bluuebunny/crossref_metadata_2025 huggingface dataset:
Gastric MALT lymphoma (GML) after helicobacter pylori (Hp) eradication: Prognostic value of histological and molecular findings in 120 patients of a prospective multicenter trial
Authors: Wündisch T. , Neubauer A. , Gunther A. , Stolte M.
Published: March 2020

8041

Background: Long lasting remissions occur in most patients with localized GML after Hp eradication. Ongoing B-cell clonality and the translocation t(11;18) have been described as factors associated with no response, relapse and histological residual disease (hRD). Systematic evaluation of histological findings associated with the clinical course and molecular data has not been described yet. Methods: Detailed analysis of long term follow up data of a prospective multicenter trial including 120 patients (median follow up > 5 years) with Hp-positive stage I1E GML was performed. Histological and molecular data of biopsies from 1187 endoscopies were analyzed using a large data base. Hp-status, granulocytic-, lymphocytic infiltration and intestinal metaplasia (IM) were histologically graduated according to the Updated Sydney system. The histological findings empty lamina propria (ELP), fibrosis, lymphoid follicles (LF) and lymphoepithelial lesions and lymphoid aggregates (LA) were evaluated. Prospective molecular data concerning B-cell clonality as well as retrospective data concerning the status of the translocation t(11;18) were also collected. Results: LA and LF were more present in patients not responding towards Hp eradication [P < 0.0001]. ELP in high frequency is a positive predictor for reaching complete remission (CR) [P= <0,0001]. Fibrosis was only found in CR patients. In patients reaching a histological CR presence of LA and LF were associated with hRD and relapse [P=0.04]. LA / LF were also more prevalent in t(11;18) positive and patients with ongoing B-cell clonality. An association between ongoing monoclonality and t (11;18) was also demonstrated [p=0,012]. In 66% of patients IM was detected, it does not disappear during long term follow up after successful Hp eradication. Conclusions: Simple histological findings can help to predict the clinical course of GML after Hp eradication and are associated with known molecular data.

No significant financial relationships to disclose.
Oral combination chemotherapy for refractory/relapsed lymphoma with the PEP-C (C3) regimen (daily prednisone, etoposide, procarbazine, cyclophosphamide): Low-dose continuous metronomic multidrug therapy
Authors: Coleman M. , Ruan J. , Furman R. R. , Niesvizky R. , Martin P. , Leonard J. P.
Published: March 2020

8064

Background: Oral daily low dose chemotherapy (metronomic therapy) may maintain continuous sequential drug levels to impact endothelial cell viability (anti-angiogenesis) or to overcome drug resistance. Methods: We retrospectively reviewed data on 97 patients with refractory/relapsed Hodgkin's and non-Hodgkin's lymphoma treated with the PEP-C (C3) regimen, which consists of oral prednisone (20 mg in am), cyclophosphamide (50 mg at noon), etoposide (50 mg at dinner) and procarbazine (50 mg at h.s.with an oral anti- emetic). Medications were administered daily until the white blood cell count fell to less than 3000/dl, when treatment was held until recovery from the nadir. Treatment was then reinstituted on a daily, alternate day, or fractionated weekly basis (e.g. 5 of 7 days) based on patient tolerance. Doses given per day were constant. Results: All patients had been previously treated, with 80% having received 2 or more prior therapies and 57% with 3 or more previous regimens. Overall, 69 patients (71%) achieved a response. Responses by histology were: follicular (n=26) 92%, mantle cell (n=22) 82%, marginal zone (n=14) 71%, small lymphocytic (n=12) 67%, Hodgkin's lymphoma (n=9) 44%, diffuse large B cell (n=9) 33%, and T cell (n=5) 40%. Time on therapy of responding patients ranged from 3 weeks to 48 months (median 9 months, mean 11 months). Toxicity was predominantly myelosuppression, with hospitalization for infection occurring in 10 patients. Five patients developed H. zoster. Gastrointestinal effects prompting cessation of therapy occurred in 6 subjects, and 2 patients developed hematuria. Conclusions: Low dose, continuous (metronomic) combination chemotherapy with PEP-C is an easily administered, generally well- tolerated and effective treatment for relapsed/refractory lymphoma, particularly in indolent and mantle cell histologies.

No significant financial relationships to disclose.
High-dose carmustine (BCNU), etoposide (VP-16), cytarabine (Ara-C), and cyclophosphamide-BVAC with autologous transplant (ASCT) in relapsed and refractory Hodgkin disease (HD): Long-term follow-up of 89 patients
Authors: Iyengar T. , Hayashi M. , Leopold C. , Smith B. J. , Gingrich R. , Carter T. , de Magalhaes-Silverman M.
Published: March 2020

8068

Background: High dose chemotherapy followed by ASCT has been established as the therapy for refractory and relapsed HD. Relapse remains the primary contributor to an unsuccessful outcome after ASCT. Intensification of the conditioning regimen is one means of decreasing relapse and improving results. We report our experience with an augmented preparative regimen in patients (pts) with relapsed or refractory HD undergoing ASCT. Methods: Retrospective analysis of 89 consecutive pts from October 1984 to October 2004. All pts received high-dose chemotherapy with BCNU 600mg/m2 IV day -8, Etoposide 400mg/m2/day days -7, -6, -5, and -4, Ara-C 3gm/m2 IV every 12 hours for 8 doses starting day -7, and Cyclophosphamide 90mg/kg IV on day-2 followed by bone marrow (40 pts), peripheral blood (43 pts) or both (6 pts) rescue. Ten pts received planned XRT post-transplant. Survival data were estimated using Kaplan-Meier curves. Cox proportional hazards regression was used to assess the impact of variables on disease-free survival (DFS) and overall survival (OS). Results: A total of 89 pts were identified. Median age was 31 (range 16–62); 51 pts (57.3%) had received one prior therapy at the time of transplant. At transplant only 28 pts (34.6%) were in CR; 79.8% had sensitive disease (CR plus PR).Time to transplant was < 1 year for 17% of pts. With a median follow-up of 811 days, the 5 and 10-year DFS rates were 63.3% and 60.4%, respectively. The estimated 5 and 10- year OS rates were 47.3% and 33.7%. The rate of secondary malignancies at 10 years was 7.8%. Lack of B symptoms and stage at transplant were associated with improved DFS (p= 0.01 and p= 0.0005, respectively) and OS (p=0.002 and p=0.02, respectively). Patients with primary induction failure and resistant relapse did as well as patients with sensitive disease. Conclusions: Though ASCT has been beneficial in prolonging DFS and OS in pts with chemosensitive HD, there has been conflicting data regarding refractory disease. We propose that an intensified regimen, i.e. BVAC, may be of benefit in that setting. Only a large randomized trial can determine whether intensification of the preparative regimen can improve OS for such a population.

No significant financial relationships to disclose.
A multi-center, open-label study to evaluate the safety and efficacy of pentostatin, cytoxan, and rituxan (PCR) in the treatment of previously untreated or treated, stage III or IV, low-grade B-cell non-Hodgkin lymphoma (NHL) or bulky stage II lymphoma
Authors: Christiansen N. P. , Mena R. , Markan Y. , Pandit L.
Published: March 2020

8071

Background: The decision to treat indolent B-cell NHL is often based on progressive disease, worsening symptoms, and increasing hematological variations. When treatment is indicated, these lymphoproliferative disorders are very sensitive to combination chemotherapies. Combination therapy with these agents, pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody, represents a promising approach in the treatment of these patients. Most regimens have utilized fludarabine (F) as the purine analog but the myelosuppression and immunosuppression of (F) combinations frequently results in severe infections. Methods: Eligibility criteria allow previously treated and treatment-naïve patients diagnosed with bulky stage II or low-grade stage III/IV NHL (REAL classification) to be enrolled. Treatment consisted of intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for a total of up to 10 cycles. Clinical evaluation was performed after cycles 2, 4, 6 and 8 and 10 (if necessary). Results: The intent-to-treat (ITT) population consisted of 87 NHL patients (median age 62.5, range 29–84) who received a total of 476 cycles (median 6 per patient). The ECOG status was 0 (62.4%), 1 (37.6%) and 2 (0%). The overall response rate of the 80 evaluable patients was 72.5% (CR 11.3%, Cru 12.5%, PR 48.8%). 14 cases of grade 4 and 17 cases of grade 3 neutropenia were documented. There were a total of 4 deaths due to acute myocardial infarction, NSCLC, a suspected cardiac event and 1 unknown cause of death. Conclusions: This immunochemotherapeutic regimen is active in indolent Grade III/IV NHL and the incidence of significant toxicities was low. Future trials evaluating the use of rituximab as maintenance therapy following this PCR regimen may also be warranted with a future goal towards possibly increasing the overall survival of patients with NHL. The presented results are preliminary and the study is currently on-going.

No significant financial relationships to disclose.
Clinical characteristics and course of chronic lymphocytic leukemia patients with the combination favorable and unfavorable cytogenetics
Authors: Harting R. R. , Venugopal P. , Hsu W. , Catchatourian R. , Ogundipe O.
Published: March 2020

8086

Background: Patients with CLL have a highly variable clinical course. Genomic aberrations detected by FISH have been shown to correlate with survival and treatment free interval (TFI). Patients with the presence of 17p or 11q deletions (del) either alone or in combination with other cytogenetic abnormalities have the worst prognosis while patients with 13q del as a sole abnormality have the best prognosis. Our objective was to further investigate poor prognosis CLL patients with either del 17p or 11q to determine if the addition of the favorable 13q del influences the predicted clinical course and survival. Methods: We performed a retrospective chart review on 22 patients (pts) who had been identified by FISH as having either the combination of del 17p and 13q or del 11q and 13q. Results: 128 CLL FISH panels were performed from April of 2003 through October of 2006. Twenty-two pts (17%) had either del 17p and 13q (9%) or del 11q and 13q (9%). Historical data notes a frequency of 7% and 8% for deletions 17p and 11q, respectively, and 55% for 13q as a sole aberration. The median age was 66 yrs, the majority of whom were male (73%). Two of 22 pts (9%) presented with advanced stage disease. Splenomegaly was seen more often in the 17p/13q pts (36%) vs 11q/13q pts (9%). With a median follow up of 46 months since diagnosis, the median TFI for all patients (20 known) was 56 months. TFI was 13 months for patients with 17p/13q del; whereas TFI was not reached for patients with 11q/13q. Historical data noted a TFI for patients with deletions 17p, 11q, and 13q (as a sole aberration) as 9, 13, and 92 months respectively. The median survival from diagnosis was not reached for the group overall or for either combination of genetic abnormalities. Historical data noted, with 70 months follow up, a median survival of 108 months overall and 32, 79, and 133 months for 17p, 11q, and 13q (as a sole aberration) respectively. Conclusions: The addition of favorable cytogenetics, del 13q, in a CLL patient with an unfavorable cytogenetic pattern (either del 17p or del 11q) appears to improve the predicted clinical outcome and survival. Additional follow up and prospective studies are needed to further define which genetic subgroups help to prognosticate CLL patients.

No significant financial relationships to disclose.
Do patients with MGUS require a bone marrow biopsy?
Authors: Singh J. , Malani A. K. , Huang C. H. , Hashmi M. , Mathur S. C. , Stasik C. , Van Veldhuizen P.
Published: March 2020

8117

Monoclonal gammopathy of undetermined significance (MGUS) increase in prevalence with age and it is associated with risk of progression to plasma cell disorder. According to ASH guidelines, patients (pts) should have a complete blood count (CBC), creatinine, calcium, and a complete bone survey and periodic follow up. There has been no clear-cut guideline regarding the role of bone marrow biopsy in these patients. There is suggestion in the literature that bone marrow aspiration and biopsy is indicated if the M protein is 1.5 g/dL. Hypothesis We hypothesize that the increase in serum immunoglobulin is correlated with an increase in plasma cell in the bone marrow biopsy. Methods: We performed a retrospective chart review of 327 MGUS veteran patients seen from 2002 to 2005. Diagnostic criteria for MGUS were defined as <3 g/dL serum monoclonal protein, <10 % plasma cells in the bone marrow and absence of radiographic or laboratory abnormality related to the plasma cell proliferative process. Patients with smoldering myeloma were excluded. Bone marrow biopsies were available on 97/327 patients. Bone marrow biopsy with plasma cell percentage, serum protein electrophoresis (SPEP) and immunofixation (SFE), and immunoglobulin levels of these patients were retrieved and statistical analysis was performed by using Pearson correlation coefficient and linear regression analysis to detect the correlation between plasma cell percentage and immunoglobulin levels. Results: Of the 97 patients whom the bone marrow biopsy was available, 66 patients had IgG, 15 had IgA and 16 had IgM monoclonal paraprotein. There was linear correlation between serum IgG and IgA levels with the percentage of plasma cells in the bone marrow. (p< 0.001 and < 0.02 respectively. By regression analysis, using a cut off value of 10% plasma cells in the bone marrow, the predicted level of IgG and IgA immunoglobulin was 2124 mg /dl and 1564 mg/dl respectively. There was no correlation between IgM immunoglobulin and plasma cell percentage in the marrow. Conclusion: There is a linear correlation between serum IgG and IgA immunoglobulin with plasma cell percentage in the bone marrow. Bone marrow biopsy with plasma cell percentage of 10% or higher may be predicted in patients with MGUS with IgG or IGA above 2g/dl and 1.5g/dl respectively.

No significant financial relationships to disclose.
Use of autologous bone marrow cells following high-dose chemotherapy (HDCT) for patients (pts) with recurrent lymphoma in whom stem cell harvesting from the peripheral blood was inadequate
Authors: Kumaran G. , Murray J. , Sweeney D. , Liakopoulou E. , Radford J. A.
Published: March 2020

8124

Background: HDCT with autologous stem cell rescue (ASCR) is an established treatment for recurrent Hodgkin and non- Hodgkin lymphoma (HL, NHL) but some of these pts fail to mobilise adequate numbers of CD34+ cells from the peripheral blood (PB). Harvest of bone marrow (BM) stem cells and use of these alone or in combination with PB derived cells is an option but there are concerns about feasibility and outcome. Methods: 29 pts who had HDCT after failed PB stem cell harvest between July 1999 and December 2005 were studied in terms of CD34+ cell yield (PB and BM), transfusion dependence, engraftment and survival. Results: There were 17 males and 12 females (median age 49yrs, range 19–66) with recurrent HL (n=16) or NHL (n=13). All had received at least 2 lines of chemotherapy (10 pts =3) and 7 had received radiotherapy (5 mediastinal, one neck and one abdominal field). Mobilisation of CD34+ cells from PB was attempted using chemotherapy followed by filgrastim. 22 pts proceeded to leukapheresis on the basis of predictive CD34+ counts (median collects 2; range 0–4) with a median total collect of 0.98×106 CD34+cells/kg (range 0.03–1.84). Subsequently, all pts had a BM harvest producing a median collect of 1.63x106 CD34+cells/kg (range 0.45–4.75). 29 pts then received BEAM/CBV followed by re-infusion of PB+BM cells except in 7 pts where only BM cells were available. In 26/29 pts surviving to day 100; total CD34+ cells infused, 2.37×106/kg (range 1.73- 5.0), time to neutrophils >0.5×109/L, 12 days (range 9–23), platelet units transfused, 6 (range 0–24), red cells units transfused 6 (range 0–18) (all medians). 2 pts continued to have red cell transfusions beyond day 100. 3/29 pts died due to severe neutropenia/septicaemia at days 23–25 (treatment related mortality 10.3%); the CD34+ dose received by these pts was 1.97×106/kg in 2 and 1.84×106/kg in 1. Beyond day 100, 9 pts have died from HL/NHL and 2 are lost to follow-up. Conclusions: In patients with HL/NHL who fail to mobilise adequate numbers of CD34+ cells from PB, a BM harvest can produce a combined BM/PB collect capable of producing haemopoeitic reconstitution following HDCT without excessive toxicity.

No significant financial relationships to disclose.
Association between use of non-steroidal anti-inflammatory drugs (NSAIDs) and statins and the risk of cutaneous melanoma (CM): A case-control study
Authors: Curiel C. , Gomez M. L. , Atkins M. B. , Nijsten T. , Stern R. S.
Published: March 2020

8500

Background: CM accounts for more than 77% of skin cancer deaths. Chemoprevention strategies have been hampered by the lack of supporting epidemiological data. Methods: A case control study examined the association between statins and NSAIDs use and CM in people over 40 years of age. A total of 400 histologically confirmed CM cases were recruited within 3 months from diagnosis between 3/04 and 12/06. Controls included 600 individuals without history of CM matched for age, gender and neighborhood in a ratio of 1:1.5. All completed a standardized telephone questionnaire that captured demographic characteristics, CM risk factors, and drug exposure history (length and frequency of use). Odds ratios were calculated with testing for statistical significance based on Chi square analysis. Results: To date, all 400 CM cases and 547 controls have been recruited. Interview results out of 387 cases (192 F/195 M) and 505 controls (254 F/251 M) were included for data analysis. Mean age was 58.4 and 58.5 years. The most significant CM risk factors included: red hair phenotype OR: 2.29, history of non-CM skin cancer OR: 2.28, family history of CM OR: 1.76, light complexion OR: 2.7, and history of more than 4 sunburns in childhood OR: 4.06. 100 cases vs. 190 of the controls had been exposed to statins OR 0.58 (CI:0.43–0.78); no greater protective effect was detected with increased duration of statin use (p=0.87 for heterogeneity of ORs for =5 vs. <5 yrs). 238 cases vs. 397 controls reported the use of NSAIDs, OR 0.44 (CI 0.32–0.59). 43 cases reported the use of aspirin-ASA for = 5 years vs. 92 controls OR: 0.37 (CI: 0.20–0.68). Similar results were observed with exposure to other NSAIDs with 38 cases reporting the use for = 5 years vs.109 controls, OR: 0.35 (CI: 0.24- 0.50). Conclusions: This study suggests that extended use of NSAIDs decreases the risk of CM development. Although any statin use demonstrated a decreased risk, the lack of an association between duration of use and protective effect raises questions about a true causal relation. Further analysis with respect to the CM subtype and specific exposure (by dose, and frequency of use) to these groups of drugs may lead to the design of CM chemopreventive clinical trials. Final analysis will be presented at ASCO.

No significant financial relationships to disclose.
Randomized phase III study of paclitaxel plus carboplatin with or without sorafenib as second-line treatment in patients with advanced melanoma
Authors: Agarwala S. S. , Keilholz U. , Hogg D. , Robert C. , Hersey P. , Eggermont A. , Grabbe S. , Gonzalez R. , Patel K. , Hauschild A.
Published: March 2020

8510

Background: Sorafenib (SOR), a potent and selective multi-kinase inhibitor, exerts its anti-tumor and anti-angiogenic effects via inhibition of VEGFR-1, -2, -3, PDGFR-a, -β, and Raf. Promising results from a single-arm study of paclitaxel and carboplatin plus sorafenib (PC+SOR) in advanced melanoma warranted further investigation in a randomized phase III trial. Methods: Eligibility criteria: measurable disease by RECIST, progressive disease (PD) on dacarbazine or temozolomide-containing regimen. Prior adjuvant immunotherapy was allowed; pts with active brain metastases were excluded. Pts stratified by stage (unresectable III vs IV, M1a/M1b vs M1c) and ECOG PS (0 vs 1) were randomized to receive P 225 mg/m2 and C AUC=6 on day 1 every 3 wks + oral placebo (PL) or oral SOR 400 mg bid on Days 2–19 every 3 wks until the occurrence of PD or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Using a two-sided test with a = 0.01, 173 PFS events were needed to detect a hazard ratio (HR) of 0.56 (SOR/PL) with 90% power. The secondary endpoints were overall survival, objective response rate (ORR) and time to progression. Results: 270 pts randomized over 12 mos in equally balanced groups had: median age 57 yrs, male 63%, ECOG PS 1 46%, Stage IV M1c 69% and elevated LDH 46%. At the time of analysis by independent assessment, the median PFS of PC+PL vs PC+SOR was 17.9 wks (99% CI: 11.3, 22.9) vs 17.4 wks (99% CI: 11.9, 23.1), HR 0.906 [p=0.492]; PFS rate at Day 180 was 29% vs 32%, ORR was 11% vs 12%. Both regimens were well-tolerated with the following selected = Grade 3 toxicities in PC+PL vs PC+SOR: neutropenia (46% vs 49%), febrile neutropenia (7% vs 9%), thrombocytopenia (12% vs 28%), sensory neuropathy (13% vs. 20%), thrombosis/embolism (6% vs 4%), rash/desquamation (0 vs 7%), hand-foot skin reaction (0 vs 7%), fatigue (10% vs 16%), diarrhea (3% vs 8%) and hemorrhage (3% vs 2%). There were 2 deaths, possibly related to treatment with PC+SOR. Conclusions: The addition of SOR to PC did not improve PFS or ORR in this second-line patient population. Toxicity of PC+SOR is tolerable. The utility of PC+SOR in chemotherapy-naïve advanced melanoma pts remains an important question and a phase III trial is currently in progress (E2603).

[Table: see text]
VEGF, VEGFR1, and VEGFR2 expression in melanoma
Authors: Mehnert J. M. , McCarthy M. M. , Aziz S. A. , Sznol M. , Flaherty K. T. , Camp R. L. , Rimm D. L. , Kluger H. M.
Published: March 2020

8520

Background: Metastatic melanoma is a chemoresistant disease with poor prognosis. Angiogenesis plays a role in progression and metastasis of melanoma. Identifying angiogenic molecules that are differentially expressed between benign and malignant tissues may enable us to create an assay to predict sensitivity to antiangiogenic agents, thus guiding selection of patients for treatment. VEGF signals through its receptor VEGFR1/flt-1 (R1) but is thought to mediate most of its angiogenic and proliferative effects through VEGFR2/flk-1/kdr (R2). In smaller melanoma studies, VEGF, R2 and less commonly R1 expression was associated with disease aggression. We characterized VEGF, R1, and R2 expression on a cohort of 540 nevi and 548 melanomas. Methods: We stained tissue microarrays to assess VEGF, R1, and R2 expression by automated quantitative analysis (AQUA), an objective method for analysis of protein levels. We used S100 to define pixels as melanoma (tumor mask) within the array spot, and measured intensity of VEGF, R1, and R2 expression using Cy5 conjugated antibodies within the mask. Results: VEGF, R1, and R2 expression was significantly higher in melanomas than in nevi by unpaired t-tests (p<0.0001). VEGF and R2 expression was higher in metastatic than primary specimens (p<0.0001). Differential expression of R1 between metastatic and primary specimens was less pronounced (p=0.0158). R2 expression correlated with Breslow depth > 2 mm (p=0.0129). Cox univariate analysis revealed an association between decreased survival and expression of VEGF (p= 0.0488) and R2 (p=0.0035); however, this was not independent of disease stage. Conclusions: VEGF, R1, and R2 expression is higher in malignant melanocytes than in their benign counterparts and higher in metastatic than primary specimens. This association with disease aggression underscores the importance of these proteins as therapeutic targets. Differential expression of R2 was found to be more significant than R1, supporting the belief that VEGF mediates its effects through R2 in malignancy. To our knowledge, this is the largest study to examine the VEGF pathway in melanoma. Future clinical trials of antiangiogenic agents in melanoma should include correlative serum and tissue assays of VEGF, R1, and R2 as biomarkers of response to therapy.

[Table: see text]
Phase II trial of extended-dosing temozolomide in patients with melanoma
Authors: Rietschel P. , Ejadi S. , Wolchok J. , Krown S. , Gerst S. , Jungbluth A. , Busam K. , Panageas K. , Smith K. , Chapman P.
Published: March 2020

8531

Background: To test the hypothesis that the ∼30% response rate we observed in metastatic melanoma (mel) patients (pts) treated with temozolomide (TMZ) using an extended dosing schedule with either thalidomide or interferon was largely due to TMZ alone, we conducted a phase II trial of TMZ alone. We also hypothesized that mel expression of methylguanine methyltransferase (MGMT) would correlate with drug resistance. Methods: Stage IV mel pts without brain metastases or prior chemotherapy were stratified into two cohorts based on whether or not they had stage M1c disease. Each cycle consisted of TMZ 75 mg/m2/day for 6 weeks followed by 2 weeks with no treatment. Treatment cycles were repeated as long as pts did not progress. The primary endpoint was the proportion of complete or partial responses by RECIST criteria. The trial was powered to exclude the null hypothesis that the response rate in each cohort was <30%. MGMT promoter methylation status was assessed by methylation-specific pyrosequencing. In pts with insufficient tumor material for pyrosequencing, MGMT expression was measured by immunohistochemistry using the monoclonal antibody MT3.1. Results: To date we have accrued 48 pts, 23 in the M1c cohort. 7 pts are still receiving treatment and are not yet evaluable for response. There have been 4 partial responses observed, 2 in each cohort. The median number of cycles was 2 (range 1–6). 9/41 pts (22%) were stable for =6 months and received =3 cycles. 56% of pts developed CD4+ lymphopenia (<500/μl) during treatment; 37% of pts developed CD4+ lymphopenia <200/μl and received PCP prophylaxis. Opportunistic infections were not observed. Conclusions: The overall response rate is 9.8% (95% CI 0.8%-19%). The estimated median survival is 11 months for the stage III/M1a/b cohort and 9.7 months for the M1c cohort. To date, the response proportion to TMZ alone appears to be <30%. There would need to be 3 more responses in a cohort to reject the null hypothesis for that cohort. MGMT analyses are ongoing and will be used to determine if promoter methylation status correlates with objective response rate or time to progression. The study was supported by Schering-Plough.

No significant financial relationships to disclose.
Final results of a phase I study of daily PI-88 as a single agent and in combination with dacarbazine (D) in patients with metastatic melanoma
Authors: Millward M. , Hamilton A. , Thomson D. , Gautam A. , Wilson E.
Published: March 2020

8532

Background: PI-88 is a heparan sulfate mimetic that inhibits angiogenesis and metastasis directly and via release of tissue factor pathway inhibitor (TFPI). PI-88 has shown some efficacy in an intermittent dosage regimen (250 mg/day 4 days/week) in melanoma (Thomson et al, ASCO 2005). This study tested PI-88 7 days per week alone (group 1) and in combination with 3 weekly D (group 2). Methods: Eligibility included inoperable metastatic melanoma, no prior chemotherapy, PS 0–1, adequate organ function, no recent use of heparin, negative anti-heparin antibody (AHA), no concurrent use of anti-coagulants or anti-platelet agents, no history of GI bleeding. Group 1 cohorts received daily PI-88 in doses of 140 mg, 190 mg and 250 mg. Group 2 received PI-88 commencing at the level below the single agent MTD plus D 1,000 mg/m2 every 21 days. Group 1 pts who had PD could continue PI-88 with the addition of D. FDG-PET scans were performed prior to and after 6 weeks PI-88 in Group 1. Free TFPI was measured in serum prior to and up to 2hr post first dose PI-88 in group 1. Results: Group 1 - DLT occurred in 0/3 (140 mg), 0/3 (190 mg) and 2/3 (250 mg) pts. Group 2 - DLT occurred in 1/6 (140 mg) and 0/4 (190 mg) pts. All DLTs were AHA positive grade III/IV thrombocytopenia with in 1 pt (250 mg) cerebral venous sinus thrombosis. No other major toxicities and no increase in expected DTIC toxicities were observed. 4 group 1 pts had pre/post PET scans. One pt had 50% fall in SUVmax with radiologic SD for 4 months. No radiologic responses occurred with PI-88 alone. 3/9 pts in group 2 had radiologic PR. 2/5 group1 pts who had D added to PI-88 had PR. Free TFPI increased from 6.9 ± 1.9 ng/ml just prior PI-88 to 56.1 ± 19.4 30 min post PI-88. The elevated levels were maintained at 60 and 120 min. Elevation of free TFPI did not correlate with PI-88 dose. Conclusion: The recommended phase II dose of continuous daily PI-88 is 190mg alone and in combination with D 1,000 mg/m2 every 3 weeks. An ongoing randomised study is comparing D 1,000 mg/m2 plus PI-88 190mg/day to single-agent D.

No significant financial relationships to disclose.
Health-related quality of life measures in melanoma patients receiving pulsed high-dose intravenous interferon alpha 2b (IFNα2b)
Authors: Mohr P. , Hauschild A. , Trefzer U. , Neuber K. , Enk A. , Raas K. , Gogas H. , Kuechler T. , Weichenthal M.
Published: March 2020

8536

Background: Major problems of high-dose interferon (HDI) in patients with malignant melanoma (MM) result from side effects and impairment of quality of life (QoL). Up to now it is unclear whether intraveneous (iv), subcutaneous (sc), or both components of HDI treatment are necessary for the efficacy in adjuvant treatment of MM. The adjuvant phase III DeCOG MM-ADJ-5 trial evaluates efficacy, safety, and tolerability of pulsed high-dose intravenous IFNa2b. In this prospective, randomized trial, 3 courses of IFNa2b 20 Mio IU/m2 iv on 5 days a week for 4 weeks repeated every 4 months are compared to the standard HDI regimen. The higher iv dosage produces more toxicity, but for a shorter period of time, since patients in the pulsed treatment arm are 9 months off treatment as compared to the conventional sc treatment with 10 Mio IU/m2 three times a week given for 11 months after 4 weeks of iv therapy. Methods: With a planned recruitment of 600 patients, an interim analysis of QoL has been performed after half of the patients completed treatment. EORTC QLQ- C30 questionnaire modified for interferon side effects was obtained before therapy, and at 4, 16, 24, and 40 weeks of treatment. The global QoL items were obtained weekly by a visual analogue scale over the whole year of treatment. Additionally, the side effects were scored using CTC- AE toxicity levels, and dose modifications were recorded. Results: A total of 300 patients were evaluated. After 4 weeks of initial iv HDI treatment the global QoL score decreased similarly in both treatment groups (35% vs. 41%). Four weeks after the initial iv pulse, the global QoL score completely recovered in the experimental arm (104%). In the conventional HDI, QoL remained reduced by an average 22% during the whole subcutaneous treatment phase. During the second and third iv-pulse in the experimental arm, QoL again decreased and completely recovered thereafter. Overall, the cumulative QoL score measured for 12 months treatment was significantly in favour of the pulsed regimen (+16% AuC value). Conclusions: Patients under pulsed adjuvant HDI treatment experience significantly less impairment of QoL and may therefore have a higher rate of completing the scheduled dosage.

[Table: see text]
A phase II trial of dacarbazine (DTIC) and bevacizumab in patients with metastatic melanoma
Authors: Munzone E. , Testori A. , Minchella I. , Mosconi M. , Passoni C. , Verri E. , Cossu Rocca M. , Lambiase A. , Goldhirsch A. , Nolè F.
Published: March 2020

8579

Background: Dacarbazine (DTIC) has been approved for treating metastatic melanoma in the 1970s, and as a single agent gives a response rate of about 20%. There have been efforts to ameliorate this poor result by using DTIC in different combinations without a significant improvement. In addition, new studies with melanoma cells in vitro show that DTIC causes transcriptional up-regulation of vascular endothelial growth factor (VEGF), suggesting a potential clinical benefit from the concomitant treatment of DTIC and anti-VEGF therapy. The purpose of this study is to determine whether a combination therapy of bevacizumab and DTIC is safe and can increase response rate and progression-free survival in patients (pts) with metastatic melanoma. Methods: From June 2006 to December 2006, 8 chemo-naive pts (1 female and 7 males) with metastatic melanoma were enrolled in the study. The median age was 53 (43–74) and PS was 0–1. Patients received DTIC 800 mg/m2 iv every 4 weeks and bevacizumab 10 mg/kg iv every 2 weeks. A treatment cycle consisted of 28 days. Results: Among 5 evaluable pts there were 1 partial response, 2 stable disease and 2 progressions, 3 pts were not evaluable because it is too early. Median number of administered cycles was 2 (2–6). The toxicity profile was particularly favourable with no G3/G4 haematological toxicity. Other most commonly seen toxicities were: nausea/vomiting (22%), mucositis (13%), diarrhea (9%). Proteinuria 1+ was reported in 3 cycles (13%). One patient with an early progression had also a G2 increase in blood pressure with a dilatative cardiomyopathy. Conclusions: The combination treatment resulted well tolerated and with a sufficient anti-tumor activity to warrant the continuing of enrolment. Updated efficacy and safety data will be presented.

No significant financial relationships to disclose.
Patterns and consequences of missed work after diagnosis of breast cancer
Authors: Mujahid M. , Janz N. K. , Hawley S. T. , Hamilton A. , Katz S. J.
Published: March 2020

9015

Background: Work loss is a potential adverse consequence of cancer. However, there is little research on patterns and correlates of paid work from diagnosis through initial treatment and the impact of missed work on family and finances. Methods: 2,030 women with non-metastatic breast cancer diagnosed from 8/05–5/06 and reported to the Los Angeles County SEER registry were identified and mailed a survey shortly after receipt of surgical treatment. Latina and African American (AA) women were over-sampled. Outcome measures included missed paid work (<1 month, =1 month, stopped all together) and impact on finances (difficulty paying bills or cutting down on general expenses). We report results on a 50% respondent sample (N=742) which will be updated based on a final respondent sample of 1,400 patients (projected response rate, 72%). Results: Of the 440 women (59%) that worked prior to breast cancer, 35%, 26%, and 39% missed <1month, =1month, or stopped working, respectively. African Americans and Latinas (especially those who primarily speak Spanish) were more likely to stop working as compared to whites [OR for stop working vs. missed <1month: 3.5 (p<.001); 4.0 (p<.001) respectively]. Women receiving chemotherapy were also more likely to stop working after adjusting for other sociodemographic and treatment factors [ORs for stopped working vs. missed <1month: 8.4 (p <.001)]. Having sick leave and a flexible work schedule available through work was protective against work stoppage [ORs for stopped working vs. missed <1month: 0.2 (p<.001), 0.1 (p<.001) respectively)] after adjusting for sociodemographic and treatment factors. Women who stopped work were more likely to report both difficulty paying bills, and the need to cut down on expenses compared to women who missed <1month [ORs: 3.3 (p=.002); 3.6 (p<.002) respectively]. Conclusions: Many women stop working altogether after a diagnosis of breast cancer, particularly if they receive chemotherapy, have limited resources, or are employed in vulnerable work settings. These women face adverse economic consequences. Clinicians and staff need to be aware of these adverse consequences of diagnosis and initial treatment particularly in ethnic minorities and low-income patients.

No significant financial relationships to disclose.
Are we training our fellows adequately in delivering bad news to patients? A survey of hematology/oncology program directors
Authors: Hebert H. D. , Butera J. , Mega A.
Published: March 2020

9023

Background: Medical Oncologists are often in a situation of delivering bad news (dbn). We were interested in the extent of formal training in dbn in Hematology/Oncology fellowships in the United States. Methods: An e-mail survey was conducted of all Hematology/Oncology Program Directors (PDs) in the United States to elicit subjective responses as to the degree of formal training fellows receive in dbn, the adequacy, perceived necessity and quality of this training as well as institutional support provided. The surveys were e- mailed to 124 PDs and responses were received either via e-mail or regular mail. Results: 49 surveys were completed and returned (40% response rate). The majority of programs, 82%, are in an urban setting and 96% of the primary teaching hospitals are considered tertiary care centers. 45% of programs carry an NCI designation; the median number of fellows in a training program is 6, with the range being 3 to 42. 90% of PDs reported that they received little to no formal training in dbn. In contrast, they report that 31% of current fellows receive little to no formal training with 43% receiving some training and additional 26% receiving moderate to extensive training. 36% of PDs felt that formal training is important for skill development in dbn while only 4% did not feel so and an additional 31% felt that some training is useful. 50% of PDs would like to see some improvements in how their fellows are trained and 28% would like to see moderate to extensive improvement. 44% reported little to no institutional support for training while 22% reported moderate to full support. Conclusions: Of the Hematology/Oncology Program Directors who responded to our survey, a large majority did not have formal training in dbn. Despite this lack of training, most PDs felt that some training was useful for skill development in dbn and the majority of today's fellows do receive training in delivering bad news. However, there was still a significant percentage of PDs who reported little or no formal training for fellows and most PDs would still like to see some improvements in how fellows are trained. Specific institutional support for training fellows in dbn remains lacking.

No significant financial relationships to disclose.
Advance care planning (ACP) prior to hematopoeitic stem cell transplantation (HSCT) in patients with cancer is associated with improved survival
Authors: Loberiza F. R. , Ganti A. K. , Armitage J. O. , Bierman P. J. , Bociek R. G. , Devetten M. P. , Maness L. J. , Vose J. M. , Lee S.
Published: March 2020

9026

Background: HSCT carries an increased risk of mortality. Thus, patients are encouraged to have ACP. However, discussions about ACP is not a casual process since it may elicit undue anxiety to the patients and their families. Anecdotally, pts fear that discussion of the possibility of death is inconsistent with hoping for the best outcome. We therefore compared the outcomes of pts with or without ACP who received HSCT for cancer. Methods: ACP was defined as having living will, power of attorney for health care, or life-support instructions conducted prior to transplant. ACP were reviewed in pts who were at least 19 yo and received first allogeneic or autologous HSCT for cancer between 2001 and 2003. Pts were classified into: 1) No ACP, 2) ACP prior to cancer dx, 3) ACP after cancer dx but prior to HSCT. Multivariate analysis (MVA) was done to evaluate the relative risk of mortality at 1 year according to ACP while adjusting for other prognostic factors. Results: 343 pts were included in the study: 172 (50%) did not have ACP, while 171 (50%) pts had ACP. Of those with ACP, 127 pts (74%) were available for review. Characteristics were similar between pts with and without reviewable ACP. 28 pts had ACP prior to cancer dx, 87 had ACP prior to HSCT, while 12 had ACP after HSCT. 64% of pts with ACP had both power of attorney and a living will, 16% had a living will alone and 19% had power of attorney alone. Older pts (p <0.001) and Caucasians (p = 0.04) were more likely to have ACP. MVA were confined to the 172 pts with no ACP and 115 who had ACP before HSCT and showed that pts with ACP prior to HSCT had a significantly lower risk of mortality (see table ). Conclusions: Despite a diagnosis of cancer and hospitalization for HSCT, only 50% of patients had engaged in ACP. ACP at any time before HSCT was associated with higher one-year survival. Engagement in ACP is not necessarily inconsistent with hoping for the best outcome in HSCT. Further study is warranted to explore the reasons for engaging or not in ACP.

No significant financial relationships to disclose.

[Table: see text]
Absorption profile, safety, and tolerability of a 200 μg dose of fentanyl buccal tablet (FBT) in opioid-tolerant cancer patients with or without oral mucositis
Authors: Shaiova L. , Jiang J. G. , Darwish M.
Published: March 2020

9053

Background: Fentanyl buccal tablet (FBT) is an effervescent formulation of fentanyl indicated for the management of breakthough pain in opioid-tolerant cancer patients. This open-label study investigated the absorption profile, safety, and tolerability of FBT in cancer patients with or without oral mucositis. Methods: Patients self-administered a single 200 μg dose of FBT. Pharmacokinetic assessments, oral mucosal examinations, and measurements of vital signs were performed at intervals of up to 8 hours following FBT placement. Adverse events (AEs) were monitored throughout the study. Results: 16 patients (8 with, 8 without mucositis) received FBT and completed the study. Mucositis was mild (functional/symptomatic grade 1 for 7 patients, grade 2 for 1 patient; clinical grade 1 for all patients). The absorption profile of FBT was similar in patients with and without mucositis. Mean±SD Cmax values were 1.25±0.78 ng/mL and 1.24±0.77 ng/mL in patients with or without mucositis, respectively. Maximum plasma concentrations of fentanyl were achieved rapidly, and were not significantly different in the two groups: median (range) tmax 25.0 (15.0–45.0) min in patients with mucositis, 22.5 (10.0–121.0) min in patients without (p=0.79). FBT was well tolerated; 4 patients experienced =1 treatment-emergent AE. Dizziness (mild) was reported by 1 patient in each group, and resolved. One patient in each group experienced a treatment-related AE (dizziness). There were no deaths, serious AEs, or withdrawals due to AEs. No application site AEs or changes in oral mucosal assessments were reported. Conclusions: The absorption profile of FBT was similar in patients with or without oral mucositis, which suggests that dose adjustment of FBT is not required when mild oral mucositis is present. FBT was generally safe and well tolerated, and not associated with adverse changes in the oral mucosa. Further studies in patients with grade 3–4 mucositis are warranted.

No significant financial relationships to disclose.
Comorbidity and survival in cancer patients receiving palliative care
Authors: Chang V. T. , Sambamoorthi N. , Zhou B. , Yan H. , Gonzalez M. L. , Osenenko P. , Alejandro Y. , Duque L. , Srinivas S. , Kasimis B.
Published: March 2020

9066

Background: Comorbidity has received increasing attention in the assessment of patients with early stage cancer, or at diagnosis. We studied whether three indices of comorbidity, the Charlson Comorbidity Index (CMI), the Cumulative Illness Rating Scale (CIRS), and the Kaplan Feinstein Index (KFI) add prognostic information for cancer patients receiving palliative care. Methods: In an IRB approved protocol, 103 patients with advanced cancer were seen at the time they were starting palliative care. They had a Karnofsky Performance Status (KPS) determination, and were followed longitudinally. Comorbidity scores were coded from the medical record. At this time, all patients had died and survival analyses were performed. Results: The median age was 69 years (range 41–87), median Karnofsky Performance Status (KPS) was 70% (range 20–90); primary sites were lung 41 pts (40%), prostate 23pts (22%), colorectal 10 pts (10%), other cancers 29 pts (28%). Median survival was 111 days (range 4–1,145 days). Median CMI was 10 (range 4–14), CIRS15 4 (2–5), CIRS16 9 (4–12), CIRS17 2.3 (1.5–3.33), CIRS18 1 (0–3), KFI 2 (0–3). In univariate survival analyses, when bisected by median values, the KPS, age, CMI, and subscales of the CIRS (CIRS 16, CIRS 17, CIRS18) were significantly related to survival, but not the KFI. In multivariate Cox regression analyses that included KPS (p<0.0001) and age (p<0.003) and a comorbidity index, the CMI (p<0.0001), and certain subscales of the CIRS were independently predictive of survival, specifically the CIRS 15 (p<0.0001), CIRS16 (p<0.0001), CIRS 17 (p<0.0001), and CIRS18 (p<0.0001). The primary site was not an independent survival predictor. Conclusion: In patients with advanced cancer receiving palliative care, measures of comorbidity may contribute to refining estimates of prognosis and ultimately to health care resource utilization. The optimal comorbidity measure remains to be determined. These results will be confirmed in larger populations. Supported in part by the Soros Open Society Institute Project Death in America and VA HSRD IIR 02–103

No significant financial relationships to disclose.