tbuckley/cabot-search huggingface dataset:
Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies
Authors: Michelle Willicombe, Jill Moss, Linda Moran, Paul Brookes, Eva Santos-Nunez, Adam G. McLean, Thomas Cairns, David Taube, Terence H. Cook, Candice Roufosse
Journal: Journal of the American Society of Nephrology (2015)

The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy-free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donor-specific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor-specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation.
Screening and genetic counseling practices for hereditary non-polyposis colorectal cancer (HNPCC)
Authors: S. Karri, S. R. Govindarajan, W. B. Bendure, S. A. Jackson, K. D. McKelvey, R. Govindarajan
Journal: Journal of Clinical Oncology (2007)

6564 Background: HNPCC, the most common cause of hereditary colorectal cancer (CRC), is inherited in an autosomal dominant fashion and caused by micro satellite instability and mutations in mismatch repair genes. Affected patients (pts) and first degree relatives tend to develop colonic and extra colonic tumors that need to be tested for the mutations. Genetic consultation (GC) should be routinely offered to the affected pts and relatives. To assess the utilization of GC, we assessed the frequency of referral for GC for the presence of HNPCC syndrome at our medical center. Methods: Patients with CRC were identified from the tumor registry at the University of Arkansas for Medical Sciences (UAMS) and the Central Arkansas Veterans Healthcare System (CAVHS) from January 1 st 2000 to September, 2006. Pts’ charts were reviewed for synchronous or metachronous HNPCC tumors and family history (FH). FH was categorized as positive according to the Bethesda criteria (BC, 2000–2002), revised Bethesda criteria (RBC, 2003–2006), negative (documented FH but no h/o cancer) or inadequate documentation. Percentage of pts with positive FH for HNPCC syndrome and those with CRC less than 50 years of age (for pts diagnosed 2003–2006) who were referred for GC was calculated. The list of these pts was cross referenced to the list in genetics clinic at UAMS and CAVHS. Results: 858 patient charts were reviewed. Table 1 shows the number of pts meeting criteria for genetic counseling. 138 (16%) pts had inadequate /no documented FH. Of the 720 pts with documented FH, 67 (9.3%) had positive FH and 126(17%) met BC / RBC. Only 13 (10.3%) of 126 pts were referred for genetic counseling. The number of pts eligible for GC increased with inclusion of RBC. However, the percentage of eligible pts referred for GC was extremely low. Conclusions: FH is not adequately documented in many pts presenting with CRC. Only a small percentage of pts who qualify for GC are referred. Education of health care providers for referral to genetics counseling is warranted. No significant financial relationships to disclose. [Table: see text]
Synthetic TGF-ß antagonist promotes healing of injured epithelial surfaces
Authors: F. E. Johnson, Y. Wang, T. Ling, S. Chuang, S. S. Huang, J. S. Huang
Journal: Journal of Clinical Oncology (2006)

18586 Background: Cancer treatment often results in injury to epithelial surfaces. These injuries are often symptomatic and can delay or prevent further treatment. Since transforming growth factor-1 (TGF-ß) mediates inflammation, fibrosis, and epithelial mitogenesis, agents modulating TGF-ß may be useful in treating such wounds. We synthesized a dodecapeptide containing the active site of human TGF-ß. It is a TGF-ß antagonist in vitro. We investigated whether application to cutaneous wounds might promote epithelialization and decrease scarring by directly blocking local TGF-ß activity. Methods: We applied synthetic TGF-ß antagonist (1.5 mM in gel carrier, topically), with gel-only and no-treatment controls, to 6 standardized thermal burn wounds in each of 4 pigs. Wounds were measured and photographed for 41 d., then excised. Wound dimensions and percent epithelialization were calculated from photographs. Scar volume was estimated as surface area (photographs) x depth (microscopy). Statistical analysis employed student’s t-test. Additional experiments utilized skin excision wounds in rabbits and pigs. Recombinant TGF-ß and platelet-derived growth factor (PDGF) were applied to identical wounds in other pigs and rabbits in parallel experiments as additional controls. Results: In TGF-ß antagonist-treated pig burn wounds, epithelialization was complete on d. 26 ± 2 (mean ± SD); control wounds were 70 ± 10% re-epithelialized by d. 26 (p &lt; 0.001). Contraction rate, collagen and fibronectin content, and scar volume were all significantly less in treated wounds. TGF- ß and PDGF each retarded wound epithelialization. Conclusions: Treatment of standard skin wounds with a synthetic TGF-ß antagonist promotes epithelialization in a whole-animal model. This agent may be useful in human epithelial injuries due to chemotherapy or radiation. No significant financial relationships to disclose.
Radiotherapy and concomitant weekly carboplatin and daily etoposide for patients with inoperable biopsy proven glioblastoma multiforme
Authors: J. M. Simon, G. Noel, K. Hoang-Xuan, A. F. Carpentier, K. Mokhtari, S. Racadot, F. Baillet, J. J. Mazeron
Journal: Journal of Clinical Oncology (2004)

1544 Background: This study was performed to evaluate the toxicity and efficacy of concomitant carboplatin and etoposide with external beam radiotherapy in the management of inoperable glioblastoma. Methods: From 8/99 to 10/01, 26 consecutive patients with inoperable biopsy proven glioblastoma were treated with radiotherapy (59.4 Gy in 1.8 Gy/fraction), weekly carboplatin (area under curve = 1.5), and etoposide (given daily as a single oral dose of 50 mg, 1 hour before each treatment session). Informed consent was obtained from all patients. This experimental group was compared to an historical group of 24 patients with inoperable biopsy proven glioblastoma treated with definitive radiotherapy in our institution. Acute toxicity was graded according to World Heath Organization criteria and scored weekly during treatment and within 2 months after the end of therapy. The primary endpoint of this study was overall survival. Results: The two groups of patients were matched for sex ratio, age (median: 55 years [range, 31 to 69 years] and 56 years [range, 40 to 69 years], for the experimental and control groups respectively), tumor location, tumor extension, Karnofsky performance status (median: 80 [range, 60 to 100] and 90 [range, 60 to 100], for the experimental and control groups respectively), and the RTOG recursive partitioning analysis (RPA) classes. The median follow-up was sixty-eight weeks. Median survival times were 40 and 36 weeks, and the 1-year overall survival rates were 46% and 4%, respectively for patients treated with carboplatin and etoposide, and for those treated in the control group (p < 0.02). Carboplatin and etoposide were well tolerated. The incidence of grade 3 and 4 hematological toxicity related to chemotherapy was 12% in the experimental group. Conclusions: Concomitant radiation plus weekly carboplatin and daily etoposide was safe and well tolerable. This regimen seemed to increase overall survival in patients with unresectable glioblastoma. A larger randomized trial is warranted to confirm these results. No significant financial relationships to disclose.
Salvage chemotherapy with gemcitabine, paclitaxel, ifosphamide, and cisplatin (Gem-TIP) for relapsed germ cell tumours (GCT)
Authors: M. J. Wheater, R. Huddart, J. White, G. Rustin, J. Abab, G. M. Mead
Journal: Journal of Clinical Oncology (2009)

e16031 Background: Patients with relapsed metastatic GCT following treatment with cisplatin based combination chemotherapy, may be cured with further intensive chemotherapy. A Medical Research Council trial of TIP achieved 1 year progression free survival (PFS) of 38% with 65% survival (Br J Cancer. 2005;93:178). A more dose intense schedule of TIP with growth factors achieved 2-year PFS of 91% (Proc Am Soc Clin Oncol. 22:2003 [abstr 1537]). Gemcitabine has activity in the treatment of multiply relapsed disease. This study aims to investigate the feasibility of adding gem to TIP with the addition of growth factor support, while maintaining TIP dose intensity, with a view to improving the outcome from TIP alone. Methods: A phase I dose escalation study of Gem-TIP was carried out in patients at first relapse from metastatic GCT following cisplatin chemotherapy. All patients received TIP without dose reduction (paclitaxel 175 mg/m2 d1, cisplatin 20 mg/m2 d1–5, ifosphamide 1 g/m2 d2–6) with GCSF days 7–18 of a 21 day cycle for maximum 4 cycles. 3 dose levels of gem were investigated, 600 mg/m2 d1, 900 mg/m2 d1 and 1,200 mg/m2 d1. Dose limiting toxicity (DLT) was non-haematological grade 3 or 4, except nausea, vomiting and alopecia. Results: 13 patients treated, 12 male, 1 female, age 21–48 years. Baseline histology seminoma 8, non-seminoma 5. Cohort 1: 4 patients treated, 1 withdrew after 1 cycle. No DLT observed. Cohort 2: 3 patients completed treatment with no DLT. Cohort 3: 1 patient treated suffered allergic pneumonitis at cycle 1 complicated by a malignant pleural effusion. A further 5 patients were treated at this dose level. The minimum course duration was 63 days. The mean duration for each cohort was 69 days for cohort 1 and 2, 64 days for cohort 3. Grade 3/4 haematological toxicity was; neutropaenia 9 patients, thrombocytopaenia 10 patients, with 2 episodes of febrile neutropaenia but no bleeding. 10 platelet transfusions were required. 10 patients were assessable for response, 5 CR, 3 PR, 2 PD. At median follow up 18 months the median PFS is 10 months. Conclusions: Gem-TIP can be delivered with 1200mg/m2 gem with manageable toxicity in the context of growth factor support. This dose will be taken forward to a phase II study. No significant financial relationships to disclose.
16α-[<sup>18</sup>f]fluoro-17ß-estradiol (FES)-PET to detect ER-positive tumor lesions in patients with breast cancer with a diagnostic dilemma.
Authors: M. van Kruchten, A. W. Glaudemans, E. F. De Vries, C. P. Schroder, E. De Vries, G. Hospers
Journal: Journal of Clinical Oncology (2010)

1087 Background: It can be problematic to elucidate the nature of a new lesion or complaint with standard techniques. A biopsy is often required, however lesions may be difficult to access. Positron emission tomography (PET) with FES permits quantification of ER expression of all tumor lesions in pts. We analyzed the FES-PET results of 24 pts with breast cancer who presented with a diagnostic dilemma. Methods: Whole body FES-PET was performed using a PET camera with 5 mm spatial resolution or a PET-CT with 2 mm. 185 MBq 18F-FES was given i.v. and a lesion was defined positive when the SUV max was higher than 2.0. Based on complaints and/or lesions pts received standard radiologic procedures. Results: In the 24 scanned pts no infusion related adverse events were noticed. The clinical indications to perform a FES-PET were: (1) to find a substrate for localized pain in 2 pts. (2) to verify whether lesions found by standard techniques were of malignant origin in 14 pts. (3) to proof retained expression of ER after hormone treatment before initiating a next line in 8 pts. In the 2 pts with localized pain, bone scan, and MRI in the patient with lower back pain and CT in the patient with abdominal pain showed no abnormalities, the FES-PET did detect an ER-positive lesion in resp. the left sacroiliac joint and in the gut. Radiotherapy and systemic antitumor treatment was initiated and in both pts their complaints resolved. In 14 pts to verify whether lesions detected on a bone scan (5 pts) or CT/MRI (9 pts) were malignant, in 7 pts these lesions showed 18F]FES uptake. In all the 8 pts the ER expression after more lines of hormonal treatment was still present and an additional line of hormonal treatment was initiated. So in 17 out of 24 patients, FES uptake in tumor lesions was demonstrated. The majority of these lesions that were known by CT, MRI, or bone scans could also be seen on the FES-PET scan, in addition new lesions (bone, lymph nodes, cecum) could be detected in 4 pts. Conclusions: Our preliminary experience with the FES-PET technique indicates that this technique has the potential to support clinical decision making in case of clinical dilemmas in breast cancer pts. Supported by grant RUG 2009-4529 of the Dutch Cancer Society. No significant financial relationships to disclose.
Isolated hepatic iron deficiency despite abundant systemic iron in Mdr2-/- mice: Integrity of the biliary transport system is important in liver iron homeostasis
Authors: Amy Sobbe, David Frazer, Kim Bridle, Lesley Jaskowski, Lesa Ostini, Erika de Guzman, Nishreen Santrampurwala, Gregory Anderson, V. Nathan Subramaniam, Darrell Crawford
Journal: American Journal of Hematology (2013)
Enzyme catalyzed therapeutic activation of NB1011 (N) selectively targets thymidylate synthase (TS)-overexpressing tumor cells: Phase I results
Authors: M. Pegram, C. H. Yeon, N. Ku, C. Gottlieb, M. Shepard, P. Cossum, E. John, S. Iqbal, A. Garcia, H.-J. Lenz
Journal: Journal of Clinical Oncology (2004)

3144 Background: Resistance to fluoropyrimidines (FP) is associated with increased expression of TS. N is a pronucleotide analog that is converted to (E)-5-(2-bromovinyl)-2'-deoxyuridine-5'-monophosphate (BVdUMP, B), a substrate for TS. TS activation of B results in liberation of product(s) preferentially cytotoxic to TS-overexpressing tumor cells. This is associated with induction of p21 and BAX, and arrest in cell cycle progression. Methods: To test the hypothesis that N may be useful in the treatment of FP-resistant cancers, we conducted a phase I study for patients with metastatic colorectal cancer (MCRC) with FP failure within the prior 6 months. Primary endpoints were safety assessment, pharmacokinetics (PK) and determination of maximum tolerated dose (MTD). Patients received escalating doses of N ranging from 200 to 3000 mg/m2/d given intravenously (IV) over 1–2 hours daily x 5 q28d. Results: A total of 45 patients were treated. Plasma PK appear linear with mean cycle 1 day 1 Cmax of 3495 ng/mL at 200 mg/m2/d and 18980 ng/mL at 2000 mg/m2/d. Mean cycle 1 day 1 AUC at 200 mg/m2/d is 2499 ng-h/mL and 18002 ng-h/mL at 2000 mg/m2/d. The half-life of N is just under 1 hour. N is clinically well-tolerated at all dose levels. Up to the 2000 mg/m2/d dose level, the most common adverse events were: Grade (G) 1–2 fatigue (n=8), G 1–2 IV site reactions (n=7), G 1 flushing (n=7), G 1–3 nausea (n=5), G 1–3 anemia (n=5), G 1 abdominal pain (n=5), G 1–2 diarrhea (n=4) and G 1 myalgias (n=4). The MTD has not yet been established. A total of 7 patients (15.6%) have confirmed stable disease for at least 3 months: 2 received 4 cycles (800, 1000 mg/m2/d), 4 received 5 cycles (200, 1250, 2250, 2500 mg/m2/d) and 1 received 6 cycles (2000 mg/m2/d). One patient remains active on study (cycle 5, 2500 mg/m2/d) as of 12/10/03. Conclusions: N is a TS-activated prodrug clinically feasible at doses up to 3000 mg/m2/d IV daily x 5 q28d in patients with FP-resistant MCRC. Phase II studies are planned for patients with TS-overexpressing solid tumors. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NewBiotics NewBiotics NewBiotics NewBiotics
BROKEN HOMES AND SUICIDE
Authors: M B COVENTRY
Journal: JAMA (1965)

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Effects of interleukin-1 alpha on carboplatin-induced thrombocytopenia in patients with recurrent ovarian cancer.
Authors: S Vadhan-Raj, A P Kudelka, L Garrison, J Gano, C L Edwards, R S Freedman, J J Kavanagh
Journal: Journal of Clinical Oncology (1994)

PURPOSE The purpose of this study was to evaluate the clinical safety and ability of interleukin-1 alpha (IL-1 alpha) to ameliorate carboplatin-induced thrombocytopenia and thus allow patients with ovarian cancer to receive multiple cycles of chemotherapy at full doses. PATIENTS AND METHODS IL-1 alpha was administered by continuous intravenous infusion daily at doses of 0.1 to 10 micrograms/m2/24 hours over 4 days (96 hours) before the first cycle and/or following the second cycle of carboplatin in 21 patients with recurrent ovarian cancer who had platinum-responsive disease. In cycle no. 1, patients received carboplatin (400 mg/m2) alone, while in cycle no. 2 carboplatin was followed by IL-1 alpha. RESULTS Treatment with IL-1 alpha before carboplatin was associated with moderate leukocytosis (baseline mean, 6.15 x 10(3)/microL; maximum mean, 17.9 x 10(3)/microL; P &lt; .001) and significant increases in platelet counts (baseline mean, 241 x 10(3)/microL; maximal mean, 392 x 10(3)/microL; P &lt; .001). IL-1 alpha following carboplatin significantly reduced the duration of thrombocytopenia (days platelet count &lt; 50,000, 5.1 to 2.9 days; P = .003) and increased the area under the curve (AUC) of platelets as a function of time (P &lt; .001). The mean nadir platelet counts were 54,000/microL and 67,000/microL (P = .08) in cycles no. 1 and 2, respectively. In fact, seven of 12 patients given 3 micrograms/m2/d of IL-1 alpha had less thrombocytopenia in cycle no. 2 than in cycle no. 1. Treatment with IL-1 alpha was associated with the tolerance of multiple cycles of carboplatin at the same dose in several patients. The maximum-tolerated dose (MTD) was 3 micrograms/m2/d; fever, chills, hypotension, and fluid retention were dose-limiting toxic effects. CONCLUSION These findings demonstrate that IL-1 alpha can enhance recovery of platelets following carboplatin therapy and suggest a potential therapeutic role for IL-1 alpha in attenuating thrombocytopenia associated with chemotherapy.
Brief Communication : C-Type Particles in Baboon ( Papio cynocephalus ) Pre-implantation Embryos 2
Authors: S. S. Kalter, M. Panigel, D. C. Kraemer, R. L. Heberling, R. J. Helmke, G. C. Smith, A. Hellman
Journal: JNCI Journal of the National Cancer Institute (1974)
Twelve-year follow-up of a randomized trial of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell support (ASCS) for high-risk primary breast carcinoma
Authors: E. O. Hanrahan, D. Frye, A. U. Buzdar, R. L. Theriault, D. J. Booser, V. Valero, S. E. Singletary, J. L. Gajewski, R. E. Champlin, G. N. Hortobagyi
Journal: Journal of Clinical Oncology (2005)

663 Background: We previously reported on the results of a randomized trial of standard-dose chemotherapy with 5-fluorouracil, Adriamycin and cyclophosphamide (FAC) versus FAC followed by HDC and ASCS for high-risk primary breast cancer (J Natl Cancer Inst. 2000;92[3]:225–33). At a median follow-up of 6.5 years, no relapse-free (RFS) or overall survival (OS) advantage was seen between the two arms. Morbidity was increased with HDC. This report updates the survival analysis. Methods: Patients with ≥ 10 positive axillary nodes after primary surgery or ≥ 4 positive nodes at surgery following primary chemotherapy were eligible. All patients were to receive 8 cycles of FAC. Patients were stratified by stage, and randomly assigned to receive no further chemotherapy or 2 cycles of high-dose cyclophosphamide, etoposide, and cisplatin with ASCS. Primary endpoints were RFS and OS. Survival was calculated by the Kaplan-Meier method. The log-rank statistic was used to compare survival between treatment arms. Results: From 1990 to 1997, 78 patients were registered: 48 after primary surgery and 30 after primary chemotherapy. 39 patients were randomly assigned to FAC alone, and 39 to FAC followed by HDC. The median follow-up of live patients is 143 months (range 45 to 169 months). Detailed outcomes are shown in the table below. In intention-to-treat analysis, there was no significant difference in RFS (p = 0.114) or OS (p = 0.136) between the two groups by log-rank test. There have been no late toxicities since the last report. Conclusions: With 12 years of follow-up, this study continues to show no RFS or OS advantage associated with the use of HDC for high-risk primary breast carcinoma. No significant financial relationships to disclose.