tbuckley/cabot-search huggingface dataset:
Reactivation of tuberculosis in cancer patients following administration of immune checkpoint inhibitors: current evidence and clinical practice recommendations
Authors: Amalia Anastasopoulou, Dimitrios C. Ziogas, Michael Samarkos, John M. Kirkwood, Helen Gogas
Journal: Journal for ImmunoTherapy of Cancer (2019)

Immune checkpoint inhibitors (ICBs) have revolutionized cancer treatment producing remarkable and durable responses for a range of malignancies. However, the additional modulation of immune response by ICBs may rarely cause immune-related infectious complications, including re-activation of latent tuberculosis infection (LTBC) with detrimental effects on those patients' outcome. Here, we present two "real-world" melanoma cases that were treated in our department with blockade of PD-1/PD-L1 and developed active <i>Mycobacterium tuberculosis</i> (MTB) during immunotherapy. In view of these cases, we review the literature for ICB-associated MTB reactivation and discuss our considerations about the possible interactions of immunotherapy and the underlying co-existent mycobacterial infection. Based on the current evidence from preclinical findings prior to this experience, we raise questions regarding cancer patients who are at higher risk for developing MTB infection, whether ICB-treated patients should be considered immunocompromised, and how they should be managed for latent and/or active tuberculosis. Aside from the well-established clinical benefit of immunotherapy, the blockade of PD-1/PD-L1 axis may concurrently disrupt the immune control of specific opportunistic infections such as tuberculosis that should be carefully and expectantly managed in order to avoid compromising the outcome of cancer treatment and the affected patient's survival.
Renal atrophy secondary to chemoradiation treatment of abdominal malignancies
Authors: K. S. Salerrno May, G. Y. Yang, R. V. Iyer, R. Chandrasekhar, G. Wilding, N. I. Khushalani, S. S. Yendamuri, J. F. Gibbs, M. Fakih
Journal: Journal of Clinical Oncology (2009)

e15532 Background: Information on renal atrophy following abdominal chemoradiation (CRT) is limited. Methods: Patients who received concurrent CRT to the abdomen between 2002 and 2008 were identified for this study to evaluate change in renal size (RS) and function following CRT. Imaging and biochemical data were obtained prior to radiation (RT) and after RT in 6 month intervals. RS was defined by craniocaudal measurement on CT images. Renal function was assessed by serum creatinine and creatinine clearance (CrCl) using the Cockcroft-Gault formula. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Results: Median patient age was 64 years (range 31–87), 51.5% of 130 patients were male. Primary disease sites were pancreas (61.5%), periampullary (16.1%), stomach (10.8%), gastroesophageal junction (10%), and retroperitoneum (1.5%). Median follow up was 9.4 months (range 0–55.4 mos). Median radiation dose was 50.4Gy (range 12.6- 55.8Gy). Mean dose to the PK was 18.6 Gy. Compensatory hypertrophy of the non-PK was not seen. Age, gender, hypertension, diabetes, smoking, pre-RT CrCl, and pre-RT RS were not associated with renal atrophy at 12 months post RT. Percent volumes of the PK receiving ≥10Gy (V 10 ), 15Gy (V 15 ), and 20Gy (V 20 ) were significantly associated with renal atrophy at 12 months post RT (p=0.0030, 0.0041, and 0.0046 respectively). Conclusions: Significant detriments in PK size and renal function were seen following abdominal CRT. V 10 , V 15 , and V 20 were associated with renal atrophy at 12 months post RT. These observations can assist with renal dose constraints in CRT treatment planning for patients at increased risk for renal complications. [Table: see text] No significant financial relationships to disclose.
P14.17 Differentiation of treatment-related changes from tumor progression: A direct comparison between dynamic FET PET and ADC values obtained from DWI MRI
Authors: J Werner, G Stoffels, T Lichtenstein, J Borggrefe, P Lohmann, G Ceccon, G R Fink, K Langen, C Kabbasch, N Galldiks
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Following brain cancer treatment, the capacity of anatomical MRI to differentiate neoplastic tissue from treatment-related changes (e.g., pseudoprogression) is limited. This study compared apparent diffusion coefficients (ADC) obtained by diffusion-weighted MRI (DWI) with static and dynamic parameters of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of treatment-related changes from tumor progression. MATERIAL AND METHODS Forty-eight pretreated high-grade glioma patients with anatomical MRI findings suspicious for progression (median time elapsed since last treatment, 16 weeks) were investigated using DWI and dynamic FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) as well as dynamic parameters (time-to-peak and slope values) of FET uptake were calculated. For mean ADC calculation, regions-of-interest analyses were performed on ADC maps calculated from DWI co-registered with the contrast-enhanced MR image. Diagnoses were confirmed neuropathologically (21%) or clinicoradiologically. Diagnostic performance was evaluated using receiver-operating-characteristic analyses or Fisher’s exact test for a combinational approach. RESULTS Ten of 48 patients had treatment-related changes (21%). The diagnostic performance of FET PET was significantly higher (threshold for both TBRmax and TBRmean, 1.95; accuracy, 83%; AUC, 0.89±0.05; P&lt;0.001) than that of ADC values (threshold ADC, 1.09x10-3 mm2/s; accuracy, 69%; AUC, 0.73±0.09; P=0.13). The addition of static FET PET parameters to ADC values increased the latter’s accuracy to 89%. The highest accuracy was achieved by combining static and dynamic FET PET parameters (93%). CONCLUSION Data suggest that static and dynamic FET PET provide valuable information concerning the differentiation of early treatment-related changes from tumor progression and outperform ADC measurement for this highly relevant clinical question.
Norman Kirby: army surgeon who parachuted into Suez
Authors: Marika Davies
Journal: BMJ (2019)

When Norman Kirby was training with the Parachute Regiment during the Suez crisis of 1956, he received some sound advice: to practise operating with fewer and fewer instruments. As a surgeon parachuting into a battlefield he would need to carry his own equipment, which meant choosing the absolute minimum required to perform adequate field surgery.

In the early morning of 5 November the assault on El-Gamil airfield in Suez began. Landing in “perfect parachuting weather,” and with smoke and explosions creating “a Guy Fawkes atmosphere,” Kirby and his team’s orders were to convert garages by the control tower into a field hospital and from here perform lifesaving surgery.

The fighting was fierce, and the hospital was soon receiving casualties. Difficulties were encountered but swiftly overcome: a soldier parachuting in with the field steriliser was waylaid, but a wounded chef who had parachuted in with his catering equipment had this put to good use—first to boil the surgical instruments, and then to make tea “for the resuscitation of both casualties and staff.” …
P11.49 An electrophysiological signature of glioma infiltration in the ex vivo human brain
Authors: A J Kirby, J P Lavrador, C Brogna, F Vergani, C Chandler, B Zebian, I Bodi, R Bhangoo, K Ashkan, G T Finnerty
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Invading glioma cells affect the physiological function of the peritumoural cortex. This may manifest clinically as seizures. Here, we investigate the effect the invading glioma cells on the electrophysiological signalling of the peritumoral cortex using living human brain tissue donated by people having a craniotomy for glioma resection (REC approval, 18/SW/002). MATERIAL AND METHODS The brain tissue was cut into thin slices, which preserved the architecture of the glioma and the adjacent healthy brain. The brain slices were incubated in 5-aminolevulinic acid to make the glioma cells fluorescent. We observed 5-ALA induced fluorescence in both low-grade and high-grade gliomas. This enabled us to make electrophysiological recordings of brain activity across the boundary between glioma and brain. RESULTS We recorded from brain slices of 5 participants with glioblastoma and 4 participants with oligodendroglioma (WHO grade II - III). Spontaneous “seizure-like” discharges were recorded in brain slices from 5/8 participants (3 GBM, 2 oligodendroglioma) who reported seizures and from one participant (GBM) who had not had any clinical seizures. Further analysis of the electrical discharges revealed that they could be subdivided into two distinct types based on the major frequencies in the discharge. CONCLUSION We concluded that human brain slices from people with either a low-grade or a high-grade glioma can generate spontaneous seizure-like discharges. This electrophysiological signature will be compared to infiltration and grade of the glioma cells in the donated sample. The living human brain tissue preparation gives us a platform to study the mechanisms of tumour-associated seizures and how abnormal neural activity affects glioma growth.
OS12.2 Targeting epigenetic pathways in the treatment of recurrent high-grade glioma
Authors: A Hau, L Houben, E Klein, A Oudin, D Stieber, B Flies, T Kaoma, F Azuaje, S Fritah, R Bjerkvig, F Hertel, M Mittelbronn, A Golebiewska, S P Niclou
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND High grade glioma (HGG) patients develop resistance to standard treatment leading to disease progression and limited life expectancy. Advances in the molecular characterisation of treatment-naïve HGGs based on next-generation sequencing and DNA methylation analyses have led to a better delineation of HGG subtypes and the identification of distinct genomic abnormalities. Furthermore, using large patient cohorts of longitudinal tumor samples, comprehensive genomic profiling studies emerged to investigate therapy-associated evolution of gliomas. All together, those studies point out the need for personalised treatment strategies, where applied drugs will be adapted to the unique patient-specific genetic abnormalities. MATERIAL AND METHODS We collected fresh samples of more than 800 brain tumors containing almost 300 glioma specimen with approximately 100 longitudinal samples of initial and recurrent tumors from 43 matched patients. By now, we have successfully established 34 patient-derived orthotopic xenografts (PDOXs) in mice. We performed comprehensive molecular profiling using array comparative genomic hybridisation, DNA methylation analysis and targeted DNA sequencing on patient specimen and their derivatives such as 3D tumor organoids and PDOXs. The custom-design sequencing panel comprises 234 genes that reflect both established genetic identifiers for individual glioma subtype classification and novel genes encoding mainly epigenetic effector genes. Based on patient-derived material we carried out drug response screening on 3D tumor organoids using a compound library matching the majority of genes that were assessed by targeted sequencing. RESULTS We succeeded in generating a live biobank of HGG patient-derived xenografts and 3D organoids that neatly recapitulates the mutational spectrum including structural DNA variation and methylation-based subtypes of gliomas. A highlight is the generation of 19 PDOXs of paired initial and relapse HGGs from a total of 9 glioma patients. A detailed analysis of the paired longitudinal samples indicated that PDOX models closely recapitulate the evolutionary trajectory of the parental tumors. Targeted sequencing of longitudinal HGG PDOXs suggests that relapse tumors accumulate somatic mutations in epigenetic effectors compared with the Initial. Differential drug responses between initial and relapse tumors were observed after screening of in vitro 3D tumor organoids. CONCLUSION Response assessment of naïve initial gliomas and recurrences provides crucial information on the differential sensitivity between initial and relapsed HGGs and offers novel personalised therapeutic options in the relapse setting. Furthermore, in depth correlation of the profiled somatic molecular landscape with drug response will enable pharmacogenomic predictions of potential inhibitors in the clinical setting.
Implementing baseline ecological and human health field assessments in the Revitalizing Informal Settlements and their Environments (RISE) programme in Makassar, Indonesia: an interdisciplinary study
Authors: Ruzka Radwamina Taruc, Maghfira Saifuddaolah, A Zulkifli Agussalim, Jane Wardani, None Ansariadi, Saifuddin Sirajuddin, None Rizalinda, S Fiona Barker, Grant A Duffy, Peter A Faber, Genie M Fleming, Rebekah Henry, Dusan Jovanovic, Audrie Lin, Joanne O'Toole, John J Openshaw, Rohan Sweeney, Pascale Allotey, Bruce Cahan, Andrew Forbes, Chris Greening, David T McCarthy, Julie A Simpson, Steven L Chown, David W Johnston, Stephen P Luby, Daniel Reidpath, Matthew French, Karin S Leder, Diego Ramirez-Lovering, Tony Wong, Rebekah R Brown
Journal: The Lancet Planetary Health (2019)

BackgroundThe Revitalizing Informal Settlements and their Environments (RISE) programme aims to assess the health, wellbeing, and ecological impacts of a water-sensitive-cities approach to improving urban informal settlements. Incorporating water-cycle management and green technology sanitation strategies, we aim to reduce flood risk and improve sanitation and waste water treatment leading to cleaner and healthier environments. Here we present the initial design pre-intervention for evaluation in the first 12 settlements in Makassar, Indonesia.MethodsInitial environmental, and wellbeing and human health assessments were implemented starting in October, 2018, in 12 settlements in Makassar, Indonesia. Ecological assessments include measuring of temperature and humidity via iButtons installed in select homes, recording of bio-acoustic to measure biodiversity within settlement boundaries, and trapping disease vectors quarterly. Implemented evaluation of environmental contamination includes sampling water and soil sources for total coliforms as well as collecting soil via bootsocks by walking predefined transects. Human assessment includes an annual baseline survey of all settlement households, assessing self-reported symptoms, health-care system utilisation, and subjective wellbeing. Additionally, children younger than 5 years are surveyed quarterly for caregiver reported symptoms of diarrhoea and febrile illness, blood samples and anthropometry are being collected annually, and faeces samples are requested quarterly.FindingsEcological assessments have provided more than a million temperature data points. 21 000 mosquitos have been captured and identified. A total of 114 water samples, 84 bootsocks, and 91 soil samples have been collected, with sampling prior to and during the wet season. We have identified over 600 households within the 12 settlements. Health assessments of children under the age of 5 years have revealed 282 children with collection of 234 faeces samples and 188 blood samples.InterpretationWe have successfully implemented baseline ecological and human health and wellbeing assessment tools in all 12 settlements, which will allow for the evaluation of water-sensitive-cities approach in RISE programme.FundingThe Wellcome Trust (Our Planet, Our Health grant 205222/Z/16/Z).
Chest Pain and Electrocardiographic Changes in a Patient With a VVI Pacemaker
Authors: Kazuhito Hirata, Takanori Takahashi, Jun Nakazato
Journal: JAMA Internal Medicine (2019)

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P11.56 Oncolytic virus and tumor microenvironment modulators an alliance to fight glioblastoma
Authors: M Puigdelloses, N Martinez-Velez, M García-Moure, M Gonzalez-Huarriz, I Iñigo, A M Marta, J Gallego Perez-Larraya
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma is the most common and malignant brain tumour in adults with a dismal overall survival. Several works demonstrated that its tumoral microenvironment is enriched of immunosuppressive cell populations resulting in a challenge for its treatment. In this study, we propose to use an oncolytic adenovirus (Delta-24-RGD) with an inhibitor of myeloid derived suppressor cells (MDSCs; pexidartinib). Therefore, we hypothesis that we will act on two arms of the immune response: the efector arm (with the virus) and the inhibitor arm (with the Pexidartinib) resulting in a greater antitumor immune response. MATERIAL AND METHODS We examined the benefit in survival of the combination Delta-24ACT with pexidarnitib (MDSC inhibitor) or a complement inhibitor in C57BL/6 mice bearing the CT-2A or the GLS61-5 murine glioblastoma models orthotopically. Three viral doses (1x108 pfu/mouse) were administered at 4, 8 and 11 days post cell implantation and the tumor microenvironment immunomodulators were administered following different schedules. Survival in different treatment groups were compared using the log-rank test. RESULTS We observed that the combination of Delta-24-ACT and pexidartinib, led to an increase in the median survival of the treated mice when compared with single treatments (PBS=24 days, pexidartinib=24 days, Delta-24-ACT= 35 days and Delta-24-ACT+Pexidartinib= 36 days). Moreover, the treatment led to 8 long-term survivors; Pexidartinib=1, Delta-24-ACT=3 and Delta-24-ACT+Pexidartinib=4. These data underscore that the combined treatment increase significantly the number of long-term survivors. These long-term survivors were subjected to a rechalleng experiment to assess the generation of immunological memory which is currently on going. We have observed that the combined treatment increase the tumor infiltratrion of CD4, CD8 and led to a less immunosuppressive microenvironment. Immunohistochemistry of macrophages and nanostring of FFPE brain samples in order to evaluate the differences of the cell populations present in the tumoral microenvironment and their functional studies is currently on going. These experiments are being also conducted in GL261-5. CONCLUSION Our data suggest that the combination of the Delta-24-ACT with the capacity of activate the immune system and a drug that downregulates the immunosupression results in a survival benefit in model of gliomas and warrants further investigation.
Current practices and attitudes in menstrual management in adolescents with cancer: A national survey of pediatric oncology providers.
Authors: Allison Close, Kelley Jones, Allison Landowski, Galen E Switzer, Elizabeth Miller, Erika Friehling
Journal: Journal of Clinical Oncology (2019)

e21533 Background: Adolescents and young adult (AYA) females with cancer are at risk of heavy menstrual bleeding (HMB) due to thrombocytopenia, coagulopathy, and/or disruption of the hypothalamic-pituitary-gonadal axis. Options for temporary menstrual suppression (MS) include combined oral contraceptives (OCPs), progestin-only therapy, GnRH agonists, and intrauterine devices. Currently, little is known about current practices to help prevent and treat HMB in AYA women with cancer. Methods: We conducted a national cross-sectional internet-based survey of providers from 100 pediatric oncology centers. Institutions were randomly selected to allow for even representation by program size and geography. Face and content validity were assessed prior to distribution. Descriptive statistics were used to analyze respondent characteristics, attitudes, and practices for managing menstrual suppression. Chi-squared test or Fischer’s Exact test (for small cell sizes across groups) were used for analysis of categorical data. Kruskal-Wallis one-way ANOVA tests were used to compare means. Results: The majority of respondents (94%) have recommended preventative MS. MS in pediatric oncology patients is most often managed by oncology (61%) versus gynecology (22%) or adolescent medicine (12%). Greater than 50% of respondents agreed that patients with the following types of cancer should receive preventative MS: sarcomas, acute leukemias, lymphomas, and germ cell tumors. GnRH agonists were the most preferred method of MS (52%). Most respondents agreed that it is important to consider MS (94%), and that a formal guideline about initiation of MS would be helpful (95%). Less than half (46%) of participants felt comfortable personally managing MS. Conclusions: The vast majority of pediatric oncologists have used preventative MS, most commonly GnRH agonists, and feel that it is important to consider in the majority of AYA cancers. Although pediatric oncologists are most often managing MS, they do not feel comfortable doing so and desire guidelines to help with management.