bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk factors for in-hospital mortality and prolonged length of stay in older patients with solid tumors
Authors: Shayne M. , Culakova E. , Poniewierski M. S. , Wolff D. A. , Lyman G. H.
Published: August 2020

9550

Background: Little is known about risk factors that contribute to prolonged hospitalization and mortality in older patients with cancer. Methods: Cancer patients ≥65 years of age hospitalized between 1995 and 2003 at 133 academic medical centers were evaluated using the University Health System Consortium discharge database. This study identified 386,377 older hospitalized patients with various solid tumors. Multivariate analyses were performed to determine variables independently associated with the primary endpoints: length of stay (LOS) ≥10 days and in-hospital mortality (IHM). Results: Average LOS was 7.5 days with 23% hospitalized ≥10 days. A significant improvement in LOS was observed over the study timeframe (p<.0001). Patients with gastric cancer had the greatest risk of prolonged LOS while those with breast cancer had the lowest risk. Additional risk factors for prolonged LOS included infection, venous thromboembolism and red blood cell transfusion (RBCT). The overall rate of IHM was 7.3% with a significant improvement in risk over the study timeframe (p<.0001). IHM was strongly associated with prolonged LOS (p<.0001). Older patients with primary central nervous system malignancies had the highest rates of IHM (OR=1.81; 95% CI: 1.59–2.07), followed by esophageal and lung cancer. Male gender was a risk factor for both IHM and prolonged LOS (p<.0001). Older African American cancer patients were more likely to experience prolonged LOS and IHM compared with Caucasian patients (p<.0001) after adjustment for cancer type and comorbidities. Additional risk factors associated with IHM included metastatic disease, active infection, neutropenia, renal disease, lung disease, arterial and venous thromboembolism, congestive heart failure, hepatic disease, and RBCT. Conclusions: Improving trends in LOS and IHM for older patients with solid tumors were observed over time in this study. Risk factors associated with IHM such as infection, neutropenia and RBCT, when modified, could potentially further reduce rates of prolonged LOS and IHM in older cancer patients.

[Table: see text]
Cognitive function and fatigue in colorectal cancer (CRC) patients: Baseline assessments prior to chemotherapy
Authors: Vardy J. L. , Dhillon H. , Xu W. , Dodd A. , Park A. , Rourke S. B. , Clarke S. J. , Ringash J. , Burkes R. , Tannock I. F.
Published: August 2020

9557

Background: A subset of women with breast cancer have cognitive impairment &/or fatigue before and after chemotherapy (CTh). We evaluated these symptoms and potential mechanisms prior to CTh in patients with CRC. Methods: Chemo-naïve patients with stage I-III CRC (Group 1) and pts with limited stage IV CRC prior to 1st line metastatic CTh (Group 2) were evaluated. Neuropsychological (NP) performance was assessed by classical and computerized (CANTAB) test batteries, with cognitive impairment defined using a global deficit score approach, and concurrent questionnaires for fatigue & quality of life (FACT-F), anxiety/depression (GHQ), and perceived cognitive function (FACT-COG). Group 1 had blood tests to evaluate 10 cytokines, clotting factors, sex hormones, CEA and apoE genotype. Primary endpoints were cognitive function (classical tests) and fatigue in group 1. Associations between test results, demographic and disease-related factors were sought. Results: We assessed 326 patients: Group 1, 253 (post-surgery [median 56 days] 174; pre-surgery 79); Group 2, 73. Median age was 59 (23–75); 61% were male. In group 1, 36% had cognitive impairment on classical tests & 29% on CANTAB; 32% and 30% in group 2. No differences were seen by disease stage or surgery status. Men had more cognitive impairment than women on classical tests (p=.001). Self-reported cognitive symptoms was 10%; higher in women (p=.08). Fatigue, QOL, anxiety/depression & self-reported cognitive symptoms were strongly associated with each other (r=.45-.76, p<.0001), but not with NP test performance. Fatigue was 52% in Group 1 vs 66% in Group 2 (p=.03); and greater in women (p=.002). All cytokines were elevated compared to healthy volunteers (p<.001). Cognitive function and fatigue prior to CTh were not associated with cytokines, sex hormones, clotting factors, CEA or apoE genotype. Symptoms of anxiety/depression were reported by 13% of group 1 pts vs 25% in group 2 (p=.02). Conclusions: Cognitive impairment was present in 36% of CRC patients prior to adjuvant CTh, with 10% self-reporting impairment and 52% reporting fatigue. Cytokine levels were elevated but were not associated with cognitive function or fatigue. The etiology of cognitive impairment prior to cancer treatment remains unknown.

No significant financial relationships to disclose.
Paradoxical cutaneous squamous cell proliferations in patients treated with sorafenib
Authors: Arnault J. P. , Mateus C. , Wechsler J. , Spatz A. , Tomasic G. , Sibaud V. , Aractingi S. , Grange J. D. , Escudier B. , Robert C.
Published: August 2020

9564

Background: The new multikinase inhibitor sorafenib is associated with multiple and usually manageable skin side effects. We report 12 patients presenting with solitary or multiple cutaneous squamous cell proliferations occurring in the months following initiation of sorafenib and we discuss the significance of this unexpected association. Results: Twelve patients treated by sorafenib for renal cell cancer or hepatocellular carcinoma presented one or several skin tumours with a typical keratoacanthoma (KA) appearance 3 to 9 months after the onset of sorafenib therapy. Some KAs had a spontaneous regression. No recurrence after surgical excision or metastatic dissemination was reported. Histologic examination of 22 lesions found classical non aggressive KAs in 16 cases and more aggressive squamous cell carcinoma-like lesions with deep dermis invasion and cellular atypias in 5 patients. Conclusions: Sorafenib treatment can be associated with cutaneous squamous cell proliferation resembling KAs. Although our observations suggest that these skin neoplasms have a low aggressive potential, these reports address the questions of the paradoxical proliferating effect of a drug that usually has an anti-proliferating effect. They also reactivate the unresolved controversy about the relationship between KA and authentic squamous cell carcinoma. More practically, although the exact frequency of this side effect is unknown, physicians should be aware of this side effect and regularly perform skin examination of their patients. Surgical excision is the treatment of choice in order to rule out authentic squamous cell carcinoma. Impact and management of these skin proliferations will have to be further evaluated, especially if sorafenib is to be tested in an adjuvant setting.

No significant financial relationships to disclose.
Neoplastic meningitis—Is MRI as sensitive as CSF cytology?
Authors: Strik H. M. , Proemmel P. , Pilgram-Pastor S. , Buhk J. H.
Published: August 2020

9566

Background: Although CSF cytology and MRI are standard methods for the diagnosis of neoplastic meningitis (NM), this complication of neoplastic disease still remains to be difficult to detect in some cases. We therefore re-evaluated the sensitivity of gadolinium(GD)-enhanced MRI and cerebrospinal-fluid (CSF)-cytology for the diagnosis of LM differentially for solid and haematological malignancies and for normal or elevated cell counts. Methods: We identified retrospectively 101 cases of NM diagnosed in our CSF laboratory since 1990 with complete data of both MRI and CSF-cytology. 34 had haematological, 67 solid neoplasms. CSF-cell counts were increased in 63 and normal in 35 patients. Results: For haematological neoplasms, MRI was positive in 53%. CSF cytology was positive in 97%. In solid tumours, we found MRI-sensitivity of 0.81 and cytological sensitivity of 0.76. With normal CSF-cell-counts, MRI was positive in 63%, (0.57 haematological, 0.75 solid malignancies), CSF-cytology in 78%, (0.9 in haematological, 0,64 in solid neoplasms). In cases of increased cell-counts, MRI-sensitivity was 0.75 (0.52 for haematological, 0.87 for solid malignancies), and sensitivity of CSF-cytology was 0.89 (1.0 for haematological and 0.82 for solid neoplasms). 23 patients were treated with intrathecal MTX or Ara-C, 16 patients with liposomal Ara-C. 62 patients were not treated intrathecally. Conclusions: We confirmed here the high overall sensitivity of MRI for the diagnosis of neoplastic meningitis. The best sensitivity, however, was seen in solid tumours and elevated cell counts. In haematological malignancies, a markedly lower sensitivity of MRI was seen. Of note, we consider the very high sensitivity of cytology in haematological malignancies to be artificial due to methodological reasons of this retrospective study. We conclude that MRI is a very sensitive method to detect NM especially in solid tumours and elevated cell counts. With normal cell counts and haematological neoplasms, CSF-cytology remains to be superior to radiological methods.

[Table: see text]
Acquired and inherited risk factors for the developing of venous thromboembolism in cancer patients receiving adjuvant chemotherapy: A prospective trial
Authors: Labianca R. , Mandalà M. , Barni S. , Falanga A.
Published: August 2020

9572

Background: To assess the thrombogenic role of adjuvant chemotherapy, following radical surgical resection, in ambulatory cancer patients, is of particular interest, because of the little or no tumor burden. The relation between adjuvant chemotherapy and thrombosis has been investigated in breast cancer. Limited information is available in GI cancers. Aim of this study was to investigate the acquired and inherited risk factors for VTE and the incidence of symptomatic VTE in patients on adjuvant chemotherapy for breast or GI cancer. Methods: In a prospective observational study (January 2003 and February 2006), 199 GI (82F/117M; age range, 26–84 years) and 182 breast (180F/2M; age range, 29–85 years) cancer patients were enrolled and followed-up for symptomatic VTE during adjuvant chemotherapy. We prospectively evaluated the effect of acquired (i.e. age, chemotherapy, tumor hystotype, history of thrombosis, body mass index and smoke) and inherited risk factors (i.e. antithrombin, protein C, protein S, homocysteine, activated protein C [APC] resistance, factor V Leiden [FVL] and Prothrombin [PT] mutations). Results: Overall 30 VTE events (7.87%) were recorded: 28 (7.35%) during treatment and 2 (0.52%) during the subsequent follow-up. Among all the 381 cancer patients, FVL was detected in 14 cases (3.67%) and PT mutation in 10 cases (2.62%). At multivariate analysis thrombocytosis (HR 2.8; 95% CI, 1.13–7.30, P< 0.026) and a previous episode of thrombosis (HR 12.4; 95% CI, 2.48–62.6, P< 0.0026) were significantly associated to the development of VTE . There was no association between the FVL or PT mutations and the risk of VTE. Conclusions: Our data demonstrate that, in the adjuvant setting, most VTE occur during therapy. Thrombocytosis prechemotherapy and an history of VTE strongly predict the developing of VTE in the adjuvant setting.

No significant financial relationships to disclose.
Randomized clinical trial of medical qigong on quality of life, fatigue, side effects, mood, status, and inflammation of cancer patients
Authors: Oh B. , Butow P. , Mullan B. , Clarke S. , Beale P. , Pavlakis N. , Rosenthal D.
Published: August 2020

9617

Background: The quality of life (QOL) of cancer patients is often diminished due to the side effects of treatment and symptoms of the disease itself. This study examines the impact of Medical Qigong (MQ), including gentle exercise and relaxation through meditation and breathing exercise based on the Chinese Medicine theory of energy channels, on quality of life (QOL), fatigue, side effects, mood status and inflammation. Methods: One hundred sixty two patients diagnosed with a range of cancers recruited from three university teaching hospitals were randomly assigned to two groups: a control group (n=83) that received usual health care and an intervention group (n=79) who participated in a MQ program for 10 weeks in addition to receiving usual health care at the hospital. Quality of life and symptoms were measured by the FACT-G, cancer related fatigue by FACT-F and mood status by POMS. The inflammatory marker serum C-reactive protein (CRP) was also monitored serially. Results: Regression analysis indicated that the MQ intervention group significantly improved on measures of overall QOL (t144= -5.761, p<0.001), fatigue (t153= -5.621, p<0.001), mood disturbance (t122=2.346, p=0.021) and inflammation (CRP) (t99=2.042, p<0.044) compared to the usual care control group after controlling for baseline variables. Analysis of the FACT-G subscales revealed that the MQ intervention group also significantly improved in satisfaction with sex life (t92=-3.783, p<0.001) and reduced side effects of nausea (t152=-2.071, p=0.040) and sleep disturbance (t150=-2.603, p=0.010) compared to the usual care control group. Pain was improved in both intervention and control groups. Conclusions: This study suggests that MQ with usual health care can improve overall QOL, fatigue, positive mood status and reduce the side effects of nausea, sleep disturbance and inflammation of cancer patients. This study supports the use of MQ as an intervention for cancer care.

No significant financial relationships to disclose.
Zoledronic acid (ZOL) treatment (Rx) of ≥2 years in patients (pts) with metastatic bone disease (MBD) or multiple myeloma (MM): Six-month results from the LOTUZ study
Authors: Duck L. , Delforge M. , Doyan C. , Wildiers H. , MacDonald K. , Lechat I. , Abraham I.
Published: August 2020

9630

Background: The bisphosphonate (BP) ZOL is frequently used to prevent skeletal-related events (SRE) in cancer pts. However, data are limited on its use beyond 2 years. LOTUZ is among the first studies to examine Rx and outcomes in pts with ZOL Rx for >2y. We report 6-month results. Methods: Prospective (18m), multicenter (50), pharmacoepidemiologic study. Baseline (0m) and 6m data available on 205 pts (of 298 enrolled), all free from osteonecrosis of the jaw (ONJ) at 0m. Prior to ZOL Rx, 27.8% had non-ZOL BP Rx. Mean pre-enrollment BP duration was 42 mo (23–145) with 38 mo (23–80) for ZOL. Results: Mean age: 64 y (38–88); M/F: 29/71%; 67.8% with MBD vs 32.2% MM. 89.3% continued ZOL RX 0–6m; 90% with dose 4mg. From 0–6m, 10 pts (4.8%) developed ONJ (4 with MM, 6 with MBD): 5 mild, 3 moderate, 2 severe (median BP duration: 38.4, 46.5, and 34.8 months, respectively). Five pts with ONJ continued on ZOL RX 0–6m (3 mild, 2 moderate). 4/10 pts with ONJ had baseline dental conditions or procedures, 8/10 at 6m (only 1/10 at neither). SREs and pain levels remained constant 0–6m compared to 6m prior to baseline (see Table ). Conclusions: Beyond 2y, 90% of pts were continued on ZOL. SREs did not increase, but ONJ was diagnosed in 10/205 pts 0–6m, of which 5 were on ZOL RX beyond 24m. Long-term data are needed to better understand the risk/benefit of long-term ZOL Rx. [Table: see text]

[Table: see text]
Placebo and nocebo effects in randomized double-blind clinical trials for fatigue in advanced cancer patients
Authors: de la Cruz M. , Hui D. , Parsons H. A. , Lynn P. , Parker C. , Urbauer D. , Bruera E.
Published: August 2020

9640

Background: We have previously reported significant placebo response in randomized controlled treatment trials for cancer related fatigue (CRF). We conducted a retrospective study to determine the frequency and predictors of response to placebo and nocebo effect in patients with CRF. Methods: We reviewed patients that received placebo in two previous randomized clinical trials conducted by our group and determined the proportion of patients who demonstrated clinical response to fatigue using an increase (ΔFACIT-F score) > 7 from baseline to day 8, and those with nocebo response as those who reported side effects. Baseline patient characteristics and symptoms recorded from the Edmonton Symptom Assessment Scale (ESAS) were analyzed to determine their association with placebo and nocebo effects. Results: A total of 105 advanced cancer patients received placebo. 59 (56%) patients responded to placebo (median Δ FACIT-F score of 22). Worse baseline anxiety and well-being subscale score (univariate) and well-being (multivariate, MR) were significantly associated with placebo response. Common side effects reported were insomnia (79%), anorexia (53%), nausea (38%) and restlessness (34%). MR analysis showed that worse baseline (ESAS) sleep, appetite, nausea, and restless are associated with increased reporting of these side effects ( Table ). Conclusions: Nearly half of advanced cancer patients enrolled in the fatigue trials responded to placebo. Worse physical well-being score was associated with placebo response. Patients experiencing specific symptoms at baseline were more likely to report these as side effects of the medication. These findings should be considered in fatigue clinical trial design. [Table: see text]

No significant financial relationships to disclose.
TAC (docetaxel, doxorubicin, and cyclophosphamide) adjuvant chemotherapy supported by G-CSF without dose-reduction in node-positive breast cancer
Authors: Suh Y. , Oh S. , Song B. , Jung S.
Published: August 2020

e11606

Background: For node-positive breast cancer, TAC (Docetaxel-Doxorubicin-Cyclophosphamide) chemotherapy is preferred as an adjuvant treatment. However, due to its high toxicity profiles such as severe neutropenia, TAC is a lot beyond enthusiasm. G-CSF support or even prophylaxis has been recommended to help patients recover from nadir, along with some dose-reduction schedule. We tried to evaluate whether TAC with G-CSF support from day 5 can be sustained without dose reduction in women under 69-years old. Methods: After getting IRB approval, between Mar. 2005 and Oct. 2008, 61 node-positive breast cancer patients (33 - 69 years old) had underwent TAC chemotherapy as an adjuvant treatment after curative resection after getting informed consent. Total of 366 cycles (6 cycles per patient, 75–50–500 mg/m2)were completed, G-CSF support was initiated from day 5 to full neutrophil recovery. In case of neutropenia, prophylactic antibiotics (cefoperazone 2 g and tobramycin 200 mg iv) were given. Results: Among 366 cycles, not a single cycle should be delayed to recover from any hematologic shortcomings such as neutropenia, anemia or thrombocytopenia. Interval of three weeks between each cycle could be maintained. No other problem happened for any patient to stop or postpone scheduled chemotherapy. None of antibiotics except prophylaxis with cefoperazone and tobramycin was needed. Conclusions: Maximum tolerable dose of chemotherapeutic agents should be given to patients to get the best oncologic outcome to fight against cancer. It is evident that huge scale prospective clinical trials can answer this question, but we presume that node-positive breast cancer patients between in her fourth and seventh decade can stand TAC chemotherapy with G-CSF support without dose reduction as routine.

No significant financial relationships to disclose.
Treatment of early breast cancer (EBC): A long-term follow-up study—GOCS experience
Authors: Iturbe J. , Zwenger A. , Lacava J. A. , Perez Verdera P. , Vallejo C. , Romero A. , Leone J. P. , Perez J. , Maccihavelli M. , Leone B.
Published: August 2020

e11610

Background: Most cases of breast cancer are diagnosed at early stage of disease, therefore treatment is oriented to increase the relapse-free survival (RFS) and overall survival (OS). The prognosis, in comparison to other malignancies, has improved in the last decades as a result of mammographic screening. The objective of this study was to evaluate the incidence of local and distant recurrence, RFS and OS in women with EBC. Methods: From 01/1978 to 12/2004, 929 women with EBC were identified, 350 were stage I and 579 stage II (AJCC 2002). RFS was analyzed from the date of initial diagnosis to the date of local or distant recurrence. OS was estimated from the date of initial diagnosis to the last follow-up or date of death. Multivariate regression analyses were carried out using proportional hazard model proposed by Cox. RFS and OS were evaluated by the product-limit method of Kaplan and Meier, and differences between curves were assessed by means of log-rank test. Results: Median age was 51 years (28–92). Conservative surgery was performed in 69.7% of patients (pts). The median number of nodes examined was 17. Hormone receptors were ER+ in 65% and PR+ in 62% of pts. Adjuvant radiation therapy was administered to 73% of pts, whereas adjuvant chemotherapy to 29% and adjuvant hormone therapy to 18.5% of cases. Combined chemotherapy and hormone therapy was given to 34% of women. The median follow-up was 8.4 years (0.3–30). Local recurrence was documented in 37 pts (3.8%) whereas 269 developed metastatic disease (29%). Bilateral breast cancer was seen in 102 cases (10.9%) and 91 pts (9.7%) developed 2nd malignancies. RFS rate at 5, 10, 15, 20 and 25 years was 71%, 67%, 65%, 65% and 64% respectively. OS at 5, 10, 15, 20 and 25 years was 82%, 62%, 49%, 39% and 28% respectively. Factors that had an effect in OS demonstrated by the multivariate regression analysis were: histologic grade, tumor size, ER status, vascular and nodal involvement (p < 0.001). Conclusions: Clinical outcomes in EBC in our experience are similar to that reported in international literature. This group of pts continues to have a good prognosis as shown by the OS rate at 5, 10, 15, 20 and 25 years, although high percentage of pts continue to have recurrence and die from breast cancer after 5, 10, 15, 20 and 25 years of follow-up.

No significant financial relationships to disclose.
Outcome of operable breast cancer with triple negative phenotype
Authors: Izarzugaza Y. , Khosravi-Shahi P. , Soria Lovelle A. , Pérez Manga G.
Published: August 2020

e11621

Background: Breast cancer(BC)is the most frequent neoplasm in women. Triple negative phenotype(TNP)is characterized by lack of expression of estrogen receptor(ER),progesterone receptor(PgR) and Her-2, and it is associated with a worse prognosis. Patients and Method: We conducted a retrospective study of consecutive cases of BC with TNP by immunohistochemistry(IHC),treated in our center within the last 5 years,with primary endpoint of analyzing the disease-free-survival (DFS).Second endpoints of the study were overall survival (OS),place of the first recurrence and cause of death. Results: After reviewing 295clinical histories of localized BC(with available ER,PgR and Her-2 by IHC),we found a total of 24 patients(p)with TNP(Prevalence=8.14%[95CI%: 5.3–11.9%].Ps characteristics:median age=50 years(26–74);premenopausal=55%;tumor grade:G3=40%;G2=60%;85.7% had high Ki-67(>40%);63.2% had stageIIB-III;median tumoral size=2.1cm;node positive=80%(25% with 4 or more positive nodes);96% was ductal carcinoma;56.5% was treated with mastectomy;78% with radiotherapy.Eighty-three percent of ps were treated with neoadjuvant and/or adjuvant chemotherapy with anthracyclines and taxanes:34.8% with adjuvant chemotherapy (AC60/600x4–>Paclitaxel-175x4);21.7% with neoadjuvant ATX(doxorubicin, docetaxel and capecitabine);and 26.1% with neoadjuvant AT(doxorubicin and docetaxel), and only 4 ps with adjuvant CMFx6.With a median follow-up of 36 months(m),median DSF was 42 m(95%CI: 33–51),and the probability of DSF at 3y was 67%.Median OS was 82m(95%CI: 41–123),with a probability at 5y of 52%.Thirty-eight percent(9/24)of ps had an event(3 recurrences and 6 deaths),and 100%of the deaths were caused by tumoural progression. Deaths according to the chemotherapy:75%(3/4 patients)in CMF group vs 15%(3/20)in anthracycline and taxane group(P=0.040; Fisher test).Mainly localization of the first recurrence was multiple in the 44.4%of the cases, followed by the liver(22.2%),lung(11.11%),bone(11.11%)and brain (11.11%). Conclusions: Our study confirmed the worse prognosis associated with triple negative BC.This subtype of BC must be treated with the most active cytostatic drugs in the adjuvant setting.

No significant financial relationships to disclose.
Short-term biological effects of zoledronic acid combined with letrozole in postmenopausal women with estrogen receptor-positive invasive breast cancer
Authors: Bundred N. J. , Landberg G. , Coleman R. E. , Morris J. , Winter M. C. , Holen I. , Cramer A. , Renshaw L. , Grassby S. , Dixon J. M.
Published: August 2020

e11625

Background: Aromatase inhibitors (AIs) reduce tumor cell proliferation and improve breast cancer survival. Recent evidence from in vivo models and the ABCSG-12 Trial suggests that bisphosphonates such as zoledronic acid add to the inhibitory effect of AIs but the mechanism is unclear. We assessed the effect of letrozole alone and in combination with zoledronic acid in a 14 day pre-surgical study in women with primary breast cancer. Methods: Postmenopausal women (n=109) aged 50–75 years with untreated estrogen receptor positive invasive breast cancer (no prior hormonal therapy) gave written informed consent to the study and were randomized to letrozole (2.5mg) or placebo tablets (2:1). Letrozole treated patients were randomized further to zoledronic acid 4mg intravenously or no treatment 2–4 days prior to surgery. Epithelial proliferation and apoptosis was measured pre and post treatment by immunohistochemistry for Ki67 and activated caspase 3 respectively counting at least 1,000 cells. Smooth Muscle Actin immunohistochemistry was also assessed pre and post treatment to determine fibroblast activation. Results: The study is powered to detect a 10% difference in epithelial proliferation with the combination arm (80% chance) compared to the letrozole alone arm. Conclusions: This preoperative biological study should provide important insight into the cellular mechanism or action of zoledronic acid in addition to AIs on primary breast cancer.

[Table: see text]
Benefits of dexrazoxane in female patients with stage II breast cancer treated with anthracycline-based adjuvant chemotherapy
Authors: Schnirer I. I.
Published: August 2020

e11626

Background: In Israel, the majority of patients receiving doxorubicin (A) are treated with dexrazoxan (D). A retro-active study was carried out on cardiac effects of A and D on female patients receiving adjuvant chemotherapy for Stage 2 breast cancer. Methods: 34 newly-diagnosed chemotherapy-naïve female patients with Stage 2 breast cancer, received anthracycline-based chemotherapy treatment A with D ± Herceptin (HER). Cardiotoxicity was assessed by echo-cardiograph pre- and post- treatment, and thereafter every 3 months for a period of 2 years, and was defined by presence of CHF or a reduction in resting LVEF to <45% or to ≥15% below baseline echo-cardiograph. Results: 34 patients were eligible for assessment. The mean age was 52, ranging from 24 to 78. Chemotherapy regimen consisted of 4 cycles of A + cyclophosphamide + D ± HER (HER treatment over a period of one year) + paclitaxel (PAC) (12 courses). Of the 34 patients, 7 (20.5%) were Her2 new positive. 17 patients (50%) were estrogen (ER)/progesterone (PR) positive. 9 patients (26.4%) were triple negative. 2 of the Her2 new positive patients were also ER/PR positive. Average m2 per study population was 1.63 (mean range being 1.39 - 1.87). Average A dosage was 60mg/m2 and mean D dose was 391.2mg (between 333.6mg and 448.8mg). Ratio of A to D was 1:10. Echo-cardiograph pre- treatment ranged from 80% - 60%, a normal range according to the New York Health Association (NYHA). Post-treatment echo-cardiograph ranged from 70% - 45%. One patient from HER positive group (generally experiencing increased cardiotoxicity by 4%) showed decrease in LVEF by 14.3% (14.2% of Her2 new patients). Remaining patients showed no change. One patient from ER/PR positive group experienced a 12.3% reduction in LVEF, representing 5.88% of the ER/PR patients. Remaining ER/PR positive patients remained unchanged, with one patient showing increased LVEF from 60% to 70%. The triple negative patient showed no change in their echo- cardiograph results. Conclusions: This study confirms that no scientific or clinical-based evidence was found of anthracycline- based cardiotoxicity following administration of A plus D, in accordance with published medical evidence. D should be a standard of care for anthracycline-based chemotherapy.

No significant financial relationships to disclose.
Profile of axillary nodal disease from the Irish National Breast Cancer Screening Program in the era of sentinel node biopsy
Authors: Barry M. , Kell M. R.
Published: August 2020

e11629

Introduction: Ireland offers a socialized national breast cancer screening program (Breastcheck) to women between 50 and 65 years of age with the aim of reducing breast cancer mortality. Historical axillary staging for screen detected breast cancer has shown nodal positivity in 25% of cases. This study examines axillary nodal disease from the Irish national breast cancer screening program in the era of sentinel lymph node biopsy (SLNB). Methods: Patients with clinically and radiologically early stage screen detected breast cancer and negative axillae are offered therapeutic surgery with SLNB. We examined prospective Breastcheck data collected from 2006 and 2007. Results: 136,527 women attended for routine screening and from these 574 invasive breast cancers were detected. 55 (9.6%) were clinically/radiologically axillary node positive at diagnosis. 519 clinically node negative patients proceeded to therapeutic surgery with SLNB, 113 (22%) were found to have a positive SLNB. Overall nodal positivity was 29.3% in this asymptomatic population. We examined tumour characteristics, hormone profile and HER-2 status from the SLNB group and tumor size was the only factor significantly associated with a positive SLNB (20.1mm vs. 14.3mm, p, 0.01). Conclusions: SLNB accurately detects axillary nodal disease from a purely screen detected population. Based on historic data, SLNB is superior to axillary sampling in this population.

No significant financial relationships to disclose.
Acute interstitial pneumonitis following adjuvant tamoxifen therapy
Authors: Ahmed S. , Shahid R. K.
Published: August 2020

e11637

Background: Tamoxifen is a serum estrogen receptor modulator that is widely used in the treatment of women with breast cancer and has a low incidence of serious side-effects. Although hypersensitivity reactions to tamoxifen have rarely been described, to our knowledge acute lung toxicity has not previously been reported. Objective: To report an unusual case of acute interstitial pneumonitis in a patient with early stage breast cancer treated with tamoxifen. Results: A 66 year old post-menopausal woman with past medical history of type 2 diabetes mellitus, and hypertension noted a lump in the right breast. An excision biopsy revealed 9 mm moderately differentiated invasive ductal carcinoma. Lymph nodes were not involvd by the tumor. The tumor cells were positive for estrogen and progesterone receptors and were negative for ErbB-2 over expression. The post operative course was complicated by wound infection treated with combination of clindamycin and ciprofloxacin. The patient was recommended adjuvant tamoxifen. Her other medication were metformin, valsartan, calcium and vitamin D. One week after the commencement of tamoxifen she noted increasing dyspnea, cough, and intermittent fever. X-ray chest showed bilateral lung infiltrates. She was hospitalized and treated with broad spectrum antibiotic. The patient condition deteriorated. She developed acute respiratory failure requiring intubation and mechanical ventilation. Tamoxifen was discontinued. A CT scan of chest showed bilateral interstitial infiltrates. Bronchoalveolar lavage was performed which was negative for infection. An open lung biopsy was done which showed focal diffuse alveolar damage consistent with interstitial pneumonia. No evidence of an infective agent, malignancy, or granuloma was noted. The patient was treated with high dose steroid. She gradually recovered and was discharge to home with normal lung function. Conclusions: Drug-induced lung injuries are usually idiosyncratic reactions and occur in an unpredictable manner. The presence of a temporal relationship between the lung injury and tamoxifen administration, a rapid clinical improvement after discontinuation of the drug, and absence of other causes strongly implicated tamoxifen as a potential cause of acute lung injury.

No significant financial relationships to disclose.
Docetaxel plus capecitabine in the treatment of previous anthracycline-treated patients with metastatic breast cancer
Authors: Bensalem A. , Bouzid K.
Published: August 2020

e12014

Background: Anthracyclines have been considered the challenge of the treatment of metastatic breast cancer. Docetaxel has changed this belief. We conducted a study in previously anthracyclines treated metastatic breast cancer by the regimen docetaxel 75 mg/m2 Day 1 - capecitabine 2500 mg/m2 day split-up over 2 daily doses from Day 1 to Day 14; every 21 Days. Methods: Patients were eligible if they had metastatic breast cancer after an adjuvant setting by anthracyclines. All patients had measurable disease, PS ≤ 2, adequate organ function. Results: From April 2004 to June 2006, 18 patients were enrolled in the study and were evaluated for the toxicity and preliminary responses to the treatment. 100 % of patients had metastatic breast cancer. The sites of metastases were liver in 14 ( 77.7%), lung in 5 (27.7%) and bone in 9 (50%). 11 patients (61.1%) had 1 or 2 metastatic sites, 7 (38.9%) had 3 metastatic sites. All of 18 patients were assessed for toxicity. The main toxicities were as follows: neutropenia grade 3 in 3 patients (16.6 %), anemia grade 2–3 in 2 patients (11.1%), fatigue in 2 patients (11.1%), hand-foot syndrome in 7 patients (38.9%), vomiting-nausea in 4 patients (22.2%), diarrhea in 2 patients (11.1%), liver toxicity in 3 patients (16.6%). The objective response was obtained in 8 patients (44.4%) (Complete response in 3 patients (16.6%), partial response in 5 patients (27.7%). Median response duration was 9 months (range 4 - 17). 7 Patients (38.9%) had stable disease, progression was observed in 3 (16.6%) of patients. Conclusions: In this preliminary analysis, the combination of docetaxel - capecitabine in the treatment of previously anthracyclines treated metastatic breast cancer appears to be an active schedule. It is safe and active, with a manageable toxicity profile and a good clinical activity.

No significant financial relationships to disclose.
MGMT methylation status may predict survival in elderly patients with newly diagnosed glioblastoma (GBM)
Authors: Gerstner E. R. , Yip S. , Wang D. L. , Louis D. N. , Iafrate A. J. , Batchelor T. T.
Published: August 2020

e13023

Background: Methylation of the MGMT gene promoter is associated with prolonged survival and response to temozolomide in GBM < 70. However, it is unclear if MGMT is a useful prognostic biomarker in the elderly GBM population who traditionally are viewed as less responsive to treatment. Methods: We retrospectively reviewed MGMT promoter methylation status and clinical characteristics in patients 70 years or older with newly diagnosed GBM undergoing resection at our institution from 1998–2008. MGMT analysis was performed by extracting tumor genomic DNA for bisulfite conversion. MGMT methylation specific PCR (MSP) was then performed using PCR primer sets specific for methylated and unmethylated MGMT promoter sequence. The logrank test was used to compare mPFS and mOS in patients who had methylated (ME) MGMT vs. unmethylated (UN) MGMT. Results: Thirty-four patients were included in the analysis. Twenty patients (59%) were ME while 14 (41%) were UN. Patients were treated with multimodality treatment (radiation + chemotherapy), radiation alone, or chemotherapy alone. ME was associated with a significantly prolonged mPFS and mOS as noted in the table below which also summarizes the characteristics of the study population. Conclusions: MGMT methylation status is associated with prolonged PFS and OS in elderly patients with newly diagnosed GBM. Knowledge of MGMT status may help improve prognostication in this patient population.

[Table: see text]

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Glioblastoma-derived cells exhibit differential responses to glycolysis inhibition under hypoxia
Authors: Pistollato F. , Abbadi S. , Rampazzo E. , Viola G. , Della Puppa A. , Cavallini L. , Panchision D. M. , te Kronnie G. , Basso G.
Published: August 2020

e13031

It has been suggested that oxygen tension is a crucial component of the brain tumor niche, as hypoxia positively correlates with tumor aggressiveness and over-activity of hypoxia inducible factor-1α (HIF-1α) reinforces tumor progression. Furthermore, hypoxia has been implicated in the regulation of several signaling pathways (Notch, BMP), angiogenesis and importantly, glucose metabolism. Here we investigate the effects mediated by in vitro glycolysis inhibition by using 2-deoxyglucose (2-DG) in glioblastoma (GBM) derived cells maintained under two different oxygen tensions, a lowered oxygen tension (2%) versus a higher non-physiological (20%). GBM account for 50% of all gliomas and arise after age 50 in most patients and it has been seen that younger patients tend to have a better prognosis than the elderly. Our results show that adult GBM displaying a highly immature phenotype manifested the highest resistance to glucose deprivation. Furthermore, increase of multi-drug resistant cell fraction, described as side population, occurred following 2-DG treatment, but only under hypoxia. Neuronal committed precursors were selected by 2-DG, but these effects were mitigated by hypoxia. Also, hypoxia inhibits the mitochondria-controlled apoptosis induced by 2-DG, by conferring cell resistance through progressive activation of pro-survival NF-kB and induction of tumor cell autophagy. Importantly, HIF-1α level reduction and proline hydroxylase 2 (PHD2) upregulation occurred following 2-DG treatment even under hypoxia, and this may depend on reactive oxygen species reduction. These results indicate differences in tumor cells behavior that may be predictive of cell response to therapy aiming to limit glucose uptake or glucose metabolism.

No significant financial relationships to disclose.
Preliminary results of an open-label phase I pharmacokinetic/pharmacodynamic study of JNJ26481585: Early evidence of antitumor activity
Authors: Postel-Vinay S. , Kristeleit R. , Fong P. , Venugopal B. , Crawford D. , Van Beÿsterveldt L. , Fourneau N. , Hellemans P. , Evans J. , De-Bono J.
Published: August 2020

e13504

Background: JNJ26481585 is a novel orally active pan-histone deacetylase inhibitor (HDACI) which showed potent antitumor efficacy in a wide range of animal tumor models. Methods: A 2-stage accelerated titration design Phase I trial was conducted to characterize safety, establish the maximum tolerated dose (MTD) and determine pharmacokinetics in patients (pts) with refractory solid tumors, of performance status <2 and with adequate hematologic, renal, hepatic and cardiac function. The drug was administered orally, once daily in 3 weekly cycles. Results: To date, 9 pts (median age 59; range 32–74) have been treated at 4 dose levels (DL): 2 (2 pts), 4 (2 pts), 8 (3 pts), and 12 (2 pts) mg. The median number of cycles administered was 2 (range 1–9). Dose-limiting toxicity was seen at 12mg (CTCAE Grade [G] 3 non-sustained ventricular tachycardia [VT] [1 pt] and G3 fatigue [1 pt]) and the 8mg cohort is being expanded. Other toxicity observed at 12mg comprised G2 palpitations with QT prolongation (1 pt), G2 anorexia (1 pt), G2 vomiting (1 pt) and G2 dysgeusia (1 pt). At 8mg, 1 pt on warfarin developed a G2 INR increase. Non-specific ECG changes were observed from the 2mg DL onwards. The drug was generally well tolerated up to 8mg. Exposure to JNJ26481585 increased proportionally over the 2 to 12mg dose range, with a constant metabolite/parent ratio (3.5 for Cmax; 7 for AUC). Two partial responses (PR) and one stable disease (SD) have been observed. PR occurred in 2 pts with metastatic melanoma treated at 12mg : one pt had a PR in visceral and complete response in subcutaneous melanoma metastases after 22 days of drug and has ongoing response 5 months after stopping treatment; the second pt had PR in lymph nodes and reduction of cutaneous lesions of melanoma. One non small cell lung cancer pt treated at 4mg showed SD for 9 cycles. Assessment of histone acetylation as a pharmacodynamic biomarker in peripheral blood lymphocytes and hair follicles is ongoing. Conclusions: JNJ26481585 is generally well tolerated at doses up to 8mg daily. Evidence of promising antitumor activity has been observed with 2 PR to date in patients with metastatic melanoma. The 8mg cohort is being expanded with increased cardiac monitoring. Other schedules may be explored in the future.

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Integrated safety findings with tesetaxel, an orally administered taxane, in patients (pts) with gastric, colon, breast, and nonsmall cell lung cancer: Phase II results
Authors: Novick S. C. , Wu J. , Ilson D.
Published: August 2020

e13516

Background: The orally active taxane tesetaxel has potent cytotoxic activity against various human and murine cancer cell lines in vitro and in xenograft tumor models, including those that express P-glycoprotein (pgp). In a Phase 1 study, 48 pts with advanced solid tumors were treated at doses of 1.5 mg/m2 to 40 mg/m2. AUC and Cmax increased in a dose-proportional manner. There was no dose-limiting toxicity (DLT) at doses ≤18 mg/m2. Above 18 mg/m2, Grade 4 neutropenia > 5 days in duration was the most common DLT. The MTD was 27 mg/m2 for heavily pretreated pts and 35 mg/m2 for minimally pretreated pts. These doses were further evaluated in a Phase 2 program in 4 studies, and activity was demonstrated in gastric, colorectal, breast, and non-small cell lung cancers. To assess safety across all indications prior to beginning randomized trials, we conducted an integrated analysis of the safety of the 27 mg/m2 dose as initial therapy in Phase 2. Methods: All pts had been previously treated with a nontaxane regimen. Tesetaxel was given on Day 1 of a 21-day cycle; the dose was rounded to the nearest 10 mg. Prophylactic treatment with such drugs as antiemetics and colony- stimulating factors (CSFs) was permitted only after Cycle 1. Results: A total of 142 subjects received tesetaxel 27 mg/m2 as initial therapy. The most common Grade 3–4 adverse events were neutropenia (33%), leukopenia (22%), and anemia (11%). Grade 3–4 neuropathy was distinctly uncommon (3%). Conclusions: Taxanes are highly active in solid tumors, but most are associated with neurotoxicity and infusion reactions. Oral tesetaxel eliminates infusion reactions and consequent requirements for extended observation and premedication, is associated with a low incidence of Grade 3–4 neurotoxicity, and may be useful in diseases associated with high pgp expression. Like other taxanes, the most common adverse event is neutropenia, which can be ameliorated with appropriate monitoring and use of CSFs. These and other safety considerations will be incorporated into planned registration trials.

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Cardiovascular safety profile of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor: Results from two independent phase I trials in patients with advanced cancer
Authors: MacRae C. , Richardson P. G. , Walker J. , Grayzel D. S. , Demetri G. D.
Published: August 2020

e14539

Background: Heat shock protein 90 (Hsp90) is a protein chaperone that regulates the proper folding, stability, and function of multiple mutated and wild type signaling proteins that promote malignant phenotypes. Numerous clinical trials are investigating the activity of the Hsp90 inhibitor IPI-504. Since Hsp90 is a novel cancer target that is ubiquitously expressed in normal cells, a comprehensive evaluation of potential cardiac effects, including the risk of ventricular arrhythmia, was performed in two Phase I trials. Methods: ECG data were pooled and analyzed from 60 pts in two-open label Phase I trials of patients with advanced cancers. Pts received 90 to 400 mg/m2 of IPI-504 IV twice weekly for 2 out of 3 weeks. Subset analyses for 35 pts who received the MTD of 400 mg/m2 were performed. ECGs were obtained in triplicate at 5, 60, and 360 minutes after IPI-504 infusion. Interpretation was conducted at a central, independent laboratory. Results: Over 6,500 ECGs were obtained from 60 pts. At the MTD 3,000 ECGs were obtained from 35 patients. No ventricular arrhythmias or changes in QTcF of ≥60 msec were noted, and no statistically significant relationship between the concentration or dose of IPI-504 and QTcF was observed. At the MTD 5 minutes post infusion, changes from baseline were observed in QTcF (5.4 ms increase), heart rate (15.2 bpm decrease), and PR interval (27.9 ms increase). All of these changes reversed by 6 hours post-infusion and no clinical hemodynamic disturbances were observed. Conclusions: In phase I studies, IPI-504 was not associated with any significant ventricular arrhythmia and no clinically significant QTcF interval changes were noted. These studies did show however that IPI-504 administration was associated with transient, dose-related bradycardia and PR interval lengthening, suggestive of autonomic effects associated with the drug infusion. No clinically significant and IPI-504 related cardiac safety events were observed at the MTD dose of 400 mg/m2. Given these findings, appropriate monitoring of heart rate immediately post-infusion is recommended during further studies with IPI-504.

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Results from a phase I safety lead-in study investigating the combination of erlotinib and the histone deacetylase inhibitor entinostat in patients with advanced NSCLC
Authors: Konduri K. , Spira A. I. , Jotte R. M. , Boyd T. , Boyd T. , Gaffar Y. A. , Reynolds C. , Witta S. E.
Published: August 2020

e14545

Background: Preclinical studies showed the synergistic effect of entinostat with epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in NSCLC cell lines. Entinostat (SNDX-275, Syndax Pharmaceuticals) is an oral, class 1 isoform selective HDACi that restores the expression of e-cadherin and sensitivity to EGFR-TKI in NSCLC cell lines. The aim of this study was to determine the safety and feasibility of combining entinostat with erlotinib in advanced NSCLC patients in order to determine the recommended Phase 2 dose. Methods: Patients with recurrent or metastatic NSCLC whose tumors progressed on prior chemotherapy were treated with either 5 or 10mg orally of entinostat once every two weeks and erlotinib 150mg daily. Results: A total of 9 patients were enrolled (3 at entinostat 5mg; 6 at 10mg). Characteristics: Sex: M/F: 6/3; Age range: 46–84 yrs; ECOG PS: 0–1; Smoking status: 1/8 (never/current or prior smokers); Number of prior treatments: 1–2. There was one DLT of grade 3 asthenia. This occurred in one of the six patients in the 10mg dose cohort. The most common adverse events were anorexia, and asthenia. This was more often noted in elderly patients. Of the 9 evaluable patients, one patient had a confirmed partial response and remains on study (>5 cycles) and another patient had stable disease for 8 months. Pharmacokinetic analysis has been completed with both drugs exhibiting levels comparable to historical data. No drug:drug interaction was observed. EGFR FISH, EGFR mutation, and epithelial-to-mesenchymal marker analysis is in progress. Conclusions: This study has established the safety and a recommended phase 2 dose of 10 mg of entinostat once every other week in combination with 150 mg daily of erlotinib in a 28-day cycle in advanced NSCLC patients. A randomized, double blinded phase 2 study has been initiated with 43 patients enrolled to date.

[Table: see text]