tbuckley/cabot-search huggingface dataset:
Treatment of meningeal relapse in childhood acute lymphoblastic leukemia. I. Results of craniospinal irradiation.
Authors: L E Kun, B M Camitta, R K Mulhern, S J Lauer, R W Kline, J T Casper, B A Kamen, B M Kaplan, S W Barber
Journal: Journal of Clinical Oncology (1984)

Fourteen children were treated for isolated meningeal relapse occurring seven to 44 months (median, 14 months) after prophylactic cranial irradiation (2,400 rad/12 fractions) and intrathecal methotrexate (IT MTX, 12 mg/m2 for four doses during cranial irradiation). Eight had "high-risk" acute lymphocytic leukemia with age less than 2 years, white blood cell counts greater than 20,000, or T cell markers. Treatment for central nervous system leukemia included IT MTX (12 mg/m2 twice weekly until clearance of spinal fluid cytology) followed by craniospinal irradiation (CSI, 3,000 rad/20 fractions to the cranium and 1,800 rad/12 fractions to the spine). No maintenance IT MTX was given. Systemic chemotherapy was continued or reinstituted for a minimum of one year after CSI. No instance of second meningeal relapse has occurred. Five patients remain in secondary complete remission 66+, 54+, 36+, 26+, and 24+ months after meningeal relapse. Disease-free survival was limited by marrow relapse in eight patients (2-20 months after CSI) and testicular relapse in one. No acute toxicities were noted with CSI. Myelosuppression occurred in seven patients. Infections within two months of CSI were noted in five. No neurologic sequelae are apparent. Serial neuropsychometric studies in 10 patients revealed a significant decline in mean values on Global IQ scales. Long-term survival with acceptable toxicity is possible following aggressive, prompt treatment of meningeal relapse occurring after prophylactic cranial irradiation. Hematologic relapse remains the major obstacle to long-term disease-free survival.
Higher oxygen saturation targets are safer for preterm infants, trials show
Authors: Susan Mayor
Journal: BMJ (2016)

Using lower oxygen saturation targets when treating preterm infants is associated with a higher risk of death and disability at 2 years than with higher targets, the combined results of two large randomised trials have shown.1

The safest ranges for oxygen saturation that most effectively minimise the risks of death, retinopathy, and later disability in preterm infants have been hotly debated. Two trials, one in Australia and the second in the United Kingdom, randomly allocated …
Brief Report: Intensification to Triple Therapy After Treatment With Nonbiologic Disease‐Modifying Antirheumatic Drugs for Rheumatoid Arthritis in the United States From 2009 to 2014
Authors: Jeffrey A. Sparks, Alexis A. Krumme, William H. Shrank, Olga S. Matlin, Gregory Brill, Edmund J. Pezalla, Niteesh K. Choudhry, Daniel H. Solomon
Journal: Arthritis & Rheumatology (2016)

Objective Several trials suggest that triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) and biologic disease‐modifying antirheumatic drugs (DMARDs) have similar efficacy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate intensification to triple therapy after initial nonbiologic prescription among patients with RA. Methods The use of triple therapy among patients with RA in 2009–2014 was evaluated using US insurance claims data. Patients with a health care visit for RA and an initial nonbiologic DMARD prescription were included. Frequencies of intensification to triple therapy or a biologic DMARD and rates of intensification per 6‐month time period were calculated. Using Cox regression, we evaluated whether sociodemographic, temporal, geographic, clinical, and health care utilization factors were associated with intensification to triple therapy. Among those patients whose therapy was intensified, we investigated factors associated with triple therapy use by logistic regression. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for intensification to triple therapy in relation to various clinical and demographic factors were calculated. Results There were 24,576 patients with a mean ± SD age of 50.3 ± 12.3 years, and 78% were female. During the study period, treatment was intensified to biologic DMARDs in 2,739 patients (11.1%) compared to 181 patients (0.7%) whose treatment was intensified to triple therapy. There was no significant change in triple therapy use across calendar years. Patients whose treatment was intensified to triple therapy were more likely to receive glucocorticoids (HR 1.91 [95% CI 1.41–2.60]) compared to patients who did not use glucocorticoids and were more likely to use nonsteroidal antiinflammatory drugs (NSAIDs) (HR 1.48, 95% CI 1.10–1.99 versus no NSAID use). Among those patients whose treatment was intensified to triple therapy or biologic DMARDs, factors significantly associated with triple therapy use included older age, US region (with the highest odds for triple therapy use in the West and lowest odds for triple therapy use in the Northeast), glucocorticoid use, and lower number of outpatient visits within 180 days of initial nonbiologic DMARD prescription. Conclusion Despite reports published during the study period suggesting equivalent efficacy of triple therapy and biologic DMARDs for RA, the use of triple therapy was infrequent and did not increase over time in this large nationwide study.
KL-6, SP-D and MMP-7 as serum biomarkers for early detection of interstitial lung diseases
Authors: Nobuhisa Ishikawa, Koji Yoshioka, Yasushi Horimasu, Hiroshi Iwamoto, Shinichiro Ohshimo, Noboru Hattori, Nobuoki Kohno
Journal: European Respiratory Journal (2013)

Background : Since therapy with corticosteroids and/or immunosuppressants is largely ineffective for advanced stages of interstitial lung diseases (ILDs), early diagnosis of ILDs is of utmost importance. Recent clinical studies have suggested that Krebs von den lungen-6 (KL-6), surfactant proteins (SP), matrix metalloproteinase (MMP), and C-C motif chemokine ligand-18 (CCL-18) are potential serum biomarkers for ILDs. However, each of these biomarkers has been studied separately and the clinical significance of these biomarkers for early detection of ILDs has not been adequately evaluated.   Aims:  We aimed to determine whether serum levels of these biomarkers are of any diagnostic value in patients with early-stage ILDs.   Methods:  We collected the data of 55 patients with early-stage ILD who underwent surgical lung biopsy and 102 healthy controls. Serum levels of KL-6, SP-A, SP-D, MMP-1, MMP-7 and CCL-18 were measured in 55 patients with ILDs and 102 healthy controls.   Results:  The receiver operating characteristic curve analysis revealed that KL-6, SP-D and MMP-7 showed greater clinical significance than other biomarkers. The cut-off levels for these biomarkers that resulted in the highest diagnostic accuracy were determined. The sensitivity, specificity and diagnostic accuracy were 94.5%, 100% and 98.1% for KL-6; 69.1%, 86.3% and 80.3% for SP-A; 83.6%, 97.1% and 92.4 for SP-D; 58.2%, 37.3% and 44.6% for MMP-1; 87.3%, 97.1 and 93.6% for MMP-7; and 81.8%, 88.2% and 86.0% for CCL-18.   Conclusion:  KL-6, SP-D and MMP-7 may be the most useful biomarkers for ILDs even in the early stages of the disease and may greatly improve the currently employed diagnostic methods for ILD.
Phase II study of bevacizumab in combination with cetuximab plus irinotecan in irinotecan-refractory colorectal cancer (CRC) patients who have progressed on a bevacizumab-containing regimen (The BOND 2.5 Study)
Authors: N. H. Segal, D. Reidy-Lagunes, M. Capanu, N. Kemeny, K. Chung, D. Kelsen, E. Hollywood, N. Goodman-Davis, L. B. Saltz
Journal: Journal of Clinical Oncology (2009)

4087 Background: We previously showed that adding bevacizumab (bev) to cetuximab (cetux) plus irinotecan (IRI) in bev-naïve, IRI-refractory CRC patients is feasible, and yielded a favorable response rate and time to tumor progression (TTP) compared with historical controls (Saltz: JCO, 2007). Since most CRC patients now receive a bev-containing regimen prior to cetux, we evaluated the addition of bev to cetux plus IRI (CBI) in patients with metastatic CRC who had previously progressed on chemo + bev. Methods: All patients were naïve to cetux. The importance of KRAS mutation was not appreciated when the trial was designed and this has not yet been evaluated. Patients received IRI at the same dose and schedule as last received prior to study, Cetux 400 mg/m 2 loading dose, then weekly at 250 mg/m 2 , plus Bev 5 mg/kg given every two weeks or 7.5 mg/kg given every three weeks. Results: 33 received treatment. Median age was 58 (range 29–85). Median number of prior regimens was 2 (range 1–2). Median performance status was ECOG 1 (range 0–1). Patients received a median of 2 cycles (range 1–15). Grade 3/4 Toxicities: Acneiform Rash 18%, hypomagnesemia 6%, hypophosphatemia 6%, Neutropenia 15%, Diarrhea 6%. One patient developed neutropenic fever and one patient had a hypersensitivity reaction to cetux. At a median follow up of 32 months (range 21–32 months) in 33 evaluable patients, we observed 3 (9%) partial responses and 11 (33%) patients with stable disease for &gt; 4 months. Median TTP was 3.9 months (95% CI: 1.3 - 6.8). Median survival was 10.6 months (95% CI: 6.6 - 13.8). Conclusions: The toxicity profile was similar to what would have been expected from the individual agents alone. Recognizing the limitations of cross-study comparisons, the response rates and TTP seen with CBI in patients who have previously progressed on bev do not appear to be as encouraging as the 37% response rate and 7.3 months TTP seen in the BOND 2 trial of bev-naïve CRC patients. Ongoing randomized trials, including SWOG 0600, will be needed to definitively determine the contribution of continued use of bev after progression on a bev-containing regimen. Supported by Genentech. [Table: see text]
Abstract P021: Association of Blood Lactate with Carotid Atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study
Authors: Ghanshyam Palamaner Subash Shantha, Richey Sharrett, Brad C Astor, Josef Coresh, Frederick Brancati, Bruce A Wasserman, Hunter J Young
Journal: Circulation (2012)

Aim: Elevated blood lactate, a marker of decreased oxidative capacity, may be associated with high levels of oxidized LDL and consequent atherosclerosis. We assessed the association between elevated blood lactate and carotid atherosclerosis in a sample of 1496 adults, aged 60 - 82 years, in the general population. Methods: Maximum wall thickness of the internal carotid artery (MICA) was measured using gadolinium-enhanced magnetic resonance imaging (MRI) in 1496 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Blood lactate was categorized into quartiles (Q1: &lt; 5.9 mg/dl, Q2: 5.9 to 7.2mg/dl, Q3: 7.3 to 9.2 mg/dl, and Q4: &gt;9.2 mg/dl). Results: Mean age was 70.3 years; 56% were women and 19% were African American. Higher lactate quartile was associated with greater odds of having MICA above the median (Odds ratio for Q1: 1.00, Q2: 1.06, Q3: 1.24 and Q4: 1.36; p for trend &lt;0.001) after adjustment for age, gender, ethnicity, stature, body mass index (BMI), LDL, hypertension diagnosis, and diabetes diagnosis. The association between MICA and lactate was attenuated but remained significant (Q1: 1, Q2: 1.02, Q3: 1.12, Q4: 1.21, p for trend 0.011) after further adjustment for triglycerides/HDL ratio. Conclusion: Blood lactate is associated with internal carotid artery maximum wall thickness, a marker of carotid atherosclerosis. Attenuation of the association with adjustment for triglyceride/HDL ratio, a marker of insulin resistance, suggests that lactate’s association with wall thickness may be mediated through insulin resistance, at least in part.
PTH-320 Exosomes: extracellular vesicles which can immortalise cancer and stromal cells in the colorectal tumour microenvironment
Authors: R Bhome, R Goh, J Primrose, E Sayan, A Mirnezami
Journal: Gut (2015)

<h3>Introduction</h3> Exosomes are nano-sized (40–100 nm) extracellular vesicles which are exchanged by cancer and stromal cells. They contain proteins and nucleotides (DNA, mRNA, microRNA) and are therefore capable of conveying genetic information. Exosome transfer affects cellular function but this is not well defined in the colorectal cancer (CRC) setting. We aimed to isolate, label and transfer exosomes from colorectal cancer cells to fibroblasts and vice versa. Moreover, we investigated the effect of exosome transfer at the cellular level, focussing on two key pathways: ERK and AKT. <h3>Method</h3> Exosomes were isolated from conditioned media from DLD-1 CRC cells or MRC5 fibroblasts by selective centrifugation and validated by transmission electron microscopy, western blotting and flow cytometry. The resulting exosome pellet was labelled with a lipophilic (green) fluorescent dye and co-cultured with the reciprocal target cell (MRC5 or DLD-1). The cells were then washed thoroughly to remove all extracellular particles and visualised by fluorescence microscopy. Cell lysate was analysed by western blotting for activation of key signalling pathways such as Ras (ERK) and AKT. <h3>Results</h3> Microscopy revealed presence of fluorescent labelled exosomes within both DLD-1 and MRC5 cells following exosome co-culture. There was marked increase in AKT pathway activation in MRC5 fibroblasts after co-culture with DLD-1 CRC exosomes. As a result, significant changes to anti-apoptotic stimuli have been observed. There was a marked increase in ERK pathway activation and moderate increase in AKT activation in DLD-1 CRC cells after co-culture with MRC5 fibroblast exosomes. Again, significant changes to downstream anti-apoptotic signals were observed. <h3>Conclusion</h3> We have shown that CRC exosomes can be transferred to fibroblasts and vice versa. This transfer induces selective phosphorylation of AKT and resistance to apoptosis in recipient fibroblasts and CRC cells. Stromal and tumour-derived exosomes promote resistance to apoptosis and can create an apoptosis resistant niche in the tumour microenvironment. <h3>Disclosure of interest</h3> None Declared.
Selective spatial up-regulation of intratumoral stromal aromatase in breast cancer patients: Evidence for imbalance of local estrogen metabolism
Authors: C. F. Singer, A. Fink-Retter, D. Gschwantler-Kaulich, G. Hudelist, K. Czerwenka, E. Kubista
Journal: Journal of Clinical Oncology (2006)

10105 Background: The suppression of local estrogens levels is of key importance in the treatment of ER positive breast cancer. Essentially all endocrine strategies act by either suppressing estrogen formation or by competitively inhibiting receptor binding in tumor cells. Nevertheless, little is still known about the local expression of aromatase and sultotransferase which are key modulators of intra-tumoral estrogen levels. Methods: We have performed immunohistochemostry to investigate the expression of aromatase and sulfotransferase in 42 samples obtained directly from malignant breast tumors, and compared it to biopsies obtained from uninvolved tissue in the vicinity of the invasion front, and to distant breast tissue. Results: We found that aromatase was equally detectable in both tumor epithelial and stroma, but was mostly epithelial in non-malignant tissues (p=0.00008, Fisher’s Exact Test). Also, aromatase protein expression was significantly more common in tumoral stroma when compared to peri-tumoral and distant breast stroma (p=0.00005, and p&lt;0.00001, respectively). With the notable exception of cystosarcoma phylloides, sulfotransferase protein was only detectable in epithelial tissues, regardless of the location within the diseased breast. Epithelial sulfotransferase was, however, correlated with epithelial aromatase (r=0.35461, p=0.0009, Spearman’s Rho test) and with the epithelial ER status (r=0.29313, p=0.005). Conclusions: Taken together, we have demonstrated a differential aromatase and sulfotransferase protein expression pattern that is dependent of the spacial relation to a malignant breast tumor. Our results indicate a net increase in intra-tumoral active estrogen levels through increased stromal aromatization, while physiological local inactivation by sulfotransferase activity remains essentially unchanged. No significant financial relationships to disclose.
A pilot study of weekly versus 3-week docetaxel in combination with capecitabine in patients with anthracycline-pretreated metastatic breast cancer
Authors: Z. Jiang, S. Zhang, X. Xie, J. Liu, J. Ren, H. Wang, Q. Sun, Y. Bai, Y. Cheng, X. Liang, S. Jiao
Journal: Journal of Clinical Oncology (2006)

10771 Background: Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in anthracycline-pretreated metastatic breast cancer (MBC), but with high toxicities. To improve the therapeutic index, we performed a clinical pilot trial to evaluate the efficacy and safety of weekly or 3-week docetaxel in combination with capecitabine given for 14 days every 21 days. Methods: Patients with at least one measurable lesion were randomized to receive the treatment arms: docetaxel 75mg/m 2 on days 1, oral capecitabine 950 mg/m 2 twice daily on days 1–14 (Arm A); docetaxel 37.5mg/m 2 on days 1 and 8, oral capecitabine 950 mg/m 2 twice daily on days 1–14 (arm B). Each cycle was repeated every 3 weeks. Patients remained on study for a maximum 6 cycles or until tumor progression or unacceptable toxicity occurred, response assessments were scheduled every two cycles. Results: 64 pts were enrolled, 62 eligible for safety and tumor assessment. Key baseline variables were well balanced. Dominant site of disease was visceral in 66.1%; 24.2% had ≥3 organ sites of disease; all patients had previously received anthracyclines, 24.2% for MBC. 43. 6% were ER negative and 46.8% were HER-2 overexpress. The overall clinical response rate of all groups was 59.7% (37/62). There was no progressive disease (PD) after two cycles. Efficacy outcomes were similar in the two arms. The response rate of group A and B were 60% (18/30) and 59.4% (19/32) respectively. There were no drug-related deaths observed. Neutropenia was the most common toxicity. In all, the frequence of Grade 3/4 neutropenia were similar in two arm, but Grade 4 neutropenia of Group A 66.7% (20/30) was higher than Group B 34.4% (11/32), P = 0.021. Conclusions: The study confirmed the superior activity of docetaxe-capecitabine combination therapy in anthracycline resistant MBC, and comparing with 3-week schedule, weekly docetaxel plus capecitabine has same high efficacy with a favourable safety profile. No significant financial relationships to disclose.
Rapidly Reversible Resistance to Immune Lysis of L5178Y Lymphoma Cells in a Tumor-Dormant State in DBA/2 Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: T Okayasu, E F Wheelock
Journal: JNCI Journal of the National Cancer Institute (1986)

L5178Y cells in a tumor-dormant state in DBA/2 mice escape lysis by cytolytic T-lymphocytes and activated macrophages. In the present report these tumor cells were found to be less susceptible to lysis by anti-H-2, anti-Thy 1.2, and anti-AKR antibodies plus complement than was the same tumor cell population removed from tumor-dormant mice and allowed to proliferate in a nonimmune environment in vivo or in vitro. This rapidly reversible resistance to immune lysis may be due to arrest of the tumor cells in the cell cycle during the tumor-dormant state.
A dose-escalation study of gemcitabine (Gem) plus oxaliplatin (Ox) in combination with imatinib in patients (pts) with gemcitabine-refractory advanced pancreatic adenocarcinoma (PC).
Authors: N. Starling, E. A. Hawkes, I. Chau, D. J. Watkins, J. Thomas, J. Webb, G. Brown, K. Thomas, J. R. Oates, D. Cunningham
Journal: Journal of Clinical Oncology (2010)

4155 Background: There is no standard 2nd-line therapy for Gem-refractory PC. GemOx has documented activity in the 1st- and 2nd-line treatment of PC. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in PC, promote oncogenesis and interstitial hypertension. Combining imatinib (anti-PDGFR) with chemotherapy may enhance antitumor activity/chemotherapy delivery and is being assessed in several solid tumours. The primary endpoint of this study was to assess the safety of combining GemOx + imatinib and maximum tolerated doses (MTD). Methods: Pts with Gem-refractory locally advanced (LA) or metastatic PC and PS 0/1 were entered into 5 sequential dose levels (DLs) of Gem (D1) and Ox (D2) two weekly (Table). Pts in all DLs received imatinib 400 mg od intermittently for 7 days (D-2 to D5) each cycle. Using a 3+3 study design, DLT was assessed in cycles 1 and 2. CT response assessment occurred every 8 weeks. Results: 26 pts were enrolled between 9/06 and 09/09, receiving a total of 148 cycles. 4 pts were non-evaluable for DLT (DL2 n=1, DL4 n=3: disease-related deterioration in cycle 1). Median age was 62 yrs (44-74 yrs), male:female 16:10, PS 0:1, 1:24 & LA:metastatic 3:23. Table 1 shows frequent G3/4 toxicities (n=25). DLT occurred in 2/2 pts at DL5 (G4 thrombocytopenia, G3 lethargy), defined as the MTD and 1/6 pts at DL4 (G3 lethargy). DL4 was expanded. Median no. of cycles given was 4 (1-24). There were 2/26 PRs and 11/26 SD (disease control 50%, 95% CI 29.9%-70.1%). 22 pts have died. Median PFS and OS were 4.6 m (95% CI 2.3-6.9) and 5.7 m (95% CI 4.6 to 6.7) respectively. Conclusions: In PC GemOx can be safely combined with intermittently administered imatinib at doses of Gem 1,000 mg/m2 and oxaliplatin 85 mg/m2. Compared to treated historical controls, preliminary efficacy data is comparable. G3/4 toxicity DL1 (n=3) DL2 (n=4) DL3 (n=3) DL4 (n=13) DL5 (n=2) Gem 400 mg/m2Ox 85 mg/m2 Gem 600 mg/m2Ox 85 mg/m2 Gem 800 mg/m2Ox 85 mg/m2 Gem 1,000 mg/m2Ox 85 mg/m2 Gem 1,000 mg/m2Ox 100 mg/m2 Diarrhea 0 0 0 1 0 Nausea/vomiting 0 0 0 3 0 Peripheral neuropathy 0 0 0 0 0 Lethargy 0 1 0 6* 2* Infection 0 0 1 2 0 Neutropenia 0 0 0 2 0 Thrombocytopenia 0 0 1 3 1* * DLT in 1 pt. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis