bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteonecrosis of the jaw associated with intravenous bisphosphonate therapy—A single institution experience
Authors: Wallace E. M. , Quintyne K. I. , Cantwell B. M. , Calvert P. M. , Leonard G. D.
Published: April 2020

18553

Background: Osteonecrosis of the jaw (ONJ) is a debilitating disease that has been associated with cancer therapy. Recently a link between ONJ and chronic intravenous (IV) bisphosphonates has been suggested. We assessed the incidence of ONJ and its risk factors in patients treated with IV bishosphonates at our institution. Methods: All patients with a cancer diagnosis treated at our institution with at least four cycles of either IV Zoledronic Acid, Pamidronate, or a combination of both, from 2000–2005 were evaluated using outpatient records. Patients with ONJ were identified and their characteristics were compared to all patients receiving bisphosphonate therapy. Results: One hundred and twenty-one patients were evaluated, 36 Male and 85 Female. Median age- 62 (Range 34–85). Seventy-six had metastatic Breast cancer, 25 Prostate, 7 Lung, 3 Colorectal, 3 Renal, 2 unknown primary, 1 each of Penile, Bladder, Seminoma, Lymphoma and Melanoma. Forty patients received Pamidronate infusions alone, 51 Zoledronic Acid alone and 30 a combination of the two. The median number of Pamidronate infusions was 8 (Range 4–10), Zoledronic infusions 10.7 (Range 4–32), and a combination of pamidronate and zoledronic acid was 12 (Range 5–66). Three patients developed ONJ. All 3 patients were female, had a median age of 62 (range 52–74) and had metastatic breast cancer. The median number of bisphosphonate infusions prior to the development of ONJ was 35 (Range 18–47). All patients had chest wall radiotherapy and 1 had chemotherapy and steroids. No patients had dental procedures or prolonged antibacterial therapy. Conclusions: ONJ is a complication associated with IV Bisphosphonate therapy. Our study suggests that female sex, zoledronic acid, and prolonged administration of bisphosphonates, may confer an increased risk for the development of ONJ. Further prospective studies with adequate power are needed to clarify what patients are most at risk for developing ONJ and what measures are needed to prevent its occurrence.

No significant financial relationships to disclose.
A collaborative demonstration project: Depression screening in patient with cancer
Authors: Adkins B. W. , Titus-Howard T. , Massey V. , Washburn N. , Molinaro J. , Lang B. , Bruning W. L. , Lanoue K.
Published: April 2020

18556

Background: A demonstration project testing the feasibly of implementing a depression screening work flow algorithm was initiated by the anti-depression committee at one of six ambulatory care sites in the Kansas City Cancer Center (KCCC) system. The object of the study was to develop a process of work flow that would assist in identifying patients with depression and facilitate appropriate interventions by providers. Methods: A flow chart was developed illustrating critical decision-making points in the screening for depression by physicians and nurse practitioners (NP). The population included half radiation therapy and the other half chemotherapy. Patients completed the PHQ-2 a two question prescreen to assess initial symptoms of depression, including feeling depressed, down or hopeless and/ or little interest or pleasure in activities. A positive response to one of these 2 questions prompted the administration of the PHQ-9 a validated depression screening instrument. The PHQ-9 scoring criteria was used to assist the physician and NP with taking the appropriate action such as the initiation of antidepressant therapy and/or referral to mental health provider, follow up for subsequent appointments and/or reassessment. Results: Seventy-one patients were tracked to evaluate the process of recognition and management of depression from April 2004 to January 2005. Of the 71 patients 37% (N = 26) scored positive on at least one question on the two question prescreen. Of the 26 patients scoring positive 27% (N = 7) of these patients had less than 3 follow up visits while 73 % (N = 19) had greater than 3 follow-up visits by the KCCC providers. Of the patients that answered positively to one of the two prescreen questions 69% (N = 18) completed the full PHQ-9 and their scores were recorded. Conclusions: The development of a new model in a community-based oncology practice allows for integrating clinically proven techniques for diagnosing and treating depression. It will allow for the committee to make recommendations for changes in the process before it is implemented on a larger scale at all KCCC outpatient sites.

No significant financial relationships to disclose.
The use of Internet as an information resource among cancer patients at a Canadian cancer centre
Authors: Verma S. , Fralick J. , Sue J. , Wu M. , Dranitsaris G. , Clemons M. , Piliotis G.
Published: April 2020

18561

Background: Understanding the nature of Internet use among cancer patients is important to facilitate patient-education interventions and for providing optimal patient care. This questionnaire study is designed to evaluate Internet use by cancer patients at a cancer centre. Methods: Cancer patients attending ambulatory clinics at a single Canadian cancer centre were approached by their health care staff. Participants filled out self-administered questionnaire collecting information on demographics, frequency of Internet usage, timing of Internet use during treatment course, type of information sought, and information on patient’s comfort level and satisfaction with Internet use. Results: Of the total 250 participants, 174 (70%) had used the Internet before and 76 (30%) had never used the Internet. Users were more likely to be younger, female, have English as their first language, and be of Caucasian descent. Individuals with breast cancer were also more likely to have used the Internet than pts with other malignancies. Of the Internet users (n = 174), the majority (87%, n = 152) accessed the Internet once per week or more, and felt strongly confident (44%, n=76) in navigating the Internet. 29 users (17%) felt that the information on the Internet was not trustworthy. Of the users, 136 (78%) used the Internet to access information on cancer, and reportedly more often before visiting the cancer centre (50%, n = 70) and before starting initiating cancer treatment (78%, n = 106). The users seeking information on cancer were most likely to look for information on cancer treatment (87%, n = 118) and side effects (74%, n = 100). The top three visited sites were those for Canadian cancer society, Google, and American cancer society. Conclusions: Despite wide availability and accessibility of Internet, it is still not being used as a cancer information tool by many of our patients. By ensuring that accurate and comprehensive information is available on the Internet, perhaps even more patients will use this medium as their information resource, to better understand their diagnosis and make optimal treatment decisions.

No significant financial relationships to disclose.
A proposal for an abbreviated onco-geriatric assessment in daily practice
Authors: Girre V.
Published: April 2020

18565

Background: In order to describe the elderly population in Institut Curie and to determine if a brief multidimensional assessment may influence our decision to treat elderly patients with cancers we decided to realize a short assessment for each patient, 70 years and older. In a prospective study we evaluated such diverse areas as functional status, comorbidity, nutrition, polypharmacy and the presence or absence of geriatric syndromes. Methods: We studied 105 elderly cancer patients, median age 80 years with solid tumors. In addition to PS, their physical function was assessed by the activity of daily living (ADL) and instrumental activity of daily living (IADL) scales. During consultation comorbidities, Geriatric depression scale (GDS), the number of falls in the past year, concomitant medications, weight measurements and social environment were collected in a questionnaire. Cognitive functions were assesed if troubles were suspected. Blood tests were performed secondary. Results: To date 105 patients were evaluated : 10 % live in institution, 16% have no social environment, 35 % have a loss of autonomy in ADL and 7% were dependant. In the IADL: 30% presented a loss of autonomy and 24% were dependant. The median Body Mass Index (BMI) was 23.8 kg/m2, but the BMI was in 14% < 19kg/m2; 20% of the patients fall more than 2 times in the year and 53% have a suspicion of depression in the GDS in 4 items. 74% take more than 3 drugs per day. The median of comorbidities was 1.3. According to the results the decision of treatment was modified in 28% of patients. Conclusion: This questionnaire is not a replacement for the entire Comprehensive Geriatric assessment but is a reasonable prescreening instrument that may be performed in less than 15 minutes and be helpful to the clinician in his decision.

No significant financial relationships to disclose.
The meanings of “hope” to patients with cancer, nearing the end of their lives
Authors: Olver I. N. , Eliott J. A.
Published: April 2020

18567

Background: In two studies of the speech of patients with cancer about end-of-life decision-making, the word hope was often spontaneously used. In 23 patients earlier in their disease there was a difference between hope used as a noun, often objective, outside the patient’s control, and presented as “no hope”, or as a verb which was directed by patients and facilitated imagining a positive future (Qual Health Res 2002, 12: 173–193). In a second study 28 patients judged within 3 months of dying, following unprompted use of hope during interview, were specifically prompted to talk about hope. Methods: Discourse analysis was used to analyze the speech from the semi-structured interviews of the patients. The sample size was determined by data saturation. Results: All in the second study were Caucasian, average age 61, 15 males, 18 had partners and 19 were Christian, 1 Druid, and 8 listing no religion. Ten patients made reference to hope as variable in amount. In general the more the better, but even 1%, while trivial scientifically, may be important personally. The problem with quantifiable hope is that it is perceived to dwindle with the medical prognosis with which “no hope” is most often identified. Twenty patients hoped for a longer life although 19 had specifically indicated that they were dying, suggesting that this hope was not death denying. Most wanted more time to achieve tasks and be with family. Hoping recognized uncertainty yet attested to the value patients placed on various activities. Eight talked of hoping for a cure, although this was not overwhelming in the present. Some mentioned the possibility of a miracle cure, reinforced by the construction that medicine gives hope. Hope sometimes shifted from life to either an acceptable dying in 8 patients or to focus on others. The legacy to others could be objects or life lessons. Hopes can be shared by partners and can change. Two patients spoke of hope sourced from God and as enduring beyond death. Conclusions: Patients found it challenging to talk of hope in the abstract. Hope can be positive and sustaining or disillusioning when not attained.

No significant financial relationships to disclose.
Improvement in anemia management with epoietin alfa (EA) in elderly and/or poor performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC) (GFPC 0202)
Authors: Lecaer H. , André M. , Thomas P. A. , Crequit J. , Falchero L. , Berdah J. F. , Delhoume J. Y. , Chavaillon J. M. , Lena H. , Perol M.
Published: April 2020

18571

Background: EA at a starting dose of 40000 UI sc once weekly (qw) has been show to be effective in the treatment of chemotherapy (CT) induced anemia in cancer pts and early intervention with EA appears important for anemia prevention and reduce CT toxicity in elderly pts. Methods: In this multicenter phase II study, chemonaive pts with stage IIIB (pleural effusion) and IV 50 pts with mild co-morbidity (Charlson score) and good performans status (PS) received docetaxel 30 mg/m2 weekly (6 wks, 2 wks off) and gemcitabine 900 mg/m2 (only on day 1, 8, 22, 29) arm A and 50 pts with higher co-morbidity and/or poor performans status (PS) received docetaxel 30 mg/m2 weekly (6 wks, 2 wks off) arm B. Anemic pts with Hb <11.5 g/dl received EA 40000 UI/qw until a target = 13 g/dl with maintenance phase during CT and 28 days after the end of CT to maintain Hb 11.5 to 12.5 g/dl. Dose could be increased to 60000 UI/qw after 4 wks depending on Hb response. Quality of life (Qol: LCSS, Spitzer score) was assessed at baseline, 8, 16 and 24 wks. This trial assessed the effect of EA on Hb level after 4 and 8 wks, tranfusion requirements and Qol. Results: From Jun 2003 to Dec 2004 100 pts were enrolled, median age was 72,7 (66–82) arm A, 76,6 (70–84) arm B, median co-morbidity 1 (0–4) arm A; 1,9 (0–5) arm B. 59 pts received EA (58% arm A; 60% arm B), mean Hb level was 11.6 at the start of CT, and 10.42 before EA. Mean Hb increase after 4 wks was 0.77 ± 1.11 (p < 0.05), and 1.63 ± 1.36 after 8 wks (p < 0.05). Only 14.1% received transfusions. There was no significant change in global Qol and fatigue (LCSS). The main grade 3/4 CT toxicity was fatigue 25% and neutropenia in arm A and fatigue 50% in arm B. Conclusions: Weekly EA increase Hb level, early EA intervention maintain Qol and decrease red blood transfusions, and mild anemia is probably associated with significant impairment in toxicity in elderly pts with advanced NSCLC.

No significant financial relationships to disclose.
Early vs. late treatment with darbepoetin alfa in patients with genitourinary tumors during chemotherapy
Authors: Elandt K. , Horak P. , Schieder K. C. , Leikermoser R. , Altmann R. , Albrecht A. , Reisenberger K. , Tomek S. , Fischer H. , Zielinski C. C. , Krainer M.
Published: April 2020

18583

Background: Anemia is a common complication in patients who receive anticancer therapy. We evaluated the efficacy of darbepoetin alfa in early vs. late treatment in patients with genitourinary tumors undergoing chemotherapy. We wanted to investigate whether an early onset of treatment with darbepoetin alfa reduces frequency of red blood cell transfusion and increases patients’ QoL. Methods: Patients on chemotherapeutic treatment for a urogenital neoplasia and a hemoglobin between 10–12 g/dl were randomized between an immediate start of treatment with darbepoetin alfa 150 μg sc weekly (group A) and a Hb below 10 g/dl or clinical symptoms (group B). Results: 52 patients out of 68 (76.5%) completed the trial, 7/40 patients (17%) in group A and 9/28 patients (32%) in group B withdraw from the study. An intent to treat analysis was performed and showed a significant superiority (p = 0.023, log-rank test) for the early treatment. In group A, only 12.5% of patients (5/40) received at least one red blood cell transfusion compared to group B, where 39% of the patients (11/28) received a transfusion. In group A the mean Hb level increased steadily, starting with a baseline value of 11.0 g/dl. In week 21 a mean Hb level of 12.8 g/dl was reached, resulting in an overall increase in Hb of 1.8 g/dl. In group B, which had a comparable baseline Hb level of 10.9 g/dl, the mean Hb value decreased initially during the first 4 weeks to 10.0 g/dl. In week 21 a level of 11.4 g/dl was reached, resulting in a total Hb-increase of 0.5 g/dl. When anemia treatment was initiated early, the mean Hb level always remained in the range of 11 to 13 g/dl from the beginning of the study, in the B group the mean level of 11 g/dl was first achieved after 12 weeks. 35% in group A compared to 54% in group B (p = 0.13) experienced a dose doubling. The mean values (EORTC-QLQ-C30) of all symptom scales in group A were markedly below those in group B with the highest difference for dyspnea, 29.1 points (p < 0.001). Conclusions: Early treatment with darbepoetin alfa in patients with urogenital cancer results in optimal hemoglobin levels according to EORTC guidelines and consequently in a reduction of red blood cells transfusion. Furthermore, in patients with earlier initiation of treatment a clinically significant improvement of dyspnea can be observed.

[Table: see text]
Bisphosphonates (BP)-related osteonecrosis of the jaw (ONJ): Clinical experience of the “Rete Oncologica di Piemonte e Valle d’Aosta” network
Authors: Fusco V. , Ortega C. , Goia F. , Ciuffreda L. , Ardine M. , Falco P. , Gorzeglio G. , Baraldi A. , Airoldi M. , Bertetto O.
Published: April 2020

18584

Background: ONJ have been recently reported in patients (pts) treated with BP, especially Pamidronate (P) and Zoledronic Acid (Z). Measures of screening, treatment, and prevention have been planned in our regional oncology network. Methods: We evaluated dental history of pts previously treated with BP and/or under treatment in 2005, finding 60 cases of ONJ, but a large number of suspected cases are under investigation/observation. Full details of oncologic and dental history have been collected so far of 43 pts. Results: Pts characteristics: sex: 14/29 M/F; median age 66 years (range 45–81); tumour: 24 breast cancer, 7 prostate cancer; 12 myeloma. BP treatment: 5 P, 14 P changed to Z, 24 Z; median number of infusions: 22 of P (range 12–52), 18 of Z (range 7–43). Site of ONJ: 33 (77%) in mandible, 9 (21%) in maxilla, 1 (2%) in both. Presenting findings included exposed bone or infections (95%), pain, mobile teeth, soft-tissue swelling, nonhealing fistulas . Dental comorbidities were present in all pts and 92 % had precipitating events, as teeth extraction, periodontal surgery, dental implants, or traumatic use of dentures. Conclusions: Our oncology network planned: a) review of all pts treated with BP since 2000, to obtain real estimates of frequency and of possible risk factors; b) screening of all pts under treatment with BP, with panoramic X-rays and maxillofacial surgeon visit (w/o CT or MR scan in selected cases); c) careful evaluation of pts candidate to be treated with BP (as above), with pretherapy dental care if necessary; d) prospective evaluation of incidence in future, after pretherapy dental care policy and avoiding (as possible) surgical dental procedures during BP treatment; e) prospective trials of evaluation of palliative treatment of ONJ and related complications in affected pts (chlorohexidine mouthwashes, antibiotics, metronidazole, hyperbaric oxygen, etc.).

No significant financial relationships to disclose.
Bisphosphonate-associated osteonecrosis of the jaws: Case reports and analysis of 184 cases
Authors: Kanat O. , Ozet A. , Arpaci F. , Ataergin S. , Kuzhan O. , Komurcu S. , Ozet B. , Ozturk M.
Published: April 2020

18595

Background: In this study, we described four new cases of bisphosphonates-related jaw osteonecrosis and reviewed the English Medical Literature for similar case reports. Methods: A MEDLINE literature search was performed from September 2003 to November 2005 for all case reports of bisphosphonates-associated jaw osteonecrosis. Results: Our patients were three female and one male with a median age of 50.5 years (range, 35–57 years). Two patients had breast cancer and two another had multiple myeloma. Two patients received pamidronate initially and were switched later to zoledronate. The two other patients were treated with zoledronate. The median duration from the first administration of bisphosphonates to the diagnosis of osteonecrosis was 48 (range, 18–75) months. Review of the literature of all published cases revealed 184 patients. Age of these patients ranged from 37 to 89 years (median, 64 years). Seventy-eight patients (43.4%) were treated with bisphosphonates for metastatic breast carcinoma, 65 (36.3%) for multiple myeloma, and 14 (7.8%) for metastatic prostate cancer. Thirteen patients (7.2%) without cancer diagnosis were treated for osteoporosis (10 patients) or Paget’s disease (3 patients). Primary disease was not specified in five patients. Eighty-two patients (46.8%) were treated with pamidronate, 47 (26.8%) treated with zoledronate, 35 (20%) treated with pamidronate initially and later were changed to zoledronate, 9 (5.1%) treated with oral bisphosphonates and 2 (1.1%) treated with oral bisphosphonates initially and subsequently switched to zoledronate. Type of bisphosphonate was not specified in ten patients. The duration of bisphosphonates treatment was available for 45 patients (24.4%) and ranged from 1 to 93 (median, 28) months. Conclusion: Oncologists and dental professionals should be aware of this potential serious complication of long-term bisphosphonates treatment and special caution should be taken before dental intervention in such patients.

No significant financial relationships to disclose.
Microscopic tumor burden in sentinel lymph nodes (SLNs) best predicts nonsentinel lymph node (NSLN) involvement in patients with melanoma
Authors: Andtbacka R. H. , Gershenwald J. E. , Prieto V. G. , Johnson M. , Diwan H. , Lee J. E. , Mansfield P. F. , Schacherer C. W. , Ross M. I.
Published: April 2020

8004

Background: Therapeutic lymph node dissection (TLND) has long been the standard of care for melanoma metastatic to the regional LNs and is commonly used for patients (pts) with microscopic disease identified by SLN biopsy. We and others have demonstrated that additional histologically positive (pos) nodes are identified in 8%-33% of completion LN dissection (CLND) specimens. The purpose of this study was to determine predictors of additional LN involvement in pts. with pos SLNs. Methods: Pts with clinically node-negative melanoma who underwent SLN biopsy at our institution between 1991 and 2003 and had pos SLNs were identified. Patient and primary tumor factors, number of pos SLNs, and extent of microscopic disease within the SLN were evaluated as potential predictors of pos NSLNs. Results: Overall, 359 (16%) of 2,203 pts had a pos SLN. Pos NSLNs were identified in 48 (14%) of the 343 pts with pos SLNs who underwent CLND. On univariate analysis, several markers of SLN microscopic tumor burden, tumor thickness >2mm, age >50 years, and Clark level >III were predictive of additional pos nodes in the TLND specimen. Primary tumor ulceration was not predictive. On multivariable logistic regression analysis, markers of microscopic tumor burden (large SLN met focus, large SLN tumor square area, presence of SLN extracapsular extension, and synchronous subcapsular and intramedullary SLN deposits) were the most powerful independent predictors of pos NSLNs; tumor thickness >2mm also predicted additional disease. A model was established using tumor thickness and SLN tumor burden to identify pts with low, intermediate, or high risk for NSLN involvement (Table). Conclusions: In melanoma pts with ≥1 pos SLN, SLN tumor burden and primary tumor thickness may be useful in identifying a group at low risk for pos NSLNs. This information is valuable in designing clinical trials in which pts may be randomly assigned to TLND versus observation alone after removal of a pos SLN.

[Table: see text]

No significant financial relationships to disclose.
NCOA3: A molecular prognostic marker for melanoma
Authors: Rangel J. , Torabian S. , Shaikh L. , Nosrati M. , Miller J. R. , Sagebiel R. W. , Kashani-Sabet M.
Published: April 2020

8007

Background: Nuclear receptor coactivator-3 (NCOA3, also known as AIB1 or SRC-3), a member of the steroid receptor coactivator 1 family, has been shown to be amplified in human breast cancer. We recently identified NCOA3 as differentially expressed in metastatic melanomas by gene expression profiling, suggesting its role as a possible molecular prognostic factor. In this study, we assessed the prognostic significance of NCOA3 expression in a large melanoma patient cohort using tissue micro-arrays (TMAs). Methods: We used a commercially available antibody against NCOA3 to perform immunohistochemical analysis of NCOA3 expression in TMAs containing primary melanoma specimens from 353 patients seen at the UCSF Melanoma Center. Cases included clinicopathologic information (e.g., age, sex, tumor location, tumor thickness, Clark level and ulceration), as well as sentinel lymph node (SLN) status, and information regarding relapse-free (RFS) and disease-specific (DSS) survival. NCOA3 expression was assessed on a 4-point scale (0–3) by an observer blinded to patient outcomes. Results: High NCOA3 expression was significantly predictive of SLN metastasis by univariate logistic regression (p=0.015), and associated with a higher mean positive SLN count (p=0.03, Le test). Kaplan-Meier analysis demonstrated a significant association between increased NCOA3 expression and reduced RFS as well as DSS (p=0.024, and p=0.031 by log-rank test, respectively). Multivariate step-wise logistic regression analysis of 12 factors revealed NCOA3 expression, along with tumor thickness, age, vascular involvement, and Clark level to be independent predictors of SLN status. Multivariate Cox regression analysis showed the independent impact of NCOA3 expression on RFS and DSS with the inclusion of the AJCC factors tumor thickness, ulceration, Clark level, tumor location, patient age and sex. Conclusions: These results reveal NCOA3 to be a novel, independent marker of melanoma outcome, with a significant impact on SLN metastasis, RFS and DSS.

No significant financial relationships to disclose.
Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients
Authors: Lorigan P. , Corrie P. , Chao D. , Nathan P. , Ahmad T. , Marais R. , Burk K. , Erlandsson F. , Gore M. , Eisen T.
Published: April 2020

8012

Background: Sorafenib inhibits tumor cell proliferation and angiogenesis through blockade of multiple kinases including Raf, VEGFR-2/-3, and PDGFR-β. In Phase I/II trials, sorafenib was generally well tolerated as a monotherapy or in combination with other agents. A Phase I study in combination with dacarbazine (DTIC) showed encouraging activity, which warranted this Phase II study. Methods: This multi-center, open-label, two-stage (30 patients in Stage 1; 52 in Stage 2), uncontrolled Phase II trial was performed to evaluate the primary endpoints of efficacy (according to RECIST) and tolerability of sorafenib in combination with DTIC in patients with advanced metastatic melanoma. Eligibility criteria included ECOG 0 or 1, life expectancy ≥12 weeks, adequate bone marrow, liver, and renal function. Oral sorafenib 400 mg twice daily (bid) was administered with repeated 3-week cycles of DTIC 1000 mg/m2. Results: At this interim end of Stage 1 analysis, 30 patients with metastatic melanoma had been treated (median age 61 years [range 30–78]; 73.3% male; 96.7% white). Five (16.7%) patients had PR as best response (two confirmed, three currently unconfirmed), 13 (43.3%) had SD, 10 (33.3%) had PD, and two (6.7%) were unevaluable for tumor response. The patients with confirmed PR continue on study drug at 6.4 months. Median progression-free survival for all patients was 3.6 months (range 0.9–6.1 months). The most frequently reported drug-related adverse events (AEs) were dermatologic (rash/desquamation [43%], hand-foot skin reaction [HFS, 33%]); gastrointestinal (constipation [47%], nausea [37%], diarrhea [27%]); constitutional (fatigue [43%]); and blood/bone marrow (neutrophils [40%], platelets [30%]). The most common grade 3/4 drug-related AEs were blood/bone marrow (neutrophils [23%], platelets [17%]), and fatigue (7%), while HFS and hypertension were observed in <5%. Conclusions: Continuous sorafenib 400 mg bid is generally well tolerated and shows promising preliminary anti-tumor activity in combination with DTIC. No toxicities were observed above those expected from either agent alone. Updated results will be presented, including the decision whether to proceed to Stage 2 of the study.

[Table: see text]
First and final report of a phase II study of the poly(ADP-ribose) polymerase (PARP) inhibitor, AG014699, in combination with temozolomide (TMZ) in patients with metastatic malignant melanoma (MM)
Authors: Plummer R. , Lorigan P. , Evans J. , Steven N. , Middleton M. , Wilson R. , Snow K. , Dewji R. , Calvert H.
Published: April 2020

8013

Background: Inhibition of PARP and thus Base Excision Repair has been shown to potentiate the cytotoxicity of DNA damaging agents preclinically. A Phase I study of AG014699 + TMZ reported at ASCO 2005 showed that a full dose of TMZ could be given in the presence of profound PARP inhibition. We report the results of a Phase II study of AG014699 12 mg/m2 and TMZ 200 mg/m2 5x daily q 4 weekly in patients with advanced MM. This Phase II study commenced in March 2005 and completed recruitment in December 2005. Methods: Patients with measurable MM who were chemotherapy naïve, performance status ≤ 2, and had standard blood indices for early trials were recruited. Patients with ocular melanoma or brain metastases were excluded. Treatment was given until progression, with repeat imaging every 2 cycles. A two stage phase II design was used, with the hypothesis to be tested that the response rate to TMZ would be increased to 25%. α and β error rates were set at 0.10. 27 patients were recruited into the first stage with continuation to 40 patients if ≥3 partial responses were observed. Results 40 patients who fulfilled the eligibility criteria were recruited and treated. The required 3 responses were seen at an early stage. More enhancement of TMZ associated myelosuppression by the addition of AG014699 has been observed compared to the phase I study (Grade 4 thrombocytopenia 12% cycles, grade 4 neutropenia 15% to date). There has been one toxic death in cycle 1 (febrile neutropenia), 3 further patients hospitalised with myelosuppression and 12 patients in total requiring dose reduction of TMZ to 150 mg/m2 (1 to 100 mg/m2). All of these patients continued treatment at the reduced dose. Other toxicities have been fatigue and mild nausea. Currently there are 4 confirmed partial responses, 4 prolonged disease stabilisations and 20 patients are too early to evaluate. Conclusions The combination of TMZ and AG014666 shows encouraging activity in MM. Myelosuppression is greater than would be expected with single agent TMZ. PARP expression and activity in blood cells and tumour will be correlated with the mature outcome data from the trial.

[Table: see text]
Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104
Authors: Gajewski T. F. , Niedzwiecki D. , Johnson J. , Linette G. , Bucher C. , Blaskovich M. , Sebti S. , Haluska F.
Published: April 2020

8014

Background: Ras-based signaling is thought to be critical in the genesis of melanoma. Farneslytransferase (FT) inhibitors (FTIs) have been developed as a pharmacologic strategy to inhibit Ras function. Additional farnesylated proteins are also important for the malignant process, and FTIs inhibit melanoma cell line proliferation in vitro. These considerations motivated the development of a phase II trial of the FTI R115777 in patients with melanoma. Farnesylated proteins are also important for T cell activation. The interest in future combinations of targeted agents and immunotherapeutics in this disease prompted analysis of T cell function ex vivo. Methods: A 3-stage design was pursued with a maximum of 40 patients planned and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included intact organ function, PS≤1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to excisional biopsy. R115777 (300 mg orally) was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST criteria. Blood was obtained pre-treatment and during week 7 for analysis of HDJ-2 farnesylation and for T cell IFN-γ production in response to SEA. In addition, tumor biopsies were performed pre- and post-treatment when feasible to directly measure FT activity. Results: 14 patients were enrolled. 2 patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses, and only 4 patients went on to a second course of treatment. All analyzed patients showed HDJ-2 gel shift in peripheral blood cells, as well as marked inhibition of FT activity (by 85–98%) in tumor tissue. T cell production of IFN-γ was also suppressed. Conclusions: Despite potent target inhibition, the FTI R115777 showed no evidence for clinical activity as a single agent in this cohort of 14 metastatic melanoma patients. Inhibition of T cell function has implications for future combination therapies and suggests the possibility for FTIs as candidate immunosuppressive agents. New therapeutic approaches for melanoma, or logically selected combination therapies, are needed.

[Table: see text]
Race, socioeconomic status and survival difference in cutaneous melanoma patients in California
Authors: Mobasher M. , Zell J. A. , Meyskens F. L. , Anton-Culver H.
Published: April 2020

8023

Background: Survival data for malignant melanoma patients of various ethnic backgrounds are lacking. Furthermore, the modifying effect of socioeconomic status (SES) on survival in melanoma patients is unknown. This study was performed to analyze survival differences for cutaneous melanoma patients of each major ethnicity, including analysis of the effect of SES on outcomes, using a statewide cancer registry. Methods: A case-only analysis of data from the California Cancer Registry database during 1992–2002 was conducted. The primary outcome measured was overall survival for each ethnic group. Univariate survival analyses were conducted using the Kaplan-Meier method and log-rank test; multivariate survival analyses were performed using Cox proportional hazards ratios. Results: 46,218 incident cases of invasive cutaneous melanoma were identified, including 39,741 Caucasians (93.47%), 2263 (5.32%) Hispanics, 331(0.78%) Asians, 172 (0.40%) African-Americans, and 12 (0.03%) Native Americans (P<0.0001). On univariate survival analysis, improved 10-year overall survival rates were noted for Hispanics (63.2%) and Caucasians (60.9%) compared to Asians (51.1%), African-Americans (39.8%), and Native Americans (30.6%) (P<0.0001). A statistically significant survival difference was observed for melanoma patients based on SES (P<0.0001), favoring those with high SES. Multivariate survival analysis revealed an increased hazard ratio (HR) for African-Americans (HR=1.594; P=0.0023) compared to Caucasians, after adjustment for age, sex, stage, Breslow depth, histologic subtype,location, and SES. Increased age, male sex, regional and remote stages, melanoma of the head/face, Breslow depth categories 2, 3, and 4, nodular melanoma, melanoma-NOS, and lowest SES quartile were independently associated with poor survival (P<0.0001). Conclusions: Among patients with invasive cutaneous melanoma, survival is significantly decreased for African-Americans compared to Caucasians. This is not explained by differences in SES, stage, Breslow depth, age, sex, histological subtype, and location. Our epidemiologic observations suggest that intrinsic differences may exist for African-American melanoma patients, adversely affecting survival.

No significant financial relationships to disclose.
Targeting Src/Stat3 pathway in malignant melanoma
Authors: Homsi J. , Messina J. , Cubutt C. , Maunglay S. , Scalf L. , Komarla A. , Yu H. , Jove R. , Daud A.
Published: April 2020

8025

Background: The Src/Stat 3 pathway has been implicated in the pathogenesis of several malignancies including melanoma. In the current study we evaluated the prevalence of Src and Stat3 activation in human melanoma and the effect of Src inhibitors alone or in combination with chemotherapeutic agents on melanoma cell lines. Methods: Activation of Src was measured by staining for Src-phosphotyrosine 416 (P-Src) and Stat3 by phosphotyrosine 705 Stat3 (P-Stat3). Immunohistochemistry was performed with anti-pStat3-Y705 and anti-pSrc-Y416 antibodies (Cell Signaling, Beverly, MA) on 3 melanoma subtypes. Staining of tumor cells for P-Stat3 was scored by percentage of stained cells as follows: 0 (no staining), 1 (1–25%), 2 (26–50%), 3 (>50%), and intensity 0–3 (0: absent, 1: low, 2: moderate, and 3: high). The sum of these was the composite P-Stat3 score: 0 (0), 1 (1–2), 2 (3–4), and 3 (5–6). P-Src staining was scored by intensity. Melanoma cell lines, A-375, SK-Mel-5 and SK-Mel-28 were exposed to Src inhibitors, SKI-606, PD 180970 and BMS 354825 alone or in combination with standard chemotherapy agents and IC-50 was determined by MTT assay at 24 and 72 hours. Results: 35 biopsies were stained. Median age was 66 years (range 23–90); 60% were women. 48% of all melanoma stained express P-Src; all samples express pStat3. We found a positive correlation between P-Src and P-Stat3 (Spearman coefficient=0.346, p=0.042). 46% stained only for pStat3 and 6% did not stain for either P-Src or P-Stat3. Most positively stained biopsies stained weakly for P-Src and moderately or strongly for pStat3. Src inhibitors inhibited the proliferation of melanoma cell lines; furthermore Src inhibitor treatment synergized with platinum and topoisomerase I inhibitors but not temozolomide. Conclusions: 1) Immunohistochemistry shows variable expression of P-Src and P-Stat3 in human melanoma 2) All tumors staining for P-Src also stain for P-Stat3 and the strength of staining is significantly related. 3) This data may be useful in planning future clinical trials with Src inhibitors in melanoma.

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Methylated estrogen receptor alpha in tumors and sera of melanoma patients
Authors: Martinez S. R. , Mori T. , Umetani N. , Nguyen S. L. , Kitago M. , Tanemura A. , Morton D. L. , O’Day S. J. , Hoon D. S.
Published: April 2020

8026

Background: The mechanisms regulating the variable expression of estrogen receptor alpha (ER-α) in melanoma are unknown. Silencing of ER-α expression in melanoma may be regulated by the hypermethylation of promoter region CpG islands. To determine the significance of ER-α hypermethylation-induced transcription silencing in melanoma progression, we assessed hypermethylation of ER-α DNA in primary tumors, metastatic tumors, and sera of AJCC stage I-IV melanoma patients. Methods: The methylation status of theER-α DNA promoter region in tumor (n = 107) and sera (n = 119) from AJCC stage I-IV melanoma patients was examined by methylation-specific PCR (MSP) and capillary array electrophoresis (CAE). To determine the significance of free circulating hypermethylated ER-α DNA, we assessed the therapeutic response, progression-free and overall survival among AJCC stage IV melanoma patients receiving biochemotherapy. Results: The frequency of ER-α DNA methylation in AJCC stage I, II, and III primary melanomas was 36% (4 of 11), 26% (5 of 19), and 35% (8 of 23), respectively. The frequency of methylated ER-α DNA detected in stage III and IV metastatic melanomas was 42% (8 of 19) and 86% (30 of 35), respectively. ER-α DNA was methylated in 38 of 54 (70%) metastatic tumors, a more than two-fold increase compared to primaries (p = 0.0003). In the analysis of 109 melanoma patients’ sera, the frequency of methylated ER-α DNA in AJCC stage I, II, III, and IV was 10% (2 of 20), 15% (3 of 20), and 26% (5 of 19), and 32% (16 of 50), respectively. The frequency of methylated ER-α DNA detected in stage III/IV was significantly higher than in stage I/II (p=0.034). In a multivariate analysis, circulating hypermethylated ER-α DNA was the only independent factor predicting progression-free (risk ratio 2.64, 95% CI 1.36–5.13, p = 0.004) and overall survival (risk ratio 2.31, 95% confidence interval 1.41–5.58, p = 0.003) among stage IV patients receiving biochemotherapy. Conclusion: Hypermethylation of ER-α DNA in primary and metastatic melanoma tumors and serum is a significant factor in melanoma progression. The detection of methylated serum ER-α DNA predicts poor response to systemic therapy and is an unfavorable prognostic factor in advanced melanoma.

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Clinical relevance of neutral endopeptidase overexpression in melanoma
Authors: Yancovitz M. , Velazquez E. , Christos P. , Pavlick A. , Berman R. , Shapiro R. , Bhardwaj N. , Nanus D. , Polsky D. , Osman I.
Published: April 2020

8028

Background: Neutral Endopeptidase (NEP/CD10) is a cell surface peptidase expressed in a variety of normal and neoplastic tissue. Both loss of and overexpression of NEP have been reported in different types of tumors. Defining the role of NEP in the clinical progression of melanoma is particularly relevant given the availability of NEP inhibitors. Our aim was to determine if NEP expression correlated with clinicopathological parameters and survival. We also investigated the upregulation of NEP transcription as a possible mechanism of NEP overexpression. Methods: Eighty-four patients who were prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group database at the New York University School of Medicine were studied. Ninety-three specimens from the 84 patients were examined for NEP protein expression using an immunohistochemical assay, including 33 primary melanoma (thickness <1mm, N=15; 1–4mm, N=15; >4mm, N=3) and 60 metastatic melanoma specimens. NEP overexpression was defined as either moderate or diffuse. NEP transcript expression was assessed using Affymetrix U133Plus2.0 GeneChips in 37 metastatic melanoma cases. NEP transcript upregulation was defined as >2 fold increase compared to NEP transcript expression in normal lymph node tissue. Results: A statistically significant difference was observed between NEP overexpression in primary [1/33 (3%)] versus metastatic disease [18/60 (30%)] (Fisher’s exact test, p=0.002). In addition, there was a statistically observed association between NEP transcript upregulation and NEP protein overexpression (p=0.002). Among patients with metastatic disease, median survival time was shorter for patients who overexpressed NEP compared to those who had normal NEP expression (10.2 yrs. versus 12.7 yrs., respectively); however this difference was not statistically significant (p=0.74 by log-rank test). Conclusions: Our data support a role for increased NEP expression in the progression of melanoma to metastatic disease. Functional studies are needed to better understand the role of NEP upregulation in melanoma pathogenesis and progression and to determine if there is a role for NEP inhibitors in the treatment of melanoma.

No significant financial relationships to disclose.
Phase II study of neoadjuvant biochemotherapy (BCT) for stage III malignant melanoma (MM): Results of long-term follow-up (LTFU)
Authors: Lewis K. D. , Lane A. , Anderson C. , Pearlman N. , Becker M. , Zeng C. , Baron A. , Gonzalez R.
Published: April 2020

8035

Background: Patients (pts) with MM metastatic to regional lymph nodes (LNs) (stage 3) are at high-risk of developing systemic disease and subsequent death. High-dose adjuvant alpha interferon (IFN) has proven in randomized studies to result in significant improvement in relapse-free survival (RFS), but the benefit on overall survival (OS) is less clear. BCT (cytotoxic chemotherapy with interleukin-2 (IL-2) and IFN) has shown high response rates in pts with metastatic MM. It is, therefore, hypothesized that using BCT in earlier stage disease may result in an improvement in OS for this high-risk population. Methods: This was a pilot phase 2 study of neoadjuvant BCT in pts with stage 3 MM with a planned accrual of 50 pts. Earlier results have previously been reported (Cancer 2002;94:470–6). LTFU is now obtained and reported here. Eligibility required biopsy confirmed MM to regional LNs without previous therapeutic lymphadenectomy. Two cycles of BCT were administered prior to and after lymphadenectomy. BCT was: cisplatin 20 mg/m2 days (D) 1–4, vinblastine 1.6 mg/m2 D 1–4, dacarbazine 800 mg/m2 D 1, IFN 5 MIU/m2 D 1–5, IL-2 9 MIU/m2 continuous infusion D 1–4. The primary endpoints were RFS and OS. Results: Fifty-one pts were enrolled from 4–96 to 5–99. Three pts had stage 4 MM and are not included in this analysis. Of the remainder, 87.5% (42/48) had clinically detectable disease, while 12.5% (6/48) were sentinel lymph node positive. Twenty-five percent (12/48) had received prior IFN therapy. At a median follow-up of 75 months (mo), 54% are disease-free (26/48) and 65% are alive (31/48). The 5-year OS and RFS are 66% [95% confidence interval (CI) 50 - 78) and 56% (95% CI 41 - 69), respectively. Median survival has yet to be reached. After the 24-month time point there have been 3 relapses and 4 deaths. Toxicity was manageable. Conclusions: Neoadjuvant BCT may be an effective regimen for stage 3 MM. The LTFU of the current study shows favorable results in terms of RFS and OS when compared to historical controls. A subsequent larger, multicenter phase 2 study of neoadjuvant BCT has been completed. In addition, a cooperative group phase 3 study comparing adjuvant BCT to IFN is currently enrolling pts.

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High-dose IL-2 in patients with metastatic melanoma after progression on biochemotherapy (BioCT). The experience of the Hospital Sírio-Libanês, Brazil
Authors: Schmerling R. A. , William W. N. , Belfort F. A. , Buzaid A. C.
Published: April 2020

8038

Background: There are limited data on systemic therapy after progression following BioCT (cisplatin, vinblastine, dacarbazine, interferon-alfa and IL-2) in patients with stage IV melanoma. High-dose IL-2 has a 16% response-rate as first-line therapy, with approximately 5% of the pts achieving long-term survival. Methods: We retrospectively reviewed our experience with high-dose IL-2 in pts who had metastatic melanoma and had progressed during or after BioCT from 1/2000 to 1/2005. One treatment course consisted of IL-2, 600.000 IU/kg IVP q8h for a maximum of 14 doses per cycle, followed by an identical cycle after a one week of rest. Responding patients received 2 additional courses after 6 weeks of rest between courses. All pts were treated in a regular ward setting under the assistance of specialized and trained nurses on high-dose IL-2 therapy. Results: A total of 23 pts (15 male, 8 female); median age 46 (range 21–68) were treated with high-dose IL-2. Two pts received only 1 cycle of therapy due to PD and 1 treatment-related death. The remaining 21 pts received at least 1 full course (2 cycles) of therapy. Median number of cycles was 2 and median number of IL-2 doses/cycle was 10. Response rates using RECIST were as follows: CR, 1 pt (5%); PR, 6 pts (27%). Duration of response was 1, 3, 8, 9, 10, 12, and 18 months. There were no long-term disease-free survivors. Among the 9 patients with a previous response to BioCT, 1 pt had CR and 3 pts had PR to high-dose IL-2. Among the 8 pts whose disease previously progressed on BioCT, 2 pts still achieved a PR. After a median follow-up of 36 months, all pts have presented disease progression and 20 pts have died. Median time to progression and overall survival were 2.5 mo and 9.5 mo, respectively. Conclusions: High-dose IL-2 has modest but definite activity in pts previously treated with BioCT, regardless of the response to the latter treatment, and may be an option in selected pts.

No significant financial relationships to disclose.