in the absence of AA also caused an (up to 8-fold) up-regulation of CYP17A1 expression. Conclusions: In AR-positive cells AA treatments cause a down-regulation of androgen regulated genes in spite of an elevated expression of CYP17A1, the very target enzyme for this drug. CYP17A1 up-regulation already occurs within 24 hour treatments of AA and does not require adaptation events over several cell cycles. CYP17A1 is also up-regulated in the absence of AA when AR signalling is physically eliminated by siAR. These results reveal an immediate counter-regulation of CYP17A1 expression whenever AR-signalling is inhibited adequately but not a persisting adaptation yielding drug resistance.
High dose rate intraoperative radiation therapy for recurrent head and neck cancer: The importance of in-field control on survival.
Authors: L. B. Harrison, W. F. Mourad, M. Perksy, M. Urken, A. Jacobson, B. Culliney, T. Tran, S. P. Schantz, P. Costantino, K. Hu
Journal: Journal of Clinical Oncology (2011)

5593 Background: High dose-rate intraoperative radiation therapy (HDR-IORT) offers an opportunity to salvage recurrent patients (pts) and dose-escalate therapy. Methods: From 1/01-2/10, 90 pts with primary (n = 13) or recurrent (n = 77) head and neck cancer total of 101 sites were treated with HDR-IORT. A single fraction (median, 12 Gy; range, 10–17.5 Gy) at a depth of 1cm from the source was delivered after gross total surgical resection (GTR) to close or positive margins. 11 of 90 pts received HDR-IORT to 2 separate sites. Sites treated were; neck 54%, face 13%, parapharyngeal space 11%, parotid 7%, nasal cavity/paranasal sinus 7%, skull base 4% and other 4%. Histology was squamous cell carcinoma 82%, salivary gland 12%, sarcoma 4%, skin 1%, and esthesioneuroblastoma 1%. GTR was obtained in all pts with positive margins in 51%. Flap reconstruction was performed in 65%. Additional chemoradiotherapy was given to median dose of 45Gy (31-69Gy). Results: No intraoperative complications related to HDR-IORT. Late complications included osteoradionecrosis (1), soft tissue necrosis (1) and carotid blowout (1). Median follow-up 11 months, the KM estimate of 1 year OS was 66%, DFS 51%, in-field failure (IFF) 35%, out-of-field failure (OFF) 22% and distant metastasis (DM) 31% for all pts. Margin status impacted on IFF (1yr 14% vs. 44%, p = 0.0138) and DFS (66% vs. 39%, p=0.059) in pts with negative versus positive margins, respectively, but not OS (1yr 76% vs. 58% p=0.46), OFF (1yr 22% vs. 21% p=0.35) or DM (35% vs. 31% p=0.90), respectively. Compared to pts with IFF, those with in-field control had improved survival (median OS 45 vs 17 ms, p=0.0136) while those who developed DM had similar OS compared to those who were DM-free (median OS 28 vs 19ms, p=0.17). Conclusions: HDR-IORT is a safe and effective modality in conjunction with radical resection and flap reconstruction in pts with recurrent or primary head and neck cancer. Margin status is the most important predictor of in-field control and DFS. In-field control extends OS in this challenging group of pts.
CREBBP Mutations In Relapsed Acute Lymphoblastic Leukemia
Authors: Charles Mullighan, Jinghui Zhang, Lawryn H. Kasper, Stephanie Lerach, Debbie Payne-Turner, Letha A Phillips, J. Racquel Collins-Underwood, Susan L. Heatley, Jing Ma, Kenneth Buetow, Ching-Hon Pui, Paul K. Brindle, James R. Downing
Journal: Blood (2010)
Neurocognitive function (NCF) in patients (pts) treated with chemo/bio-radiotherapy (C/B-RT) for head and neck cancers (HNC).
Authors: A. R. Abdul Razak, L. L. Siu, A. Chan, G. R. Pond, K. M. Tirona, E. X. Chen, A. J. Hope, J. Ringash, B. O'Sullivan, J. N. Waldron, K. Chan, H. K. Gan, L. J. Bernstein
Journal: Journal of Clinical Oncology (2011)

5522 Background: There is evidence that cancer and/or its treatment can impair thinking abilities. To date, there have been no longitudinal studies exploring NCF in HNC pts. We present a prospective NCF assessment in HNC pts treated with C/B-RT. Methods: Baseline information including pt demographics, primary tumor site, stage, smoking/alcohol history, systemic therapy details and RT dosimetry were collected. All pts underwent a 2-hour battery of NCF testing at baseline and at 1-year (yr). Domains evaluated included memory, motor skills, intelligence, language, attention, processing speed and executive function (EF). Performances on the various tests were transformed to Z-scores using normative data. NCF decline was defined as a Z-score decrease of ≥-1 and improvement as a Z-score increase of ≥+1. Pts also had subjective assessments of anxiety, depression, NCF and quality of life (QOL) using the Hospital Anxiety and Depression Scale and FACT questionnaires. QOL was considered significantly altered if FACT score changes were ≥ +10 (improvement) / -10 (decline). Results: Pt demographics (n= 24) were M:F= 19:5, mean age= 61.2, CRT(cisplatin):BRT(panitumumab):RT= 14:6:4, oropharynx:other= 21:3. At 1-yr, 6 pts (25%) had NCF decline in at least one cognitive domain, with memory and attention being most frequently affected (n= 3 each). Three of 6 pts with NCF decline had multiple domains affected, most frequently in memory, attention and EF. One pt with NCF declines in intelligence, memory and attention received the highest RT dose to the frontal and temporal lobes. Five pts had NCF improvements, albeit only in a single domain each. Although 96% of pts did not report severe levels of anxiety or depression, more pts subjectively reported lower NCF (46%) and QOL (33%) than those reporting higher NCF or QOL (17% and 8% respectively) at 1-yr. There was no clear association between changes in objective NCF and changes in subjective NCF or QOL. Conclusions: C/B-RT in HNC pts may be associated with NCF decline at 1-yr and can affect multiple domains. Subjective declines in NCF and QOL were more frequent than objective NCF declines. Longer-term follow up is underway to further characterize these findings.