tbuckley/cabot-search huggingface dataset:
Genetic anticipation in BRCA1/2 families after controlling for ascertainment bias and cohort effect.
Authors: Rodrigo Santa Cruz Guindalini, Andrew Song, Dezheng Huo, James Fackenthal, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2014)

1550 Background: Although genetic anticipation has been reported in hereditary breast and ovarian cancer syndrome (HBOCS), little is understood about the underlying genetic and molecular mechanisms for BRCA1/2 families. Two previously unaddressed biases affecting the accuracy of previous studies are ascertainment bias and cohort effect. Methods: We retrospectively reviewed 178 pedigrees of BRCA1/2 families who had at least two consecutive generations of the same cancer (breast or ovarian) in our Cancer Risk Clinic registry. Using paired t-test and BRCAPRO scores as analytical weights in a parametric anticipation model, the calculation of generational differences in breast/ovarian cancer age of onset was performed. This model was then modified to control for ascertainment bias by excluding probands. Multilevel linear regression using breast cancer age of onset, birth year cohort, and generation was applied to study potential cohort effect. Results: Earlier onset of breast cancer and ovarian cancer in successive generations was found (Table). After controlling for ascertainment bias, statistically significant anticipation phenomenonpersisted only for breast cancer. In the cohort effect analysis, generational differences in age of breast cancer onset were not significant but earlier onset in later birth cohorts was significant. Conclusions: To our knowledge, this is the largest study that exclusively included families with deleterious BRCA1/2 mutations, controlled for ascertainment bias, and used individual risks of having BRCA1/2mutations as analytical weights to address and report significant anticipation phenomenon in HBOCS. The observed anticipation effect is due to a decrease in age of onset in the cohort over time and not generational differences. Future studies are warranted to confirm these findings. Anticipation phenomenon in BRCA1/2 families. Breast cancer, N=579 Ovarian cancer, N=81 Gen N Mean AOO (y) Δ From Gen 3 (y) P Gen N Mean AOO (y) Δ From Gen 3 (y) P 1 81 51.8 9.8 <0.001 1 14 57.1 8.4 0.013 2 225 48.7 6.8 <0.001 2 36 53.5 4.8 0.048 3* 242 41.9 0 (ref.) 3* 27 48.8 0 (ref.) 4 31 34.7 -7.2 0.002 4 4 38.3 -10.5 0.038 Abbreviations: AOO, age of onset; Gen, generation; y, years; ref, reference. *, probands’ generation.
CAR T Cells Targeted with a High Affinity Scfv Against the HCMV Glycoprotein Gb As Adoptive T Cell Therapy after Hematopoietic Stem Cell Transplantation
Authors: Renata Stripecke, Laura Gerasch, Sebastian Theobald, Bala Sai Sundarasetty, Maksim Mamonkin, Thomas Shum, Cliona M. Rooney
Journal: Blood (2016)
Routine molecular screening of advanced refractory cancer patients: An analysis of the first 2490 patients of the ProfiLER study.
Authors: Olivier Tredan, Veronique Corset, Qing Wang, Romain Varnier, Camille Pacaud, Alexia Torroja, Nicolas Luppi, Monia Ezzalfani, Magali Myard, Xiaojun Jiang, Valéry Attignon, Daniel Pissaloux, Christian Baudet, Philippe Alexandre Cassier, Jérôme Fayette, Mélodie Carbonnaux, Alice Bonneville-Levard, Alain Viari, David Pérol, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2017)

LBA100 Background: ProfiLER (NCT01774409) is a molecular profiling clinical trial exploring cancer cell genomic alterations in pts with advanced disease to guide treatment. Methods: Pts with confirmed diagnosis of advanced cancers are eligible. DNA extracted from either archival or fresh collected tumor samples was analyzed by targeted exon sequencing of 60 cancer related genes and whole genome array comparative genomic hybridization (CGH). A multidisciplinary molecular board analyzes genomic data and recommends molecular targeted therapies (MTT) when actionable alterations are found. Results: As of Jan 2017, 2490 pts (55% female, median age 59, range 1-90) were consented; 1826 (73.3%) tumors were analyzed, 301 (12%) are ongoing (not done in 363 pts (14.6%) for technical issues). Tumor types were colorectal (10.3%), gyneco (9.5%), breast (8.8%), head &amp; neck (7.1%) carcinomas, sarcomas (7.1%) and brain tumors (6.5%). 940/1826 pts (51.5%) had at least 1 actionable mutation (AM): 579 pts with only one AM, while 358 with 2 or more AM (up to 6). Mutations (including substitutions and small indels), amplifications and homozygous deletions (HD) were observed respectively in 55.3%, 42.1% and 25.5% of tumor samples. The most common AM were on KRAS (n = 156; 8.5%), PIK3CA (n = 150; 8.2%), CDKN2A HD (n = 174; 9.5% ), PTEN HD (n = 49, 2.7%), CCND1 (n = 97; 5.3%), FGFR1 (n = 56; 3.1%), MDM2 (n = 53; 2.9%), HER2 (n = 42; 2.3%) and HER1(n = 41; 2.2%). MTT were recommended in 644 pts. Among them, 101 (gyn [28%], GI [18%], breast [12%]) initiated a recommended MTT. Collection of treatment data is ongoing for 202 pts. MTT received were mTOR inhibitors (39%), anti-angiogenic TKI (21%), EGFR TKI (9.8%), inhibitors of cell cycle (6.9%). Best responses were CR (n = 2, 2.3%), PR (n = 13, 15.1%), SD (n = 29, 33.7%), PD (n = 42, 48.8%), with a median PFS of 2.8 months (95% IC: 2.2-3.5). 24% are alive progression free at 6 months. Updated data will be presented at the meeting. Conclusions: In this series of 2490 cancer pts, CGH and NGS identified actionable alterations on 51% of pts, with treatment recommendation in 35%. Most patients treated derived benefit from the recommended MTT, but these represent a minority of the whole population screened. Clinical trial information: NCT01774409.
Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma
Authors: Tammy Linlin Song, Maarja-Liisa Nairismägi, Yurike Laurensia, Jing-Quan Lim, Jing Tan, Zhi-Mei Li, Wan-Lu Pang, Atish Kizhakeyil, Giovani-Claresta Wijaya, Da-Chuan Huang, Sanjanaa Nagarajan, Burton Kuan-Hui Chia, Daryl Cheah, Yan-Hui Liu, Fen Zhang, Hui-Lan Rao, Tiffany Tang, Esther Kam-Yin Wong, Jin-Xin Bei, Jabed Iqbal, Nicholas-Francis Grigoropoulos, Siok-Bian Ng, Wee-Joo Chng, Bin-Tean Teh, Soo-Yong Tan, Navin Kumar Verma, Hao Fan, Soon-Thye Lim, Choon-Kiat Ong
Journal: Blood (2018)
More Than a Rape Kit
Authors: Elizabeth Chang, Jocelyn Brown
Journal: Annals of Internal Medicine (2017)

On Being a Doctor6 June 2017More Than a Rape KitElizabeth Chang, MD and Jocelyn Brown, MD, MPHElizabeth Chang, MDFrom Rady Children's Hospital, San Diego, California, and Columbia University Medical Center, New York, New York.Search for more papers by this author and Jocelyn Brown, MD, MPHFrom Rady Children's Hospital, San Diego, California, and Columbia University Medical Center, New York, New York.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M16-2139 Audio Reading - “More Than a Rape Kit” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "More Than a Rape Kit," by E. Chang and J. Brown. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail On a seemingly average emergency room shift in the height of winter, I grab the next chart and am relieved that the words following “chief complaint” do not contain any combination of fever, cough, or vomiting. When the actual chief complaint of “sexual assault” registers and my eyes search for your age, complete disquiet washes over me when I read you are only seven. I see now that there are two police officers hovering outside of your room, sticking out like blatant reminders that this will not be a routine visit.Amidst beeping alarms and the rest of the emergency ... Author, Article, and Disclosure InformationAffiliations: From Rady Children's Hospital, San Diego, California, and Columbia University Medical Center, New York, New York.Corresponding Author: Elizabeth Chang, MD, 3020 Children's Way, MC 5075, San Diego, CA 92123; e-mail, [email protected]org. PreviousarticleNextarticle Advertisement Audio Reading - “More Than a Rape Kit” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "More Than a Rape Kit," by E. Chang and J. Brown. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 6 June 2017Volume 166, Issue 11Page: 854KeywordsAssaultAttentionChartsChildrenDisclosureEmergency departmentFeversForensicsSemenVomiting ePublished: 6 June 2017 Issue Published: 6 June 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Prediction of radiation therapy response in breast cancer patients.
Authors: Divya Arora, Salman Hasan, Deborah Jebakumar, Yolanda Munoz, John Ford, Celine Ord, Arundhati Rao, Niloyjyoti Deb
Journal: Journal of Clinical Oncology (2017)

565 Background: While radiation portals are tailored to a patient’s unique anatomy and the selection of systemic agents routinely employs biomarker data, the selection of radiotherapy based on a patient’s tumor biology is not routinely utilized in breast cancer. The purpose of this study was to identify which genetic markers are possible predictors for local recurrence as a surrogate for radiation response. Methods: We identified 200 patients who received radiotherapy for breast cancer. Selected tumor markers included: Androgen receptor (AR), Hypoxia Inducible Factor 1-α (HIF-1), Phosphotidylinosotol-4,5-bisphosphate 3-kinase (PI3K), and Interleukin 13 (IL-13). Biomarkers were analyzed in terms of “extent” and “intensity” on a scale of 0-3 and scored by 2 separate pathologists. The primary endpoint of local recurrence (LR) &amp; secondary endpoint of overall survival were analyzed using Kaplan-Meier survival curves, log-rank test for differences, and Cox regression models. Results: Median follow up was 7.98 years. At 5 years, the rate of LR was 92.6% and overall survival was 89.4%. On multivariate Cox regression analysis, a one unit increase in IL-13 extent increased the hazard of LR by 73%. A one unit decrease in AR extent increased the hazard of LR by 134%. The hazard of death increased 3.2 times for each unit increase in HIF1 extent. The hazard of death increased 1.5 times for each unit increase in PI3K extent. PI3K extent and intensity was increased, and AR extent and intensity was decreased in triple negative breast cancer (TNBC) (n = 68) vs non-TNBC (p &lt; 0.0001). African Americans had a 4.2 times hazard of LR vs Caucasians. Conclusions: Expression of IL-13 was associated with a higher risk of LR; expression of AR was associated with decreased LR. These two markers may be instrumental in predicting radiation response. If this study is validated, cancers that express more IL-13 may require higher doses or targeted therapy. In contrast, those cancers expressing AR may not require as aggressive therapy. Lastly, PI3K and HIF1 α expression were significant predictors of worse overall survival. The clinical implications of these biologic markers are significant as they may help to guide biologically-driven, personalized breast cancer radiotherapy.
Percutaneous Mitral Valve Repair
Authors: Juliëtte F. Velu, Friso A. Kortlandt, Tom Hendriks, Remco A.J. Schurer, Ad J. van Boven, Ben J.L. Van den Branden, Jan A.S. Van der Heyden, Berto J. Bouma, Benno J. Rensing, Jan Baan Jr.
Journal: Journal of the American College of Cardiology (2017)
Risk of breast or ovarian cancer in family members who do not carry the BRCA1 or BRCA2 family mutation: Findings from the EMBRACE study.
Authors: Fabio Girardi, Daniel R. Barnes, Daniel Barrowdale, Debra Frost, Douglas F. Easton, Antonis C. Antoniou
Journal: Journal of Clinical Oncology (2017)

1558 Background: BRCA1/BRCA2 true-negatives are proven non-carriers of the BRCA mutation segregating within their family. Currently, there is no conclusive evidence on the risk of developing breast or ovarian cancer in these individuals, potentially leading to non-uniform clinical practices. The purpose of this study was to estimate breast and ovarian cancer risks for true-negatives from the EMBRACE prospective cohort study. Methods: Risks were calculated separately for incident invasive breast cancer and epithelial ovarian cancer (EOC). We used cohort analysis to estimate incidences, cumulative risks and standardised incidence ratios (SIRs). Results: A total of 1895 unaffected women were eligible for inclusion in the breast cancer analysis and 1736 for the ovarian cancer analysis. There were 23 incident invasive breast cancers and 2 EOCs diagnosed during follow-up. The cumulative risk of invasive breast cancer was 9.4% (95% CI 5.9%-15%) by the age of 85-years, whilst the corresponding risk of EOC was 0.6% (95% CI 0.2%-2.6%). The SIR for breast cancer was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in non-carriers from BRCA1 families and 1.03 (95% CI 0.57-1.87) in non-carriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort and 1.74 (95% CI 0.44-6.98) in non-carriers from BRCA2 families. Conclusions: This is the largest cohort to date of prospectively ascertained true-negatives from BRCA1/ BRCA2 families. Our results did not provide evidence for elevated risks of invasive breast cancer or EOC in proven non-carriers. Risk-reducing bilateral mastectomy and risk-reducing salpingo-oophorectomy may not be appropriate for these individuals. Female relatives of a known BRCA1/BRCA2 mutation carrier should be advised towards genetic testing to avoid unnecessary surgical procedures. However, we were not able to investigate variation in risks by cancer family history. Therefore, we cannot rule out that risks may be slightly higher for close relatives of affected mutation carriers. In such cases, model-based estimates incorporating family history, such as those given by BOADICEA, can be used in the counselling process.
Randomized surgical multicenter trial to evaluate the usefulness of lymphoscintigraphy (LSG) prior to sentinel node biopsy (SLNB) in early breast cancer: SenSzi (GBG80) trial.
Authors: Sherko Kummel, Johannes Holtschmidt, Bernd Gerber, Albert Von der Assen, Joerg Heil, Marc Thill, David Krug, Christian Schem, Carsten Denkert, Juliane Lubitz, Jens Uwe Blohmer, Michael Hötzeld, Fenja Seither, Valentina Nekljudova, Ilka Schwidde, Klara Uhrhan, Gunter Von Minckwitz, Mahdi Rezai, Sibylle Loibl, Thorsten Kuehn
Journal: Journal of Clinical Oncology (2017)

555 Background: It is not clear whether SLNB performed with LSG is necessary to reliably detect sentinel lymph nodes (SLN) in breast cancer. The omission of LSG might offer an accelerated preoperative workflow, cost reduction, and the opportunity for developing innovative, safe detection strategies. Methods: Patients with cN0 early breast cancer or extensive/high grade DCIS received standard radiolabeled colloid LSG and SLNB. Patients were randomized 1:1 to either conducting SLNB with the performing surgeon knowing the preoperative LSG pictures and results or without knowledge of the LSG results. Since the false negative rate (FNR) of SLNB correlates with the number of harvested SLN, our primary endpoint was the average number of histologically detected SLN per patient in both treatment arms in a non-inferiority design. An average number of 2.7 SLN with a standard deviation of 1.8 was assumed. LSG of all patients were collected postoperatively for central review. Results: Between May 2014 and October 2015 n = 1198 patients were randomized in 23 participating breast centers. Baseline characteristics were well-balanced between the treatment arms. Modified intention-to-treat analysis (n = 1163) confirmed the omission of LSG. The average number of histologically detected SLN was 2.207 with LSG and 2.258 without. The range for the one-sided 95% CI for the difference between the arms was (-0.18, +infinity), i.e. above the pre-specified non-inferiority margin of -0.27. Secondary endpoints were analyzed to rule out differences in reliable detection of nodal metastases. Rates of nodal positive disease as identified by SLNB (Odds ratio (OR) 1.005, 95%CI (0.759, 1.33), p = 0.972) and rates of completion axillary dissection (OR 0.984, 95% CI (0.567, 1.71), p = 0.954) in the two treatment arms and in specific subgroups showed no statistically significant differences. Conclusions: Our results support the hypothesis that SLNB is equally effective irrespective of the knowledge of preoperative LSG results. We therefore suggest performing SLNB without LSG to accelerate the preoperative workflow, reduce costs, and improve the comfort for the patients. Clinical trial information: NCT02481128.
Frequency of <i>EGFR</i> gene mutations in patients with lung adenocarcinoma in the southwestern region of Russia.
Authors: Sergey N. Kabanov, Liubov Yu Vladimirova, Evgeniya M. Nepomnyashchaya, Dmitriy I. Vodolazhskiy, Konstantin V. Dvadnenko, Anna V. Antonets
Journal: Journal of Clinical Oncology (2014)

e22209 Background: Asian origin,female sex and non-smoking status in lung adenocarcinomaare associated with increased frequency of EGFR gene mutations. These mutations occur in 5-15% of adenocarcinoma cases in Europe, 40-50% in Asia, 20% in Russia. The purpose of the study was to investigate the occurrence of EGFR gene somatic mutationsin patientswith lung adenocarcinoma in the South-Western region of Russia. Methods: An examination of 176 patients with lung adenocarcinoma from different regions of the South of Russia was made. 106 men and 70 women participated, among them 59 and 4 smokers, 38 and 4 past smokers, 9 and 62 non-smokers respectively. Samples with not less than 20% of tumor cell content were used for a molecular genetic study. DNA was extracted from paraffin-embedded tissue blocks. The procedure of DNA extraction was conducted with the use of QIAamp DNA FFPE Tissue Kit (QIAGENE, Germany) after standard deparafinization with ortho-xylene. A detection of 29 EGFR gene somatic mutations was performed with EGFR RGQ PCR Kit (QIAGENE, Germany) with the use of Rotor-Gene Q thermocycler (QIAGENE, Germany). Results: According to the findings, general mutation frequency in 19-21 EGFR exons in patients with lung adenocarcinoma in the South of Russia amounted 22,3%. 30 women (42,9±1,4%) and 9 men (8,5±0,9%) (p < 0,01), among whom there were 2 smoking women and 4 men, 27 non-smoking women and 2 men, 1 former smoking woman and 3 men, had the mutation. Thus, among patients with EGFR gene mutation there were 29 non-smokers (74,4±2,6%), 4 past-smokers (10,3±2,6%) and 6 smokers (15,4±2,6%) (р < 0,01) (Student’s t-test). Conclusions: The results confirm “intermediate” frequency of EGFR gene mutations in Russia in comparison with Europe and Asia, and the correlation with smoking status. Gender difference is probably caused by a high percentage of non-smoking women and low percentage of non-smoking men.
Phase I/II study of amrubicin and nedaplatin in patients with untreated, advanced non-small cell lung cancer.
Authors: Hiroaki Senju, Daiki Ogawara, Yoichi Nakamura, Minoru Fukuda, Katsumi Nakatomi, Hiroshi Gyotoku, Hirofumi Nakano, Hiroyuki Yamaguchi, Nanae Tomonaga, Takaya Ikeda, Kosuke Mizoguchi, Kohei Motoshima, Seiji Doi, Kazuhiro Tsukamoto, Shigeru Kohno
Journal: Journal of Clinical Oncology (2012)

7569 Background: We conducted a phase I/II study of combination chemotherapy with nedaplatin (CDGP) and amrubicin (Amr) for patients with untreated, advanced non small-cell lung cancer (NSCLC). Methods: Eligible patients were having adequate organ function and PS of 0-1. CDGP was given on day 1 and amrubicin on days 1, 2 and 3. The treatment was repeated every 3 weeks. We fixed the dose of CDGP as 100 mg/m2, and escalated the dose of amrubicin from a starting dose of 25 mg/m2 by 5mg/m2 per each levels until the maximum tolerated dose (MTD). The MTD was defined as the dose level at which at least two of three or two of six patients experienced a dose-limiting toxicity (DLT). Results: Between June 2009 and May 2011, 36 patients were enrolled. In the phase I study, two DLTs occurred in six patients at level 2; dose level 1 was therefore recommended (25 mg/m2 Amr, 100mg/m2 CDGP). DLTs included cerebral infarction and grade 4 thrombocytopenia. In the phase II study, including phase I study, a total of 36 patients were enrolled and 132 cycles of chemotherapy were conducted. Grade 3 or 4 neutropenia, grade 3 anemia and grade 3 or 4 thrombocytopenia occurred in 75%, 16.6% and 19.4% in all cycles, respectively. Febrile neutropenia occurred in 4cycles (3%) but all of them were controllable. Eighteen patients achieved a partial response and the overall response rate was 51.4%. Conclusions: Combination of CDGP and Amr was highly effective and well tolerable in patients with untreated, advanced NSCLC.
A young goalkeeper with buttock pain and fever
Authors: Valentina Moressa, Serena Pastore, Samuele Naviglio, Alessandro Ventura
Journal: BMJ (2017)

A previously healthy 13 year old boy presented to the emergency department with pain in the right buttock and fever. Five days earlier he had fallen diving to catch a ball during a football match, and two days later had a fever of up to 39°C and had started to complain of buttock pain. Physical examination on presentation was unremarkable except for pain on abduction of the right hip, with limited range of motion. Radiography of the pelvis was normal. Oral ketoprofen was prescribed for pain and he was discharged. Three days later the pain had worsened and he was still feverish. He returned to the emergency department. Physical examination was unchanged from the previous visit. Ultrasonography was performed on the right hip, which was normal. Laboratory findings included elevated C reactive protein (155.4 mg/L, normal values <5) and erythrocyte sedimentation rate (56 mm/h, normal values <20), and leucocytosis (leucocyte count 17 × 109/L (normal range 4.0-10.5 × 109/L), with 88% neutrophils (normal range 50-65%)), with normal haemoglobin and platelet count. Creatine kinase levels were within the normal range and blood cultures were negative. Magnetic resonance imaging (MRI) of the pelvis was performed (fig 1⇓).



Fig 1  Magnetic resonance imaging of the pelvis after gadolinium infusion (T1 weighted, turbo spin echo with fat suppression)



1.  What is the most likely diagnosis?

2.  What complications can arise?

3.  How is this condition managed?

### 1. What is the most likely diagnosis?

#### Short answer

Pyomyositis of the right gluteus maximus muscle. There are no specific laboratory tests for pyomyositis; MRI is the gold standard for diagnosis.

#### Discussion

MRI shows marked enhancement of the right gluteus maximus muscle, with distortion of the muscular fibres (fig 2⇓ …