bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the response to first-line chemotherapy (chemo) in the chemotherapy-induced anemia control with the administration of Erithropoyetins (Epos) in metastatic non-small cell lung cancer (NSCLC) patients (pt)
Authors: Gasent Blesa J. , Giner Marco V. , Alberola Candel V. , Juan O. , Giner-Bosch V. , López A. , Provencio Pulla M. , Grande Pulido E.
Published: August 2020

e20647

Background: The aim of this retrospective study, is to measure the influence of the tumor control with chemo on the results of the chemo-induced anemia treatment with epos in pts with nsclc, that were non-anemic before chemo, and in whom the only recorded cause of anemia was chemotherapy treatment. cycle. Methods: We analyzed 57 stage IV nsclc pt (21 Squamous, 26 Adenocarcioma, 4 Lare cell, 6 non specified), 41 male, 16 female, 30 with tumor progression (progression) and 27 with partial response (responders). Average age was 60.3 years (CI 95%: 57.2; 63.4). Pt were treated between April 2004 and May 2008. Any patient with disease stabilization was included. 52 pt were treated with platin-gemcitabine, and 5 with cisplatin-paclitaxel. 17 pt received Erithropoyetin-α and 40 darbepoetin. Pt who received radiotherapy as part of their treatment, were excluded of the analysis. Pt began treatment of epos when hemoglobin (hgb) was <12gr/dl. Epos treatment was discontinued if the hgb level increased over 13gr/dl. No patient received epos with the first chemo cycle. Results: Pt with progression began the epos significantly before ( 100% before 4th chemo, 50% in the 2nd cycle) than responders ( 100% before 5th cycle, 7,4% at 2nd cycle) (p<0.001). Pt with progression, had a lower value of hgb at the beginning of the epos (median 9.82 in responders; 8.89 in progression; p=0.009). Recovery of the anemia was observed in 25.9% of the responders front to 3.3% of the pt with progression (p=0.014). No significant differences appeared in the requirements for red-cells transfusion (14.8% responders vs 30% progression; p=0.172). The mean hgb increase by each chemo cycle with epos was of 0.74gr/dl in responders and of 0.25gr/dl in pt with progression (p<0.001 CI 95%: 0.232–0.748 for the odds ratio). The mean absolute hgb increase in responders was singnificanly greater than in pt with progression (1.49 gr/dl vs 0.7 gr/dl p=0.008CI 95% 0.21–1.368 for the difference of the means). Conclusions: From the obtained data, we can conclude that the tumor response can have a direct impact on the efficacy of chemo-induced anemia treatment with epos; and that anemia control may reflect beneath disease control.

No significant financial relationships to disclose.
Doctor, how long?
Authors: Fêde A. B. , da Costa Miranda V. , Martins F. D. , Magalhães N. P. , Schaffhausser H. L. , Riechelmann R. P. , Del Giglio A.
Published: August 2020

e20653

Background: In practice it is common to start terminal sedation for patients with advanced cancer who develop physical discomfort not amenable to be treated by other means. We aimed at quantifying the average survival time of terminal cancer patients once sedation was started until death and identify potential variables that may influence their survival time on sedation. Methods: This is a retrospective cohort analysis of all consecutive terminal cancer patients who died after starting terminal sedation at public tertiary brazilian Hospital during 2 years (January 2005 to January 2007). Results: 532 cancer patients died in Hospital Estadual Mário Covas during this period and 181 out of them who received terminal sedation were included in this analysis. The median survival was 27 hours. By multivariate analysis, increase in the dose of sedative drug during sedation (Odds Ratio 1.576, 95% CI 1.113–2.232); use of opioids alone for sedation (Odds Ratio 1.438, 95% CI 1.046–1.977); and dyspnea as cause of sedation (Odds Ratio 1.564 95% CI 1.045–2.341) were independent risk factors for a shorter survival time after starting terminal sedation. Conclusions: Sedated, terminal cancer patients usually live about one day. We identified risk factors for a shorter sedation period. This study is limited by its retrospective design and by the frequent use of opioids as the main sedative medications. Prospective studies must be carried out in order to validate these data in settings in which non-opiods are the main sedative medications.

No significant financial relationships to disclose.
Final results of a prospective, observational study of the effectiveness of darbepoetin alfa administered every three weeks for the treatment of chemotherapy-induced anaemia in elderly patients
Authors: Esquerdo G. , Doménech M. , Bermejo J. C. , López P. , Pedro C. , Villadiego K. , Constenla M. , Sánchez-Rovira P. , Gasquet J. A. , Rodríguez C. A.
Published: August 2020

e20654

Background: Cancer incidence is increasing in elderly but specific treatment data in this population is not often available. The objectives of this study were to evaluate the effectiveness and safety of darbepoetin alfa (DA) administered once every 3 weeks (Q3W) for the treatment of chemotherapy-induced anaemia (CIA) in elderly within routine clinical practice. Methods: Prospective, observational, single-arm, multicentre study performed in 28 centres across Spain. Eligible patients (pts):≥65 years, anaemic (haemoglobin [Hb] 11 g/dl), with non-myeloid malignancies, and scheduled to receive ≥9 weeks (wks) of chemotherapy. Pts were treated with a fixed dose of DA 500 μg Q3W and treatment stopped if Hb levels exceeded 13g/dl. Primary endpoint was hematopoietic response (Hb increase ≥2g/dl or Hb ≥12g/dl without transfusions in the previous 28 days). Secondary endpoints included percentage of pts achieving target Hb (>11g/dl from wk 5 till end of treatment without red blood cell transfusion within 28 days), changes in the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale and the incidence of adverse reactions. Results: Data were prospectively collected from 153 pts: women (56.86%), mean (SD) age 73.43 (5.77) years, ECOG Performance Status 0–1 (65.36%) with solid tumors (66.67%) and lymphoproliferative malignancies (33.33%) and stage III/IV (63.40%). Most pts (90.20%) had baseline Hb levels between 9–11g/dL. DA was administered for a median of 9.0 wks (range: 1–22.57). The Kaplan-Meier percentage (KM; 95% CI) of pts who achieved hematopoietic response was 69.70% (56.06–83.34) and 72.22% (57.5–86.94) for pts who achieved target Hb (>11g/dL). FACT-F median score at baseline was 29.00 and 33.00 at the end of the study. Only one (0.7%) non-serious adverse reaction (cutaneous eruption) was reported. Conclusions: These results suggest that DA given at 500 μg Q3W to elderly pts with non-myeloid malignancies is an effective and well-tolerated treatment for CIA.

[Table: see text]
Prospective evaluation of incidence and pattern of nausea in patients receiving combined chemotherapy and radiotherapy (RT) above the diaphragm
Authors: Axelrod R. S. , Machtay M. , Werner-Wasik M. , Anne R. , Schlossberg H. , Laudadio M. , Kotak D.
Published: August 2020

e20676

Background: Nausea (N), vomiting (V) remain distressing effects of chemotherapy. Prevalence of N, V in patients (pts) receiving daily (5/7) RT with weekly (wkly) doublet chemotherapy is not well studied. Methods: We used a modified Functional Living Index Emesis (FLIE) (Lindley and Mullin) to study N, V in pts receiving 2 chemotherapy agents with RT for upper aero-digestive malignancies. Exclusion criteria were: other causes of N,V or RT below the diaphragm. Pts completed a written questionnaire wkly during therapy. A 6 point scale was used, 0 representing no symptoms and 6 representing intolerable or uncontrolled symptoms. Questions addressed N, V, use of medication in daily diary and overall wkly assessment of N, V, ability to eat, effectiveness of medications and effect on daily routine. Results: 21 Patients enrolled: 15 completed 4 weekly questionnaires, 17 completed 3. Most patients received a total of 5 weekly chemotherapy treatments. Participants: 17 M: 4 F with 17 head/neck sites, 4 lung. 6 pts received wkly carboplatin (AUC 2) and paclitaxel (45/m2 for lung, 30/m2 for h/n); 15 pts cisplatin (20/m2) and paclitaxel. All patients received our standard anti emetic therapy (steroids and 5 HT3 receptor antagonist). Pts with early nausea tended to experience continued or worsened symptoms despite anti emetic therapy; at wk 4, more pts experienced V. Selected results are shown in the table . Conclusions: The modified FLIE questionnaire was a useful tool for evaluation. Despite advances in anti emetic therapy, nausea and vomiting resulting from the combination of radiation therapy with dual agent chemotherapy exerts a significant adverse effect on daily comfort but little effect on overall function.

[Table: see text]

[Table: see text]
Needs in breast cancer patients (pts) during chemotherapy: Customer satisfaction evaluation
Authors: Ferrari V. D. , Ferrari L. , Grisanti S. , Consoli F. , Valcamonico F. , Amoroso V. , Rangoni G. , Vassalli L. , Marpicati P. , Marini G.
Published: August 2020

e20679

Background: Satisfied patients demonstrate higher levels of compliance for the course of their treatment and the probability of successful treatment completion thus considerably increases. Analysis of pts needs is the base of pts satisfaction. The present analysis aims to identify the needs of our in-outpatients who received chemotherapy. Methods: 134 pts with breast cancer who underwent chemotherapy during 3 months (from 15 September to 30 November) were eligible for study. We administered the “Need Evaluation Questionnaire” (NED) validated by U.O. Psiconcologia Istituto Nazionale Tumori Mi) to 125 pts after consent, 9 pts (7%) refused to answer items. NED was built on 23 items in 7 domains of necessity: 1) information on diagnoses, prognoses, diagnostics tests and treatments (items 1–4); 2) relationship between pts and physicians or nurses (items 5–8), 3) nursing and supportive care (items 9 -13) 4) Hospital service (item 14); 5) economical aspects (items 15–16); 6) psychological, ethical, spiritual care (items 17,18,19,23); 7) relationship with relative. NED makes a quantitative evaluation of necessity with simple questions. Eligibility criteria required age ≥ 18 yrs (median age of pts was 55 yrs), histologically proven breast cancer; at lest 1 completed cycles of neoadjuvant or adjuvant or palliative chemotherapy. 96 (77%) pts completed questionnaire by their self, and 29 pts (23%) were helped because of practical problems (infusional therapy, no glasses at so on ). We choose a descriptive quantitative statistical evaluation for every item. Results: 93 % of pts completed NED questionnaire. More significant data were reported afterward and answers were allocated among the 7 domains: 1) more information about prognosis was required by 52 % of pts; 2) 90 % of pts thought that physicians embroiled them in therapeutic choices, but 36% of pts required information about future and quality of life 3) 96% of pts considered very good nursing care; 4) positive for all pts 5) 26% of pts required more informations about insurance, tickets 6) 13 and 14 % of pts required psychological or spiritual relationship; 7) women generally had support by relatives. Conclusions: this analysis shows that needs of our pts generally received responses, but answers also emphasized assurances on pts’ future.

No significant financial relationships to disclose.
Factors influencing in-hospital length of stay and mortality in cancer patients suffering from febrile neutropenia
Authors: Lal A. , Kumar P. , Bhurgri Y. , Rizvi N. , Shaikh A. J. , Adil S. , Masood N. , Virwani M.
Published: August 2020

e20716

Background: Febrile neutropenia (FN) is a major complication of chemotherapy, costly in terms of morbidity, mortality and associated financial expenditure. The present study was conducted with the goal of highlighting FN as a serious problem in Pakistan, with the longer term objective of improved cancer survival, reduction in length of stay (LOS) in hospital, morbidity, mortality and costs in our existing developing country scenario. Methods: A cross-sectional descriptive study was conducted on patients, >18 years, admitted with FN as a consequence of chemotherapy at a referral hospital in Karachi from 1st September 2006 to 30th April 2007. Results: A total of 80 patients [43 (53.8%) males and 37 (46.2%) females] were selected. The mean age was 47.4 (SD ±16.6; range 18–79) years. Sixty eight patients (86%) were < 65 years, 50% were < 50 years. Overall, in hospital mortality was 11%; 4% for patients on granulocyte colony stimulating factor (G-CSF) prophylaxis as against 20% for those without. The cause of death was either pneumonia or septic shock. Mean LOS was 7.53 (SD ±3.8; range 2–17) days. Hematological malignancies, older age, severity of dehydration, pneumonia and culture positivity were significantly associated with LOS and death. Those above 50 years of age were 1.5 times as likely to be hospitalized longer and > three times as likely to die. Bacteremia conferred a 5-fold and pneumonia an 8-fold increase in the risk of death. Conclusions: The results of this study indicate that age, vital instability, dehydration, high creatinine, culture positivity and hematological malignancies are high risk factors in chemotherapy induced FN. Identification of FN risk factors with poor outcomes may help in devising protocols for modified dosage or including GCFs initially. This may help reduce the cost of cancer care as well as mortality and morbidity. Prospective studies of FN in multiple centers in Pakistan may be beneficial in evaluating these risk factors further.

No significant financial relationships to disclose.
Nurse practitioner-led breast cancer survivorship clinic
Authors: Cureton A. , Pritham W. , Royce M. , Zahn K.
Published: August 2020

e20723

Background: The 2.5 million breast cancer survivors in the US demands increasing awareness of and need for healthcare organizations to address survivorship issues. Cancer survivorship care has become a specialty emphasizing health promotion, disease prevention, and patient satisfaction. It is a natural setting for advanced practice nurses to be leaders. This abstract presents a model for a nurse practitioner-led breast cancer survivorship clinic. Methods: Eligible patients are those previously diagnosed with invasive and/or in situ breast cancer and at least 5 years post-diagnosis without recurrence. Eligible survivors are identified annually through the University of New Mexico Tumor Registry. Clinic notes are reviewed to confirm the patient has not had a recurrence, new diagnosis, or death. Letters are sent to eligible survivors introducing the Breast Cancer Survivorship Clinic (Clinic) and inviting them to participate, and oncologists are encouraged to transfer eligible patients into the Clinic. Results: Eighty-six survivors are currently participating in the Clinic. Survivors are seen on an annual basis after mammogram. Each survivor receives a personalized Survivorship Care Plan at the first visit. The care plan was developed by a multi-disciplinary team of a breast oncologist, psychologist, social worker, nutritionist, and patient educator to provide input on the issues that survivors face. Components of Survivorship Care Plan: pathologic and genetic findings, summary of treatment, bloodwork, bone health, lymphedema, secondary malignancies, health maintenance recommendations, psychological assessment, nutrition/weight assessment. Conclusions: The establishment of the Clinic has several advantages: Breast cancer survivors are being followed in this specialty clinic after 5 years instead of being discharged from the Cancer Center. The Clinic has allowed oncologists more time for patients actively on therapy and more time to accommodate newly diagnosed patients. The Clinic addresses the unique issues faced by long term survivors, which could increase patient satisfaction. A multi-disciplinary team is key to developing a care plan for a survivorship clinic. However, the day-to-day operation of the clinic can be effectively led by a nurse practitioner.

No significant financial relationships to disclose.
Rates of psychiatric illness in patients with cancer: An analysis of a psycho-oncology service
Authors: Devitt P. , Breathnach O. , Grogan L. , Cotter D. , MacHale S.
Published: August 2020

e20731

Background: The diagnosis of cancer represents a major physical and psychological challenge for patients and their families. Psycho-oncology services are limited throughout the country. We assess the service profile of patients assessed between 1/2003 and 6/2008 to determine how the needs of patients have changed. Methods: Case notes from all patients referred by medical oncologists, clinical nurse specialists and/or social workers to the psycho-oncology service were reviewed for the period 7/07 to 6/08. Demographic details, cancer diagnosis and stage, time since diagnosis, psychiatric diagnosis (past/current), and need for psychiatric intervention were collected. This data was compared to a similar review performed from 1/03 to 12/03. Results: 106 patients were psychiatrically assessed during the period 07/08 compared with 63 from 2003, representing a 68% increase in activity. All major cancers were represented. There was a 30% increase in patients assessed with lung cancer (14% in 07/08 vs. 11% in 2003). More patients were referred with localised disease in 07/08 than in 2003 (37.5% vs .19%, p=0.012).Patients with a past history of psychiatric disorder were more likely to be referred in 07/08 compared to 2003 (54% vs. 32% p=0.005). There was a significant decrease in the numbers diagnosed with depression in 07/08 (29% vs. 51%, p= 0.004) with a corresponding increase in the diagnosis of adjustment disorder (26% vs. 6%). Conclusions: Psycho-oncology services remain an important component of care for patients with cancer. The increased rate of referrals may reflect an increased awareness amongst oncology staff of psychological distress in this vulnerable population.

No significant financial relationships to disclose.
The use of intrathecal ziconotide to manage refractory malignant pain: Five case studies
Authors: McDowell G. C. , Mitchell J. W. , Moore T. D.
Published: August 2020

e20737

Background: Chronic malignant pain is often difficult to manage. Intrathecal (IT) ziconotide monotherapy has been shown to be effective in treating patients with chronic pain associated with malignancy. Intrathecal admixtures containing ziconotide may also be viable treatment options for refractory malignant pain. Methods: The medical records of 5 patients with malignant pain managed with IT ziconotide as monotherapy or as a component of combination therapy were reviewed. Patient characteristics, medical history, IT drug doses, Numeric Pain Intensity (NPI: 0–10 scale, with higher scores indicating greater pain intensity) scores, and clinical observations (including adverse events [AEs]) were identified. Results: Four women (aged 27, 31, 46, and 68 years) with metastatic breast cancer and a 61-year-old man with metastatic prostate cancer were intolerant of or experienced inadequate analgesia with systemic analgesics and/or IT opioids with or without clonidine or bupivacaine. Ziconotide was either started as monotherapy or used in combination with an IT opioid with or without bupivacaine. Initial ziconotide doses of 0.46 to 1.50 mcg/d were titrated upward to 1.16 to 7.26 mcg/d at the last assessments. Although the 46-year-old woman experienced substantial pain relief (55.6% reduction in NPI score) and quality of life improvement during ∼3 months of ziconotide therapy, she died of cancer complications that were unrelated to ziconotide. From baseline to last assessment, the remaining 4 patients experienced 25% to 83% reductions in NPI scores with ziconotide therapy. Meaningful improvements in patient mobility and functionality were evident. The 68-year-old patient experienced transient dizziness after a 3-mcg bolus trial of ziconotide but did not experience any AEs during continuous infusion of ziconotide. No other ziconotide-related AEs were reported. Conclusions: These cases suggest that ziconotide, alone or in combination with other IT agents, can be a viable treatment option for patients with refractory malignant pain.

[Table: see text]
Oncologic patients in the emergency room
Authors: Pajares I. , Tobeña M. , Ferrer A. , Serrano S. , Vidal M. , Lopez D. , Lambea J. , Ruiz-Echarri M. , Millastre E. , Tres A.
Published: August 2020

e20748

Background: Cancer is a very frequent pathology with a gradual increase of its prevalence. Oncologic patients are exposed to suffer many complications which may need emergency attention. The aim of this study is to describe patients which consult in the emergency room and frecuency of different causes of complaint. Methods: Between October 2007 and October 2008, we collected all oncologic patients who consulted in our emergency room. We describe tumor location and causes of complaint. Results: 560 oncologic patients were attended in 12 months (median 12 per week). By tumor location, 134 (23,9%) patients had not small cell lung cancer (NSCLC), 101 (18%) colorrectal cancer, 64 (11.4%) breast cancer, and 261 (53%) other malignancies. Of all patients, 440 (82.7%) had stage IV disease and 318 (56.8%) were receiving chemotherapy treatment The most common causes to complaint were oncologic pain (22.5%), fever (17.5%), dysphnea (12.7%), neurologic symptoms (9.1%), and asthenia (8.6%). Conclusions: Oncologic patients consult frecuently in the emergency room, mainly those with NSCLC and colorrectal cancer. Metastasic disease and chemotherapy treatment are common too. Oncologic pain, fever and dysphnea are the most frequent causes of complaint,with an important impact on their quality of life.

No significant financial relationships to disclose.
MRI evaluation of soft tissue sarcomas
Authors: Faizi N. , Sharma R. , Sharma S. , Chandrashekhara S. , Shukla N. K. , Malhotra A. , Kumar R. , Deo S. V. , Thulkar S.
Published: August 2020

e21523

Background: Althouth soft tissue constitute large part of the body, STS are rare (1% of all neoplasms) and can arise anywhere in the body. Imaging is require to confirm the diagnosis and for staging. We conducted a prospective study to evaluate the role of MRI scan in characterization and staging of the tumor. Methods: This study between 2006 and 2008 included 20 patients with histologically proven soft tissue sarcoma in whom preoperative MRI of the local site was performed and the findings were correlated with the surgical and histopathological findings. Only those patients in whom surgical and histopathological findings were available were included in the study. All MRI were performed on 1.5 T MRI using body and appropriate surface coil. T1W, T2W, and STIR sequences were acquired in axial, coronal, and sagittal planes. Contrast enhanced MRI was performed in four patients. Surgical findings were recorded by the operating surgeon and resected specimens were analyzed by pathologist for assessing extent and histologic typing. All demographic data of the patient, the clinical features, preoperative imaging analysis, operative and histopathological findings were tabulated as per the given proforma. Results: Age of the patients was 16 - 72 years (mean age 44.4 years). Male female ratio was 2.3:1 . Eleven cases were recurrent. Most common histologic type was MFH (30%) while synovial sarcoma was second most common (20%) type of the STS in our study. Eighteen of 20 soft tissue sarcomas were of high grade. Average size on MRI was 9.25 cm (range) and operative size was 9.8 cm (range). Statistically significant agreement existed between MR and operative size. The sensitivity of MRI for individual muscle involvement was 92.3% and specificity was 96.5%. MRI had a sensitivity of 93% and specificity of 100% in predicting fascial involvement. MRI had 100% sensitivity and specificity in showing skin and subcutaneous tissue involvement. MRI had 100% negative predictive value in predicting NV bundle involvement. None of the patients had bone or joint involvement. No distant parenchymal metastases were seen. Specific diagnosis based on MRI image characteristics was suggested in 35% patients. Conclusions: Overall staging accuracy of MRI was 75% in staging of STS when correlated with surgical and histopathological MSKCC staging.

No significant financial relationships to disclose.
Characterization of triple-negative breast cancer utilizing microarray-based gene-expression profiling
Authors: Schmidt M. , Daniel B. , Lebrecht A. , Koelbl H. , Hengstler J. G. , Gehrmann M.
Published: August 2020

e22014

Background: Triple-negative breast cancer (TNBC) is characterized by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and HER-2. This makes it one of the most challenging subgroups for clinical decision-making. Methods: We analyzed gene-expression profiles of 200 node-negative breast cancer patients utilizing the Affymetrix HG-U133A array. After performing an unsupervised hierarchical cluster analysis using 2579 genes selected for variable expression within our dataset, we constructed metagenes for five dominant cluster (basal-like, luminal, proliferation, T-cell, B-cell). The interrelation of the median expression of these metagenes between TNBC and those cancer specimens expressing at least one of those receptors was analysed with the Wilcoxon-Mann-Whitney test. An intrinsic gene list was used to define basal-like breast cancer (BLBC). Sensitivity and specificity of TNBC to correctly classify BLBC was calculated. Metastasis-free survival (MFS) at 5 years was calculated according to Kaplan Meier. Results: Of the 200 node-negative breast cancer patients, 33 (16.5%) were triple-negative and 20 (10%) basal-like. Sensitivity of TNBC to correctly predict BLBC was 100%, specificity was 93.1%. TNBC showed an overexpression of the basal-like metagene (P=7.905e-13), an inverse relation with the luminal metagene (p=1.151e-12) and had higher proliferation and higher expression of T-cell (P=6.316e-5) and B-cell (P=3.551e-6) metagene. A higher expression of the B-cell metagene was associated with longer MFS in both TNBC (P=0.048) and BLBC (P=0.041). Conclusions: Characterization of TNBC reveals marked differences in gene-expression. Overexpression of mRNA transcripts related to the humoral immune system might serve as a protective factor in this particular subgroup.

No significant financial relationships to disclose.
High-sensitivity KRAS mutation detection in colorectal and lung cancer using SURVEYOR Nuclease scanning
Authors: Koul M. , Mahurkar S. , Legendre B. , Jiang J. , Kaldjian E.
Published: August 2020

e22023

Background: Mutations of the KRAS gene in colorectal and lung cancers have been associated with lack of response to epidermal growth factor receptor (EGFR) inhibitor therapies. Here we describe a highly sensitive assay that identifies mutations by scanning the entire coding region of KRAS exons 2 and 3 using SURVEYOR Nuclease, an endonuclease that cleaves double-stranded heteroduplex DNA at base pair mismatch sites. Methods: DNA was extracted from formalin-fixed paraffin- embedded tissue sections from a set of 30 colorectal and lung cancer samples. Two amplicons covering the coding and splice junction regions of the KRAS gene exons 2 and 3 were PCR-amplified, hybridized to allow heteroduplex formation, incubated with SURVEYOR Nuclease and analyzed on the WAVE-HS DHPLC system. The sensitivity of SURVEYOR Nuclease mutation detection was assessed by creating serial dilutions of 50:50 mixtures of original PCR products from mutant samples with wild type amplicons from control DNA. Results: 6 samples were identified as KRAS mutant by WAVE-HS profiles containing two fragment peaks in addition to the full length amplicon peak, indicating SURVEYOR Nuclease cleavage at a mismatch site. Mutations were found in both exon 2 (codons 12, 13) and exon 3 (codon 59). Sequencing confirmed the KRAS mutations in these samples. Levels of mutant DNA as low as 2% (1 ng/ul) were identified by this method, consistent with other SURVEYOR-based assays. Conclusions: SURVEYOR Nuclease technology is a sensitive and comprehensive method for detecting mutation in KRAS.

[Table: see text]
Radiation risks to lymphoma patients undergoing 18F-FDG studies
Authors: Hardin L. V. , Ravenel J. , Gordon L. , Huda W. , Mah E.
Published: August 2020

e22024

Background: To investigate radiation risks to patients undergoing 18F-FDG studies that take into account patient age, sex, and weight. Methods: We obtained patient demographics and weights of 54 consecutive patients with lymphoma who each underwent a18F-FDG PET study. The administered activity was converted into an effective dose using the patient size dependent dosimetry data provided in ICRP Publication 80. Patient effective doses were converted into estimates of the lifetime attributable risk of cancer incidence and cancer mortality using age and sex dependent risk factors provided in BEIR VII. Results: The average patient age/weight in this study was 43 years/68 kg for males and 33 years/61 kg for females. Patient effective dose are proportional to patient weight(-0.784) (r2 >0.99). The average administered activity was 410 MBq, which resulted in an average effective dose of 8.5 mSv for males and 8.9 mSv for females. The average cancer incidence was 0.71/1,000 cases for males, and 1.27/1,000 cases for females, with cancer mortality being about half the incidence. Cancer rates for the youngest patients were an order of magnitude higher than those for the oldest patients. Conclusions: Average lifetime attributable cancer risks to lymphoma patients from a single FDG-PET study is approximately 1 per 1,000, but are strongly influenced by patient age, gender and weight. Cancer risk in younger patients is a magnitude of order greater.

No significant financial relationships to disclose.
Interaction between the p53 genotype of lung cancer and response to mTOR inhibitor combined with irradiation therapy
Authors: Nagata Y. , Tojo T. , Ohnishi K. , Takahashi A. , Ohnishi T. , Taniguchi S.
Published: August 2020

e22028

Background: Frequent activation of the PI3K/Akt/mTOR pathway and aberrations of tumor suppressor gene p53 are associated with therapeutic resistance in lung cancer. Nevertheless, the possibility of the variants of p53 genotype to affect response to mTOR inhibitor combined with irradiation therapy remains still unclear. Methods: Human non-small lung cancer cell line H1299 with p53 null genotype, was transfected with wild type or mutated p53 gene (H1299/wtp53 (WT), H1299/mp53 (MT)). Both cell survival and cell proliferation were estimated by colony formation assay to assess differences between WT and MT in sensitivity to rapamycin and ability of rapamycin to enhance radiation sensitivity. Cells were treated according to the individual study; DMSO (control), rapamycin (100 nM for 1 hour), irradiation (IR) (increasing doses), combination (RR) (rapamycin followed by irradiation). Changes in the cell cycle were also analyzed by flow cytometry. Results: Rapamycin decreased cell survival only in WT (P < 0.01, vs. control). MT was resistant to rapamycin exhibiting slightly inhibited cell proliferation. Compared with IR, RR with no less than 6 Gy radiation enhanced inhibitory effects on both cell survival and proliferation independent of p53 genotype (P < 0.01 in WT and P < 0.01 in MT, respectively), that indicating additive interaction. Cell cycle analysis demonstrated rapamycin induced G1 cell cycle arrest in both types of cells compared with controls (P < 0.01 in WT and P < 0.05 in MT, respectively) at 24 hours after treatment. Enhancement of G1 arrest by RR was observed in both WT (P < 0.01, vs. IR) and MT (P < 0.01, vs. IR) at the same time point. In addition, RR caused a greater reduction of cells in S phase than that of IR regardless of p53 gene status (P < 0.01 in WT and P < 0.01 in MT, respectively). Conclusions: Rapamycin is an effective radiosensitizer in a p53 independent manner, in which increased G1 cell cycle arrest and decrease in S phase cells are responsible for increased growth inhibitory effect. It will enable us to provide more appropriate treatment to patients with mutated p53 gene.

No significant financial relationships to disclose.
Use of gene expression profiling to identify fibronectin 1 and MIG as candidate biomarkers for breast cancer screening
Authors: Ruiz-Garcia E. B. , Scott V. , Machavoine C. , Bidart J. M. , Lacroix L. , Delaloge S. , Andre F.
Published: August 2020

e22034

Background: There is a need to develop blood-based bioassays for breast cancer screening. We used differential gene expression between breast cancer samples and benign tumors to identify candidate biomarkers for blood-based screening Methods: 3 candidate proteins (Fibronectin 1, CXCL9, Complement Factor B) were identified from a gene expression dataset that included 120 breast cancer samples and 45 benign lesions. Proteins selection was done with these criteria: differential gene expression between cancer and benign lesion, protein released in the extracellular medium (SwissProt), commercially available ELISAkit, accuracy of the ELISA assay in a feasibility study (n=23). Proteins concentrations were determined in blood samples by ELISA. Blood samples were from normal volunteers blood donors (n=119) and early breast cancer patients (n=133). Results: 73% of the patients were cT1-T2 tumour. CA15.3 was within normal range (<30 IU/ml) in 114 patients (86%). Blood concentrations of CXCL9 and Fibronectin 1 were higher in cancer patients as compared to normal volunteers, mean concentration for CXCL9 was 851pg/ml (range 121- 3941) and 635 pg/ml (range 12–4327) in cancer patients and normal volunteers respectively (p=0.013). CXCL9 concentration was significantly higher in patients with ER-negative breast cancer (mean: 999 pg/ml) as compared to normal volunteers (p=0.003), data consistent with gene expression profile. Fibronectin 1 mean concentration was 190 μg/ml (range 11–326) for cancer patients and 125 μg/ml (range 58–212) for normal volunteers (p<0.001). AUC for breast cancer diagnosis were 0.78 and 0.62 for Fibronectin 1 and CXCL9 respectively. A combined score including Fibronectin 1 and CXCL9 dosages presented a sensitivity of 53% and a 98% specificity. Similar performances were observed for ER-negative tumors Conclusions: This study suggests that Fibronectin 1/CXCL9 dosage in serum could screen a significant rate of breast cancer, including ER-negative breast cancer. These data suggest that analysis of differential gene expression is a good approach to select candidate biomarker to set-up blood assays cancer screening. Prospective validation of the combined score, and development of in house ELISA assay for 25 additional proteins are ongoing.

No significant financial relationships to disclose.
The role of whole body 18F-FDG PET/CT scan in patients with carcinoma of unknown primary
Authors: Hu M. , Yu J. , Liu N. , Kong L. , Zhang P.
Published: August 2020

e22051

Background: Carcinoma of unknown primary (CUP) is a heterogeneous group of tumors and usually follows an aggressive biological and clinical behavior. Difficult challenges in oncology which the identification of the primary tumor and a complete disease staging could offer a more rational and efficient treatment in order to improve the survival time. Our aim was to evaluate the role of 18F-FDG PET/CT scan with two aspects: detection of the primary site, and estimation of tumor biological behavior which essential for the development of new, individual and targeted effective therapies. Methods: One hundred and seventeen patients presenting with histologically confirmed metastatic carcinoma (76 lymph nodes, 41 visceral biopsy proven) of unknown primary site were included in this retrospective study. The evaluations as follows had not revealed a primary site: detailed medical history, full physical and laboratory examinations, and diagnostic imaging methods. All patients underwent PET/CT. Results: In 42 (35.90%) patients, a primary tumor site which was confirmed by follow-up or surgery was showed by PET/CT. In 15 (12.82%) patients, the primary tumor site was suggested by PET/CT but not confirmed. In 60 (51.28%) patients, the primary tumor site was not localized modifying the stage of disease. In the other 17 (14.53%) patients, PET/CT scan identified further unexpected metastases. Overall, the following oncological treatment was influenced by the PET/CT scan, in a total of 38 (32.47%) patients. Between the adenocarcinoma and squamous cell carcinoma groups, no significant difference in SUVmax was found ( t=1.191, p = 0.244). A significantly higher SUVmax was found among patients with poorly or undifferentiated carcinoma compared with patients with well to moderately ( t=4.013, p<0.01) differentiation; In 42 patients with a confirmed primary tumor site, the SUVmax of Metastatic tumours have a closely relationship correlate with those of primary tumours, ( r=0.738, p<0.01). Furthermore, a significantly higher SUVmax was found among metastases compared with primary tumors ( t=3.470, p<0.01). Conclusions: Our data strongly support 18F-FDG PET/ CT imagings not only provide new insights in the diagnosis and staging of patients with CUP, but also evaluate biologic characters of tissue. 1

No significant financial relationships to disclose.
Protective effect of metformin in lung cancer patients
Authors: Gagnon B. , Roseman M. , Kasymjanova G. , MacDonald N. , Kreisman H. , Small D.
Published: August 2020

e22063

Background: Over the past decade, dozens of studies have shown that metformin not only decreases mortality in diabetics, it also significantly reduces CRP and reduces the risks of cancer in rodent and human cell lines. We report on the survival of lung cancer patients concomitantly exposed to metformin in our community-based program. Methods: 850 patients undergoing treatment from a prospectively collected pulmonary oncology database of the SMBD-Jewish General Hospital over an 8-year period were analyzed. Pilot observational study of survival was performed using Cox regression model. The factors that were included in the model were age, gender, stage, histology and metformin use. Results: 850 patients (F: M=375:475; mean age of 66) were diagnosed since 2000 and followed in pulmonary oncology outpatient clinic for NSCLC. 523 (62%) of those patients were diagnosed with adenocarcinoma; 488 (57%) were stage IIIB with pleural effusion/IV. 79(9%) patients were receiving treatment with metformin for their comorbid type 2 diabetes. The Cox regression analysis demonstrated that age, gender, stage and use of metformin were significant prognostic factors for survival. The use of metformin is associated with a 37% (HR 1.37; CI 1.01–1.84) (p=0.039) increase in survival. Conclusions: Thus, the result obtained from our model suggests that use of metformin may be associated with better survival of lung cancer patients. As this is a pilot study, we will consider alternative explanations.

No significant financial relationships to disclose.
Interactions of breast cancer cells with the microenvironment of the human bone marrow
Authors: Kaiser T. , Klein G. , Solomayer E. , Wallwiener D. , Fehm T.
Published: August 2020

e22097

Background: Bone is one of the most favored sites for metastasis of breast cancer cells (BrCa) resulting in the formation of osteolytic and/or osteoblastic lesions. There is increasing evidence that the bone marrow (BM) microenvironment plays a pivotal role in modulating tumor cell homing to the bone, metastasis and progression. However, the molecular crosstalk between BrCa cells and the cellular and extracellular components of the bone marrow leading to osteotropism still remains a poorly characterized step in the metastatic process. Methods: Cell adhesion and migration assays using the invasive MDA-MB-231 and the noninvasive MCF7 BrCa cell lines were performed to investigate the impact of BM components on cellular functions of tumor cells. Results: Cell-matrix adhesion assays showed a strong and concentration-dependent attachment of BrCa cells to several extracellular matrix components present in the human bone marrow such as fibronectin, different laminin isoforms, collagens type I and IV or tenascin-C. Moreover, the BrCa cells attached avidly to the BM-derived primary osteoblasts, whereas the binding to stromal cells was significantly weaker. Notably, cell-cell adhesion experiments with primary osteoclasts revealed an anti-adhesive effect on tumor cell binding leading to no attachment activity of BrCa cells with the cell surface of primary osteoclasts. The influence of cellular components of the BM on tumor cell migration was analyzed by cell migration assays using conditioned media of osteoblasts, osteoclasts and stromal cells or a modified Transwell chamber technique. The migration assays with invasive MDA-MB-231 cells clearly showed that osteoblasts, but not osteoclasts or stromal cells released factors which led to a faster wound closure, suggesting an enhanced migratory ability of the metastatic tumor cells, whereas the migration of nonmetastatic MCF7 cells was unaffected. Conclusions: These data indicate that the crosstalk with osteoblasts affects both the adhesive and the migratory ability of BrCa cells favoring the bone colonization process. Furthermore, the presented experimental conditions may provide useful tools to study effects of antiresorptive drugs like bisphosphonates to improve therapeutic strategies for treatment metastatic bone disease.

No significant financial relationships to disclose.
Preliminary validation of two novel immunoassays for detecting VEGF in human and mouse plasma using single molecule counting technology
Authors: Puskas R. , Held D. , Sheets D. , Klein B. K. , Macy E. , Agee S. J. , Todd J.
Published: August 2020

e22099

Background: Growth in biomarkers as therapeutic targets and as surrogate markers for efficacy presents a need for increasingly sensitive immunoassays to expand biomarker applicability. Improved immunoassays will provide: (1) better evaluation and validation of new drug candidates, (2) better matching of patients to new therapies, (3) accelerated drug approval (4) earlier diagnosis of at-risk patients, and (5) a deeper understanding of cancer biology. Towards this end, Singulex has developed two ultra- sensitive VEGF Immunoassays for human and mouse vascular endothelial growth factor (VEGF). Here we report the preliminary validation of these two novel assays. Methods: Two novel assays were developed with the Erenna Immunoassay System for detecting VEGF: human (hVEGF) and mouse (mVEGF). Analytical sensitivity, cross-reactivity and precision were determined and compared to an ELISA based VEGF assay. Both the Singulex assay and ELISA assay were used to test a range of specimen types (plasma, cell lysates, conditioned media, and tissue specimens) from humans and mice. Preliminary assays with human plasma and tissue specimens were conducted to compare hVEGF levels between normal and breast cancer samples. Results: The Singulex hVEGF assay had an LOD of 0.1 pg/mL, an LLOQ of 0.3 pg/mL, and 84–107% spike recovery; 90X more sensitive than the ELISA assay. Human VEGF concentrations were quantified in all specimens tested compared to the ELISA, which quantified VEGF in only 8% of plasma samples, but all of the cell lysate samples. The Singulex mVEGF assay had an LOD of 3.5 pg/mL, LLOQ of 5 pg/mL, and 68–111% spike recovery; 3X more sensitive than the ELISA assay. Cross-reactivity for the two assays was minimal for all specimen types tested, except for human plasma samples where the mVEGF assay demonstrated 80–100% CR. Conclusions: We show that the Singulex hVEGF and mVEGF Immunoassays can detect VEGF at or below pg/mL levels, and can effectively quantify VEGF levels in plasma, cell lysates, conditioned media, and tissue samples from mice and humans. These novel assays are an important tool when used to assess tumor and normal breast cancer tissue and plasma.

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Prognostic significance of BRCA1, PARP1, and PARP2 in sporadic breast cancer
Authors: Gennari A. , Sormani M. , Varesco L. , Pronzato P. , Viassolo V. , Mirisola V. , Pfeffer U. , Bruzzi P.
Published: August 2020

e22114

Background: Breast cancer susceptibility gene (BRCA1) is a tumor suppressor gene whose mutation is associated with the development of hereditary breast cancer. In sporadic tumors, loss of BRCA1, resulting from reduced expression or incorrect subcellular localization, has been suggested to be associated with prognosis. Cells with BRCA1 loss of function are deficient in DNA double strand break repair thus activating poly(ADP-ribose) polymerases (PARPs) whose catalytic activity is immediately stimulated by DNA strand-breaks. The aim of this study was to evaluate the prognostic value of BRCA1 and PARPs (PARP1 and 2) in sporadic breast cancer. Methods: We merged two previously published Affymetrix gene expression datasets: GSE 1456 (159 patients, median follow up 7 years) and GSE 2494 (249 patients, median follow up 10 years). Microarray data preprocessing was carried out using Bioconductor software (gcrma procedure). Expression of BRCA1, PARP1 and PARP2 mRNA were evaluated as continuous variables. Kaplan Meier survival curves and Cox regression analysis (stratified by database) were used to assess the prognostic capability of the identified biomarkers. Results: High mRNA expression of BRCA1, PARP1 and PARP2 was correlated with an adverse prognosis. Relapse Free Survival (RFS) Hazard Ratio was 1.6 (95% CI, 1.2 to 2.1) for BRCA1 (p = 0.002), 1.7 (95% CI, 1.2 to 2.4) for PARP1 (p = 0.002) and 1.7 (95% CI, 1.3 to 2.3) for PARP2 (p = 0.001). By multivariate analysis all 3 genes resulted independently correlated with RFS. When interaction with systemic adjuvant therapy (107 patients treated) was tested, BRCA1 mRNA expression was strongly associated with treatment: HR 2.3 (95% CI, 1.4 to 3.7, p 0.001); p for interaction = 0.06. Conclusions: This study shows that BRCA1, PARP1 and PARP2 are all significantly associated with prognosis in sporadic breast cancer.

No significant financial relationships to disclose.
Clinicopathologic and prognostic features of triple-negative breast cancer analyzed in registration data of the Japanese Breast Cancer Society, 11705 cases
Authors: Iwase H. , Yamamoto Y. , Kurebayashi J. , Tsuda H. , Ota T. , Kurosumi M. , Miyamoto K. , Iwase T.
Published: August 2020

e22122

Background: Triple-negative (TN) breast cancers which are negative for ER, PgR, and HER2 by immunohistochemistry are associated with a poor prognosis. To clarify the characteristics of TN tumors, the data of the registration committee of the Japanese Breast Cancer Society were analyzed with respect to clinicopathologic factors, response to neoadjuvant chemotherapy (NAC) and prognosis. Methods: Of 14,748 cases that were registered in 2004, 11,705 cases (79.4%) were examined for ER, PgR, and HER2 status, which was based on local institute. In the 2,331 cases of all registered cases, the prognosis and details of the treatment were analyzed with 47.8 months as median follow-up period. In 184 cases (7.9%), NAC was mainly performed using anthracycline and taxane based chemotherapy. Results: Luminal A type with positive for ER and/or PgR and negative for HER2 was most prevalent (53.8%), followed by TN type (15.5%). TN cancers were diagnosed at a slightly advanced stage and more of the cases had lymph node metastases compared to other types. Mucinous or tubular carcinoma was frequently seen in the Luminal A type. Squamous cell, spindle cell carcinoma, or metaplastic carcinoma with bone/cartilage metaplasia was found in only TN type. The HER2 type and TN type had statistically worse outcome compared to Luminal type in DFS and OS (P<.0001 and P<.0001, respectively). Pathological response rate of NAC, including grade 2 and 3, was higher in TN tumor as 51.5 % (22/53) than in Luminal A tumor as 16.7% (12/72). Responders in TN tumors have a better prognosis than non-responder (P=.0016), but this tendency was not recognized in non-TN tumors (P=.15). Conclusions: The ratio of the TN tumors in Japan was 15–6%. Central reviews of immunohistochemistry, such as ER, PgR, HER2, CK5/6, EGFR etc, will be confirmed in this cohort, for TN tumors are similar to basal-like tumors discriminated by gene- profiling.

[Table: see text]