tbuckley/cabot-search huggingface dataset:
Safety of tremelimumab (CP-675,206) in patients (pts) with advanced cancer
Authors: N. Wallis, C. A. Bulanhagui, P. C. Dorazio, D. I. Healey, M. A. Marshall, J. Q. Liang, D. Pavlov, J. Gomez-Navarro
Journal: Journal of Clinical Oncology (2008)

3040 Background: Tremelimumab is an investigational anti-CTLA4 monoclonal antibody that prolongs T-cell activation and expansion. It has been shown to induce durable tumor responses in patients with melanoma and is undergoing evaluation as a cancer therapy. Methods: An analysis of safety data across 6 single-agent clinical studies at the intended dose (15 mg/kg Q3mo) was performed. Adverse events (AEs) were graded according to NCI-CTC criteria. Results: As of November 2007, 786 pts (91% with melanoma) had received ≥1 cycles of tremelimumab constituting 1,249 doses (range 1–7 doses/pt). 60% of pts were male, 93% were white, and 29% were >65 years of age. Seventy-nine percent of pts reported one or more treatment-related AEs; 70% of which were mild to moderate (CTC grade 1 or 2). 15.4% of pts had grade 3 and 2.8% had grade 4 treatment-related events. Treatment discontinuation due to AEs was 6%. Event frequency and severity was lower in cycle ≥2. The most common and clinically significant AE was diarrhea (36% of pts during cycle 1), which was mild to moderate in 73% (CTC grade 1 or 2). Typical episodes started 2 to 4 weeks after infusion and lasted a median of 8 days. The second most common side effect was rash, which was rarely severe and did not lead to treatment discontinuation. Other treatment-related AEs occurring at ≥5% included fatigue, pruritus, nausea, vomiting, anorexia, abdominal pain, and headache. As anticipated from the mode of action, there were immune-related AEs, such as thrombocytopenia, Evan's syndrome, hepatitis, adrenal insufficiency, thyroid abnormalities, and hypophysitis, all of which occurred in <1% of patients, except thyroid abnormalities, which occurred in 2.4%. Most events resolved without treatment or responded to appropriate treatment. Conclusions: Treatment with 15 mg/kg tremelimumab Q3mo is well tolerated in most patients. Ongoing trials will provide further data on the AE profile and management. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer
Response to Comment on Xu et al. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes. Diabetes Care 2015;38:1858–1867
Authors: Stefan Brandmaier, Tao Xu, Thomas Illig, Karsten Suhre, Jerzy Adamski, Rui Wang-Sattler
Journal: Diabetes Care (2015)

We thank Sonne and Knop for their comments (1) on our article (2). They recalled that the induced AMPK pathway we investigated is not the only potential root of the observed decrease in LDL cholesterol (LDL-C) levels after metformin treatment. Sonne and Knop indicated the highly probable influence of the bile acid synthesis and the underlying mode of action (1). We fully agree with this comment.

However, we would like to clarify more precisely two points referred to by the authors. First, the statement referring to “decreased concentrations of three metabolites” when case subjects were compared with control subjects in our cross-sectional study (1) would be better described with the …
Phase I study of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic carcinoma
Authors: K. Sudo, T. Yamaguchi, H. Ito, T. Ishihara, K. Nakamura, H. Kawakami, T. Uno, H. Saisho
Journal: Journal of Clinical Oncology (2005)

4187 Background: Chemoradiotherapy using 5-fluorouracil(5FU) has been generally accepted as the standard treatment in patients with locally advanced pancreatic carcinoma. S-1 is an oral fluoropyrimidine preparation with reported response rate of 20.0%1)∼21.1%2) for advanced pancreatic carcinoma (1)Hayashi et al. Oncol Rep. 2002;9;1355–61 2)Okada et al. ASCO 2002). We hypothesized that S-1 might be an attractive alternative of 5FU, and conducted a phase I study to determine the maximum-tolerated dose(MTD) and dose-limiting toxicity (DLT) of S-1 when administered concurrently with radiotherapy to patients with locally advanced pancreatic carcinoma. Methods: Patients with histologically or cytologically proven, unresectable, locally advanced pancreatic carcinoma were enrolled in this study. S-1 was administered orally twice a day from day 1 to 14 and 22 to 35. Radiotherapy was delivered up to a total dose of 50.4Gy in 28 fractions over 5.5 weeks. The planning target volume was defined as the primary tumor plus a 15∼20mm margin, and no prophylactic nodal irradiation was given. The initial dose of S-1 was 60mg/m2/day(level 1) and then escalated to 70mg/m2/day(level 2) and 80mg/m2/day(level 3) every 3∼6 patients according to the standard phase I study design. DLT was defined as grade4 hematologic toxicity; or grade 3 or 4 nonhematologic toxicity except nausea and anorexia observed during treatment or within 2 weeks after treatment. Results: 9 patients have been enrolled in this study (level 1; 3 patients, level 2; 3patients, level 3; 3 patients). Their median age was 62 years and Karnofsky Performance status was 70∼90. Although 1 of 3 patients experienced grade 3 anorexia at dose level 1, 3 patients at dose level 2 developed no grade 3 or 4 toxicity. Most toxicities were mild and DLT has not been observed. Of 7 evaluable patients, 3 (42.9%) achieved partial response during maintenance chemotherapy. Conclusions: This combination therapy was well tolerated and promising. MTD has not been reached, and the study is on-going at dose level 3. No significant financial relationships to disclose.
Characteristics and comorbidities associated with pain in people with chronic obstructive pulmonary disease (COPD)
Authors: W. Darlene Reid, Bahareh HajGhanbari, Cristiane Yamabayashi, Vanessa Soloviov, Jeremy Road
Journal: European Respiratory Journal (2012)

Background : A recent survey demonstrated that the prevalence of pain in people with COPD was more than twice that in age-matched people without COPD, and pain was ∼2.5 times more severe. Purpose/Hypothesis: to determine the characteristics and comorbidities associated with pain in people with COPD.

Methods: Patients were recruited from respiratory clinics and pulmonary rehabilitation programs. Respondents participated in a mail survey that included: the McGill Pain Questionnaire (MPQ), the Brief Pain Inventory (BPI), a form to list comorbidities (modified from the Charlson Index) and medications.

Results: Sixty-five of 92 COPD patients responded to the survey (70% response rate). They had an FEV1 of 44±17 % pred, a BMI of 27.6 kg/m2 and were 74±8 years. Forty-four respondents (67%) self-reported pain. On the BPI, 64% of these COPD patients had moderate to very severe pain and 73% had moderate to very high pain interference with daily activities. Average pain severity scores on the MPQ and BPI were correlated (r= 0.74). Of 44 COPD patients who experienced pain, 39 (89%) reported ≥2 comorbidities and 20 (45 %) reported ≥4 comorbidities; the most common were musculoskeletal (21%) and circulatory disorders (21%). Twenty-eight (64%) of COPD patients used pain alleviating treatments, the most common were non-prescription pain medications (acetaminophen and ibuprophen [n=18; 64%) followed by prescription NSAIDS and narcotics.

Conclusions: Moderate to severe pain is common in people with COPD. This pain likely compromises full participation in rehabilitation and the ability to increase physical activity. Musculoskeletal causes appear to be a major contributing factor.
Serial changes in bone marrow cellularity, reticulin fibrosis and microvessel density in patients with chronic myeloid leukemia (CML) in chronic phase treated with imatinib
Authors: N. M. Lokeshwar, L. Kumar, M. Vijayaraghavan, R. Dawar, A. Sharma, V. Kochupillai
Journal: Journal of Clinical Oncology (2006)

6596 Background: Imatinib Mesylate, a BCR-ABL tyrosine kinase inhibitor produces sustained complete hematological response (CHR) in CML patients in chronic phase. There is a paucity of information on the effects of imatinib on the bone marrow (BM) morphology and angiogenesis. We evaluated the sequential changes in these parameters in 22 CML chronic phase patients treated with first line imatinib (400 mg) and compared with 10 controls (non-hematological malignancies). Methods: Trephine BM biopsies were evaluated by means of morphology, morphometry, Gomori’s stain and CD 34 staining. Reticulin fibrosis was graded from grade 1 to grade 4. Microvessel density (MVD) was calculated by counting the microvessels in hot spots (400 ×). Final value was mean of 10 fields. Total vascular area (TVA) was calculated by image analysis and expressed as percentage of the total area. Results: 22 patients were included in the study. Median age was 34 years (range 20–58 years). All patients attained a CHR at a median of 18 days. Major cytogenetic response was seen in 64%, minor response in 27% and no response in 9% of patients. Baseline BM cellularity was increased in all patents as compared to controls. The median cellularity at 6 months and 1 year was decreased to 60% and 50% respectively. The median grade of reticulin fibrosis at baseline was grade 3 as compared to controls (median grade 1). There was a significant decrease in reticulin fibrosis at 6 months and 1 year (median-grade 1, p=0.04). The median MVD at baseline was 8.25 (range 6–26) and was increased as compared to controls (median MVD-3.6). There was a significant decrease in MVD at 6 months and 1 year (median MVD-4.0, p=0.04). Similarly the TVA decreased from 6.2% at baseline to 4.3% at 1 year. These changes correlated with the cytogenetic responses. Two patients who had disease progression during therapy showed reversal in the bone marrow changes. Conclusions: Imatinib Mesylate produces significant effects on bone marrow morphometry and angiogenesis in patients with CML in chronic phase. There is a consistent decrease in bone marrow cellularity, reticulin fibrosis and microvessel density during therapy. No significant financial relationships to disclose.
Spontaneous Human Mononuclear Cell Cytotoxicity to Cultured Tumor Cells: Reproducibility of Serial Measurements With the Use of a Chromium-51-Release Microcytotoxicity Assay 2 3
Authors: Arleen C. Levin, Richard J. Massey, Friedrich Deinhardt
Journal: JNCI Journal of the National Cancer Institute (1978)

Twenty-three healthy human adults with naturally occurring (spontaneous) mononuclear cell cytotoxicity (MCC) to cultured human tumor cells were evaluated in a serial study over 23 months to determine whether their initial MCC levels remained stable. A 3-hour 51Cr-release microcytotoxicity assay, in which the HBT-3 cancer-derived cell line with HeLa markers and the ALAB breast cancer-derived cell line were used, was standardized and its suitability for such serial studies was evaluated. The data showed that the 51Cr-release assay is reproducible and suitable for use in serial studies of MCC. The intrinsic technical error for a single assay averaged 12.5% (2-26%) coefficient of variation. The greatest sources of technical variation with time were the passage level of the target cells and the temperature at which the effector cells were stored and handled. When these technical factors were controlled, naturally occurring MCC was fairly reproducible with time. Of the healthy individuals with initial high or low MCC levels, 61% tended to retain these levels in a stable fashion, but the remaining 39% studied showed fluctuations of MCC greater than 33% coefficient of variation.
Abstract 2666: PI3K inhibition induces homologous repair defects in endometrioid endometrial cancer patient derived xenografts leading to synergistic anti-tumor activity with PARP inhibitors
Authors: Bo Rueda, Celeste Digloria, Tracilyn Hall, Rosemary Foster, Darrell Borger, Whitfield Growdon
Journal: Cancer Research (2015)

Abstract Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to induce defective homologous repair in breast carcinoma leading to heightened sensitivity to poly-ADP ribose polymerase (PARP) inhibitors. Our objective was to assess the effects on DNA repair pathways following single agent and combined PI3K and PARP inhibition utilizing endometrial cancer (EnCa) patient derived xenografts (PDX) with and without identified PIK3CA mutations. Under an institutional protocol, tumors from consenting patients with endometrioid carcinoma were collected at the time of primary surgery and genotyped for common oncogenic mutations utilizing the SNaPshot® platform. NOD/SCID mice bearing xenografts derived from two primary human endometrioid endometrial tumors with and without PIK3CA gene mutations (ENCA1 &amp; ENCA2 respectively) were divided into four arm cohorts with equivalent tumor volumes. Vehicle or NVP BKM-120 (30 mg/kg) was administered alone and in combination with veliparib (25 mg/kg) and endometrial xenograft tumor volumes were assessed. Immunoblotting was used to assess downstream PI3K pathway and DNA repair pathway alterations in post treatment samples at specific time points. While NVP BKM120 as a single agent failed to induce significant anti-tumor activity compared to vehicle in either model, decreased pAKT, RAD51 and increased γ-H2AX levels were observed in response to NVP BKM120 alone. PIK3CA mutation status did not affect these molecular alterations. Dual NVP BKM-120 and veliparib therapy significantly impeded tumor growth (p &amp;lt; 0.01) in the ENCA1 model, while in ENCA2, significant tumor regression was observed (p &amp;lt; 0.001). No changes in mouse weight or premature death were observed in the various treatment arms. Combination therapy was associated with reconstitution of baseline RAD51 and increased γ-H2AX levels. In conclusion, these results suggest that PI3K inhibition induces defects in homologous repair mediated by RAD51 and increases reliance on PARP mediated DNA repair mechanisms. Our in vivo data suggest that PI3K inhibition sensitizes endometrial tumors with and without PIK3CA mutations to a PARP inhibitor. Citation Format: Bo Rueda, Celeste Digloria, Tracilyn Hall, Rosemary Foster, Darrell Borger, Whitfield Growdon. PI3K inhibition induces homologous repair defects in endometrioid endometrial cancer patient derived xenografts leading to synergistic anti-tumor activity with PARP inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2015-2666
Microbubbles and ultrasound increase intraventricular polyplex gene transfer to the brain
Authors: James-Kevin Y. Tan, Binhan Pham, Yujin Zong, Camilo Perez, Don O. Maris, Ashton Hemphill, Carol H. Miao, Thomas J. Matula, Pierre D. Mourad, Hua Wei, Drew L. Sellers, Philip J. Horner, Suzie H. Pun
Journal: Journal of Controlled Release (2016)
Epidermal growth factor receptor dimerization status determines response to HER-kinase targeted therapies in keratinocytes
Authors: I. Laux, A. Jain, C. A. Tindell, D. B. Agus
Journal: Journal of Clinical Oncology (2004)

3062 Background: Acne-like skin rash is common among cancer patients treated with EGFR tyrosine kinase inhibitors (Gefitinib, Erlotinib) or anti-EGFR antibodies (C225). Interestingly, these cutaneous side effects are rarely observed in patients treated with 2C4, a humanized monoclonal antibody which abrogates HER2-mediated signaling. Our molecular hypothesis for this observation is that in skin EGFR homodimers are preferred to EGFR/HER2 heterodimers which lead to strong cutaneous side-effects in response to gefitinib but not to 2C4. Methods: This hypothesis was tested in primary human epidermal keratinocytes (NHEK) by evaluating absolute mRNA and protein expression levels of the HER-kinase axis members and the effect of HER-kinase directed therapies by phospho-MAPK western blot analysis. The preference status of HER2-specific heterodimers was determined using semi-quantitative co-immunoprecipitation analysis. The results were compared to an ovarian cancer cell line (OVCA433) which is responsive to both gefitinib and 2C4. Results: Gefitinib inhibited ligand-mediated EGFR phosphorylation and MAPK activation in both OVCA433 and NHEK cells in a dose-dependent manner. In contrast, 2C4 blocked EGFR phosphorylation and downstream signaling only in OVCA433 cells but did not demonstrate any effect in keratinocytes. Co-immunoprecipitation studies showed that significant levels of HER2 interact with EGFR in OVCA433 cells while HER2 is absent in EGFR-immunoprecipitations performed with NHEK lysates. These results were not driven by the level of receptor expression. Studies are underway to validate our observations using a colorimetric heterodimerization assay to assess the EGFR dimerization status in these cell lines and in skin biopsies from patients who developed a skin rash in response to gefitinib treatment. Conclusions: Our results suggest a preference for EGFR homodimerization in primary keratinocytes and indicate the inability of HER2 to engage in active EGFR/HER2 heterodimers. This is of particular interest as the cutaneous adverse effects of gefitinib result from direct interference of EGFR signaling in skin. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech
Patient commentary: Consider the person alongside the pathology
Authors: Tessa Richards
Journal: BMJ (2015)

My experience of being discussed at multidisciplinary team (MDT) meetings backs Eigenmann’s view that someone who can present the patient’s perspective should be there.1 It also suggests that patients should be alerted to these meetings and might value the option to represent themselves.

As a three operation, 11 year survivor of metastatic adrenal cancer,2 I knew that it was likely to come back again one day. I dreaded annual scans and happily agreed to forgo them two years ago. This year, during reappraisal of my hyperparathyroidism, recurrence was detected.

The senior registrar broke the bad news gently by phone and mentioned that my case was due to be discussed at an MDT meeting. I asked whether I might be allowed to attend and be sent a copy of the scan results in advance. The consultant kindly agreed.

I sat at the back of the room, looking at my scans on the screens, listening to the thoughtful discussion between radiologists, oncologists, and …
Altered central nervous system pharmacology of methotrexate in childhood leukemia: another sign of meningeal relapse.
Authors: M Morse, J Savitch, F Balis, J Miser, J Feusner, G Reaman, D Poplack, A Bleyer
Journal: Journal of Clinical Oncology (1985)

CSF and plasma antifolate concentrations during 257 intravenous (IV) infusions of high-dose methotrexate were measured in 60 children with acute lymphoblastic leukemia. In 49 children who have never had evidence for CNS leukemia, the mean steady-state CSF to plasma methotrexate ratio was 0.013 (SD = 0.01). In contrast, 11 children with overt meningeal leukemia had a 12-fold higher mean ratio of 0.157 (range, 0.013 to 0.844, p less than .01). In the group of patients studied, all of those with a CSF methotrexate concentration greater than 2 SD above the mean either had leukemic cells in the CSF or subsequently developed this condition. In two patients, overt CNS leukemia was preceded by a high CSF:plasma drug ratio at a time when there was no cytologic or clinical evidence for CNS leukemia. As previously observed with intrathecal methotrexate, we conclude that overt meningeal leukemia increases CSF drug concentrations during IV methotrexate therapy. An elevated CSF to plasma ratio may be useful to predict imminent CNS relapse or to verify completeness of response to therapy.
Mammary Adenocarcinoma Induced in Organ Culture by 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Thomas L. Dao, Dilip Sinha
Journal: JNCI Journal of the National Cancer Institute (1972)

Mammary glands from 50- to 60-day-old W/Fu female rats were cultivated 9 days in a synthetic medium supplemented with insulin, estrogen, prolactin, and progesterone, and a carcinogen, 7,12-dimethylbenz[a]anthracene. Adenocarcinoma developed in the mammary explants transplanted to the isologous host after a 9-day culture. No tumors developed in explants cultured in medium containing hormone combinations only.
Chronic nonspecific diseases of lungs (CNDL) and iodine deficiency diseases in children
Authors: Turdikul Bobomuratov, Gulchekhra Isakova, Dilshoda Akramova, Alimardon Kuziev
Journal: European Respiratory Journal (2011)

During the chronic bronchopulmonary pathology as CNDL on children on background of iodine deficiency diseases, accompanied with the chain of unfavorable event in immune system, metabolic processes which aggravate the clinical course, as well as make ill effects.  Under observation were 68 children with CNDL average age patients 8,4±0,2. Remoteness of diseases 4,71±0,4 years.  At determination of the size of the thyroid gland on US have revealed: hyperplasia of thyroid gland I-degree on 52,3% children with CNDL, on 28,5% II-degree, on 19% are normal size of the organ.  The Analysis have shown that the level of TTG in contents of serum in all patients were higher than checking group (R  Also contents of cortisol on patients with severe condition were high (144±6,56 mg/ml) as compared with patients in medium condition (89,6±8,3 mg/ml).  For estimation of iodine insufficiency degree we defined the concentration of the iodine in single portion of the urine by photometrical method. On 25% examined, median concentration of the iodine in urine was found the moderate iodine insufficiency degree (20-49 Mκg/l), on 55.8% light degree (50-99 Mκg/l), but on 19% iodine concentration in urine was above 100 Mκr/l. Thus, presence of iodine deficiency diseases in children with CNDL, has a definite significance during and outcome of chronic bronchopulmonary process, which requires additional and regular introduction of iodine-containing preparation and thyroid hormone.
California Umbilical Cord Blood Collection Program: Addressing The Diversity Of The National Registry Through Creative Partnerships With Cord Blood Banks and Provision Of High-Quality Cord Blood Units For Research
Authors: Jon Walker, Geralyn Annett, Karen O'Donnell, Christine C. Posey, Delia Roberts, Kevin Yanamura, Jan A. Nolta, Suzanne Pontow
Journal: Blood (2013)