Frequency In Cancer Patients Research Articles

Ethnic Differences, Lung Cancer Risk, and Association of NRF2 Gene Polymorphism with Gemcitabine-Based Chemotherapy.

The cancer burden is rising every year. Lung cancer is one of themost common cancers and non-small cell lung cancer is the most common type. Chemotherapy based on platinum drugs and third-generation nucleoside anti-metabolites such as gemcitabine are used widely. Gemcitabine has a complex metabolic pathway, with many mechanisms contributing to its cytotoxicity. Derangements in the metabolic pathway genes contribute to drug resistance and toxicity with this drug. Association studies including these genetic polymorphisms in the metabolic pathway, clinical outcomes, and cancer risk reported inter-individual differences. Thus, the aim of this study was to ascertain the role of these genetic variants in South Indian cancer patients treated with gemcitabine-based therapy. The study was done with 184 healthy volunteers for frequency establishment and 123 cancer patients were treated with gemcitabine-based chemotherapy for response and toxicity assessment. The participants were aged 18-65 years and resided in the southern states of India. DNA extraction was done from the leukocyte fraction of the blood by phenol-chloroform extraction procedures and genotyping was done by reverse transcription-polymerase chain reaction (RT-PCR) techniques to identify DNA repair gene polymorphisms. Tumor response was determined using Response evaluation criteria in solid tumors (RECIST) guidelines and toxicity using Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. The patients were followed up for survival analysis. The minor allele frequency of the single nucleotide polymorphism (SNP) NRF2-617 C>A (rs6721961) in the healthy population was 12.8%. SNPs were in Hardy-Weinberg equilibrium (p>0.05). Gender-based differences were not observed with the studied SNP in the healthy population and the lung cancer patients. These frequencies of NRF2 were found to be similar when compared to EUR (European) and all the South Asian subpopulations. They are significantly divergent compared to AFR (African), AMR (American), and EAS (East Asian) populations. The minor allele frequency in cancer patients was found to be 14.2% and the lung cancer risk with the SNP studied could not be detected. There was no association found with the response, toxicity, and survival among lung cancer patients. NRF2, being a multifaced molecule, did not showa significant association with lung cancer risk, response, and toxicity in patients with gemcitabine-based chemotherapy.

Erythrocyte PIG-A mutant frequencies in cancer patients receiving cisplatin.

Cisplatin is a primary chemotherapy choice for various solid tumors. DNA damage caused by cisplatin results in apoptosis of tumor cells. Cisplatin-induced DNA damage, however, may also result in mutations in normal cells and the initiation of secondary malignancies. In the current study, we have used the erythrocyte PIG-A assay to evaluate mutagenesis in non-tumor hematopoietic tissue of cancer patients receiving cisplatin chemotherapy. Twenty-one head and neck cancer patients undergoing treatment with cisplatin were monitored for the presence of PIG-A mutant total erythrocytes and the young erythrocytes, reticulocytes (RETs), in peripheral blood for up to five and a half months from the initiation of the anti-neoplastic chemotherapy. PIG-A mutant frequency (MF) in RETs increased at least two-fold in 15 patients at some point of the monitoring, while the frequency of total mutant RBCs increased at least two-fold in 6 patients. A general trend for an increase in the frequency of mutant RETs and total mutant RBCs was observed in 19 and 18 patients, respectively. Only in one patient did both RET and total RBC PIG-A MFs did not increase at any time-point over the monitoring period. Cisplatin chemotherapy induces moderate increases in the frequency of PIG-A mutant erythrocytes in head and neck cancer patients. Mutagenicity measured with the flow cytometric PIG-A assay may serve as a tool for predicting adverse outcomes of genotoxic antineoplastic therapy.

Ralstonia mannitolilytica septicaemia, an added burden in cancer care: Recognizing the unrecognized

Background: Ralstonia mannitolilytica is an often underrecognized pathogen, that can cause infections in immunocompromised hosts. The propensity to form biofilms makes it particularly likely to cause catheter related infections, which is used with increasing frequency in cancer patients. In this study we report on an outbreak of Ralstonia septicaemia at our facility. Aim: To characterize an outbreak of Ralstonia infections at a tertiary care facility with a focus on the antibiotic sensitivity and added burden on treatment. Design: A retrospective analysis of an outbreak of sepsis attributed to Ralstonia mannitolilytica. Methods: We report on nine cases of proven Ralstonia mannitolilytica septicaemia in the period from January 2022 to June 2023. Results: Blood cultures were positive in 66.7%, and three had tip cultures positive . 77.8% of the patients required removal of their central venous access, due to hemodynamic compromise and/or persistent fever despite adequate coverage with empirical antibiotics. 85.7% required reinsertion of PICC lines. Eight of the isolates (88.9%) were resistant to Meropenem, and seven were resistant to Piperacilin + Tazobactam (77.8%). Resistance to Ceftazidime was seen in six isolates, Sensitivity to Cefaperazone + Sulbactam and Levolfloxacin was seen in seven and six patients respectively. Conclusion: Ralstonia mannitolilytica is an emerging pathogen, that can cause significant additional burden in terms of hospitalization and infectious complications in cancer patients with CVC access. There needs to be strict infection control measures in place, for prevention and early recognition.

Chemotherapy-Induced Nausea and Vomiting (CINV) Based on Blood Types among Cancer Patients in Yogyakarta, Indonesia

Background: Studies related to blood type in cancer patients have been conducted extensively, but they are inclined to cancer incidence or survival rate. Meanwhile, there is limited research on Chemotherapy-Induced Nausea and Vomiting (CINV), the most disturbing side effect of chemotherapy, in relation to blood type.Purpose: This study aimed to compare CINV frequency in cancer patients by blood groups in Yogyakarta, Indonesia.Methods: A descriptive comparative study with a cross-sectional approach was conducted purposively on 70 chemotherapy patients in two hospitals in Yogyakarta. Patients with anticipatory CINV and brain cancer (primary or metastases) were excluded. The data were collected between July and November 2020 using a sheet for patient characteristics and a filled-in diary from the first to the seventh day post-chemotherapy to collect CINV data. The descriptive statistics and Kruskal Wallis test were used to analyze the data.Results: Of 70 total samples, most of them were breast cancer (71.4%) and were in stage IV (50%). They received chemotherapy alone as their primary therapy (94.3%) and received moderate to high emetogenic agents (31.4% and 35.7%). Samples mostly had A blood type (34.3%) and had undergone chemotherapy for 3-18 months (min-max). As many as 64.6% of patients experienced CINV with a delayed type and experienced moderate severity (52.9%). The bivariate test showed no difference in CINV frequencies based on blood groups in general (p=0.068). However, based on the CINV onset, there was a significant difference in CINV frequencies in the A blood group against other blood groups (p=0.020) on the fourth post-chemotherapy day.Conclusions:Unless the fourth-day post-chemotherapy, the frequency of CINV based on blood groups showed no difference. Since CINV incidence is still high, the provision of both pharmacological and non-pharmacological therapy to treat CINV has to be given to patients after chemotherapy. Blood group factors can be considered for more extensive management, especially in delayed CINV cases.

Feasibility and Safety of Active Physiotherapy in the Intensive Care Unit for Intubated Patients with Malignancy.

Physiotherapy leads to improvements in critically ill patients who receive mechanical ventilation. However, cancer patients have not been included in previous studies on this subject. This study explored the feasibility and safety of physiotherapy in the intensive care unit for patients with malignancy. Observational prospective single-centre study, comparing cancer and control patients. All consecutive patients admitted to the intensive care unit who needed invasive mechanical ventilation for more than 2 days with no contraindication to physiotherapy were included in the study. The main outcome was the proportion of physiotherapy sessions at the prescribed level in each group. A total of 60 patients were included within 1 year. A total of 576 days were screened for physiotherapy sessions and 367 physiotherapy-days were analysed (137 days for control patients and 230 days for cancer patients). The ratio of physiotherapy sessions performed/prescribed did not differ between groups: 0.78 (0.47-1) in the control group vs 0.69 (0.6-1) in the cancer group (odds ratio 1.18 (IC95% 0.74-1.89); p = 0.23). A sensitivity analysis including patient effect as random variable confirmed those results (odds ratio 1.16 (0.56-2.38), p = 0.69). Adverse events occurred with the same frequency in cancer patients and non-cancer patients. Physiotherapy in cancer patients who require intubation is feasible and safe. However, only two-thirds of prescribed physiotherapy sessions were performed. Studies are warranted to explore the barriers to physiotherapy in the intensive care unit setting.

Human Leucocyte Antigens as Prognostic Markers in Head and Neck Squamous Cell Carcinoma.

Simple SummaryHuman leucocyte antigens (HLAs) play a crucial role in the immune defense by presenting antigens to T lymphocytes. The particular combination of HLA alleles determines a patient-specific presentation of cell-derived peptide fragments to the patrolling immune cells. Since deregulated protein expression and mutations are hallmarks of cancer, such abnormal peptides can be presented by tumor cells and eventually recognized, and the presenting tumor cells are then killed by T cells. Therefore, the HLA composition might influence the formation and fate of cancer and might differ between tumor patients and healthy individuals. We performed HLA typing of 84 patients with head and neck cancer, and the results were compared to survival. Two of fifty HLA alleles analyzed showed a significantly different frequency compared with the normal population (HLA-A*25 and HLA-C*06). Patients with HLA-C*04 had poorer oncological outcomes, while patients with HLA-A*02 had significantly better survival.Background: The induction and regulation of immune responses depend on human leucocyte antigen (HLA) molecules that present peptides derived from mutated neoantigens or tumor-associated antigens to cytotoxic T cells. The natural variation of HLA molecules might differ between tumor patients and the normal population. Thus, there might be associations between the frequencies of HLA alleles and the survival of tumor patients. Methods: This issue was studied in a cohort of 84 patients with head and neck squamous cell carcinomas (HNSCCs) of different localizations. The cohort was followed up for more than 10 years. HLA-A/B/C CTS-PCR-SSP typing at 1 field level from blood samples was performed, and the results were correlated with survival. Results: HLA-A*02 was the most prevalent allele in our cohort and was present in 51.1% of patients. The HLA-A*25 and HLA-C*06 alleles exhibited a significantly higher frequency in cancer patients than in the normal population of 174 blood and kidney donors (p = 0.02 and p = 0.01, respectively, Fisher’s exact test). For HLA-C*04, a negative impact on overall survival in univariate analysis (p = 0.045) and a negative, but statistically insignificant effect on survival toward poorer survival in multivariate analysis (HR: 1.82; 95% CI: 0.99–3.34, p = 0.053) were observed. In addition, HLA-A*02 was also beneficial for overall survival and progression-free survival in multivariate analysis (HR 0.54; 95% CI: 0.31–0.92; p = 0.023). Conclusion: HLA-A*02 allele expression might not only predict better survival but might also indicate superior tumor antigen presentation and, thus, help to select patients who could benefit from T-cell-dependent immunotherapies.

Cancer patients\u2019 perspectives on remote monitoring at home during the COVID-19 pandemic- a qualitative study in Norway

BackgroundThe COVID-19 pandemic triggered an unprecedented demand for digital health technology solutions, such as remote monitoring. Previous research has focused on patients with chronic diseases, and their experiences with remote monitoring during the pandemic. Several recommendations have been presented to reduce the frequency of cancer patients’ visits to oncology centers and minimizing the risk of exposure to COVID-19, such as remote monitoring. However, few studies have explored how this has influenced the healthcare services to cancer patients.AimTo explore cancer patients’ perspectives on remote monitoring at home during the COVID-19 pandemic.DesignThe study had a qualitative design, using in-depth, individual interviews.MethodsA total of eleven interviews were conducted with patients who received remote monitoring during the COVID-19 outbreak. Three of the interviews were conducted by telephone, and eight on a digital platform, audio recorded, and transcribed verbatime. Data were analyzed using reflexive thematic analysis as recommended by Braun & Clarke.ResultsAll participants were conscious about being vulnerable to infections due to having cancer and receiving cancer treatment, and the pandemic to them represented an extra burden. Most of the participants experienced that their healthcare services had changed due to the pandemic, but there was no consensus on how the services had changed. All of the participants presented remote monitoring as something «new». Whether they received remote monitoring by telephone, video consultations or more advanced solutions with the possibility to complete a questionnaire or fill in measurements, did not seem to impact their views. However, all agreed that remote monitoring could never totally replace physical consultations in hospital. Participants’ views seemed to grow more positive over time, but still they emphasized both positive and negative aspects of remote monitoring solutions in cancer care.ConclusionRemote monitoring was introduced as a necessity in cancer care during the COVID-19 outbreak. This may seem as an efficient solution, allowing for patients to stay at home and avoid infection. Our results indicate that, in the case of cancer patients, it is important that healthcare personnel balance the remote monitoring solution with person-to-person contact.

DNA repair gene (XRCC3) polymorphisms and its association with ovarian carcinoma in Egyptian PATIENTS

The DNA repair gene polymorphisms are supposed to boost the tumorigenesis and prognosis of cancers. The X-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3) gene has a pivotal role in the DNA repair process which if mutated may be entangled in the tumorigenesis. Although there are many studies examining the DNA repair gene polymorphisms in cancers, the association of the XRCC3 SNPs with ovarian cancer in Egypt remains not fully defined. We aimed to examine the impact of the XRCC3 genetic polymorphisms with the ovarian carcinoma development and prognosis. Moreover, to analyze the relation of the SNPs alleles and haplotypes with the different tumor stages and subtypes. MethodsGenomic DNA was extracted from 50 histopathologically confirmed ovarian cancer patients and 20 cancer-free control subjects using PCR-RFLP assays. ResultsThe mean ages of the subjects were non- significantly differed between the patients and controls with significant increase with advanced tumor stage (F = 5.344, P = .003). The serous carcinoma was the most common type of ovarian tumor among our patients (40%) (X2 = 9.49, P =.023). A non-significant association was noticed between the studied SNPs (rs 861539 C > T, rs 1799794 G > A) genotypes with the ovarian cancer stages and subtypes. The rs 861539 T carriers had a higher frequency in cancer patients when compared to controls, otherwise, it showed a non-significant correlation with the tumor subtypes. The rs 861539 T/rs 1799794 A haplotype occurred at a higher frequency in ovarian cancer patients more than controls (X2 = 10.32, P = .016), with non- significant association with tumor subtypes. ConclusionDNA repair gene XRCC3 polymorphism rs 861539 T allele and the rs 861539 T/rs 1799794 A haplotype may boost the susceptibility to ovarian carcinoma with no correlation with the tumor histological subtypes and stages. They may be salutary as a DNA-based diagnostic biomarker for identifying the high-risk Egyptian females susceptible to ovarian cancer. More studies are needed to clarify the underlying mechanisms that can contribute to ovarian cancer, assess the cancer prognosis, and help to determine adequate therapy regimen.

Analysis of the exome aggregation consortium (ExAC) database suggests that the BAP1-tumor predisposition syndrome is underreported in cancer patients.

The BAP1-tumor predisposition syndrome (BAP1-TPDS) has been recently identified to predispose patients to a variety of cancers and preneoplastic lesions. About 130 unrelated probands have been identified worldwide; however, the impact of the syndrome is suspected to be much larger given the diversity of the cancer phenotype. To evaluate the frequency of germline BAP1 mutations in the general and cancer populations, we analyzed the Exome Aggregation Consortium (ExAC), a database that contains 53105 exomes of unrelated individuals unaffected by cancer (general population) and exomes of 7601 unrelated individuals affected by cancer provided by the Cancer Genome Atlas (TCGA, cancer subjects). BAP1 null variants were seen at much higher frequency in the cancer subjects (0.0526%) compared to the general population (0.00188%) with a relative risk of 27.93 and (P = 0.0011, [95% CI: 3.122-249.883], Fisher's exact test). We also studied a reported BAP1 null variant, c.1203T > G, p.T401* (rs200156887), observed commonly in the general population. Sequencing and restriction fragment polymorphism of the RT-4 cell line that contains this variant revealed that it is in fact a 3bp deletion/insertion, c.1201_1203delinsGAG, a likely benign missense alteration p.Y401E explaining the relative high frequency of this variant in the general population. In conclusion, germline null mutations in BAP1 have a significantly higher frequency in cancer patients than the general population. Given the low frequency of reported families with BAP1-TPDS, our results suggest that the syndrome is underreported especially in patients with cancer.

The dilemma of monotherapy or combination therapy in community-acquired pneumonia.

To study the factors associated with mortality in hospitalized patients with community-acquired pneumonia treated with monotherapy or combination therapy. PubMed and Scopus were searched. Patients receiving macrolides, β-lactams and fluoroquinolones, as monotherapy or in combination, were included. Meta-analyses and meta-regressions were performed. Fifty studies were included. Overall, monotherapy was not associated with higher mortality than combination (RR 1.14, 95% CI 0.99-1.32, I2 84%). Monotherapy was associated with higher mortality than combination in North American and retrospective studies. β-lactam monotherapy was associated with higher mortality than β-lactam/macrolide combination in the primary (1.32, 1.12-1.56, I2 85%) and most sensitivity analyses. There was no difference in mortality between fluoroquinolone monotherapy and β-lactam/macrolide combination (0.98, 0.78-1.23, I2 73%). In meta-regressions, the moderators that could partially explain the observed statistical heterogeneity were the frequency of cancer patients (P = .03) and Pneumonia Severity Index score IV (P = .008). Due to the considerable heterogeneity and inclusion of unadjusted data, it is difficult to recommend a specific antibiotic regimen over another. Specific antibiotic regimens, study design and the characteristics of the population under study seem to influence the reported outcomes.

Genetic Predisposition to Cervical Cancer and the Association With XRCC1 and TGFB1 Polymorphisms.

Cervical carcinoma (CC), a multifactorial cancer, is assumed to have a host genetic predisposition component that modulates its susceptibility in various populations. We investigated the association between CC risk in Saudi women and 6 single-nucleotide polymorphisms (SNPs) in hypothesis-driven candidate genes. A total of 545 females were included, comprising 232 CC patients and 313 age-/sex-matched control subjects. Six SNPs (CDKN1A C31A, ATM G1853A, HDM2 T309G, TGFB1 T10C, XRCC1 G399A, and XRCC3 C241T) were genotyped by direct sequencing. Of the 6 SNPs studied, TGFB1 T10C (odds ratio, 0.74; 95% confidence interval, 0.57-0.94) and XRCC1 G399A (odds ratio, 1.45; 95% confidence interval, 1.11-1.90) displayed different frequencies in cancer patients and control subjects and showed statistically significant association in univariate (P = 0.017, P = 0.005, respectively) analysis. The Cochran-Armitage trend test had confirmed the results (P = 0.027 and P = 0.006, respectively), indicating an ordering in the effect of the risk alleles in CC patients. The 2 SNPs, TGFB1 T10C and XRCC1 G399A, showed also degrees of deviation from Hardy-Weinberg equilibrium in cancer patients (P = 0.001 and P = 0.083, respectively) but not in the control subjects. Furthermore, correction for multiple testing using multivariate logistic regression to assess the joint effect of all SNPs has sustained significant statistical association (P = 0.025 and P = 0.009, respectively). TGFB1 T10C and XRCC1 G399A SNPs were associated with CC risk in univariate and multivariate analysis and displayed allele-dosage effects and coselection in cancer patients. Patients harboring the majority allele TGFB1 T10 (Leu) or the variant allele XRCC1 399A (Gln) have approximately 1.5-fold increased risk to develop CC. Host SNPs genotyping may provide relevant biomarkers for CC risk assessment in personalized preventive medicine.

Cancer patients’ use of primary care out-of-hours services: a cross-sectional study in Norway

Objective: To investigate how cancer patients in Norway use primary care out-of-hours (OOH) services and describe different contact types and procedures.Design: A retrospective cross-sectional registry study using a billing registry data source.Setting: Norwegian primary care OOH services in 2014.Subjects: All patients’ contacts in OOH services in 2014. Cancer patients were identified by ICPC-2 diagnosis.Main outcome measures: Frequency of cancer patients’ contacts with OOH services, contact types, diagnoses, procedures, and socio-demographic characteristics.Results: In total, 5752 cancer patients had 20,220 contacts (1% of all) in OOH services. Half of the contacts were cancer related. Cancer in the digestive (22.9%) and respiratory (18.0%) systems were most frequent; and infection/fever (21.8%) and pain (13.6%) most frequent additional diagnoses. A total of 4170 patients had at least one cancer-related direct contact; of these, 64.5% had only one contact during the year. Cancer patients had more home visits and more physicians’ contact with municipal nursing services than other patients, but fewer consultations (p < 0.001). Patients in the least central municipalities had significantly more contacts than more central municipalities (p < 0.001).Conclusion: There was no indication of overuse of OOH services by cancer patients in Norway, which could indicate good quality of cancer care in general.KEY POINTS Many are concerned about unnecessary use of emergency medical services for non-urgent conditions.• There was no indication of overuse of out-of-hours services by cancer patients in Norway.• Cancer patients had relatively more home visits, physician’s contact with the municipal nursing service, and weekend contacts than other patients.• Cancer patients in the least central municipalities had relatively more contacts with out-of-hours services than those in more central municipalities.

HLA-Restricted CTL That Are Specific for the Immune Checkpoint Ligand PD-L1 Occur with High Frequency in Cancer Patients

PD-L1 (CD274) contributes to functional exhaustion of T cells and limits immune responses in patients with cancer. In this study, we report the identification of an human leukocyte antigen (HLA)-A2-restricted epitope from PD-L1, and we describe natural, cytolytic T-cell reactivity against PD-L1 in the peripheral blood of patients with cancer and healthy individuals. Notably, PD-L1-specific T cells were able not only to recognize and kill tumor cells but also PD-L1-expressing dendritic cells in a PD-L1-dependent manner, insofar as PD-L1 ablation rescued dendritic cells from killing. Furthermore, by incubating nonprofessional antigen-presenting cells with long peptides from PD-L1, we found that PD-L1 was rapidly internalized, processed, and cross-presented by HLA-A2 on the cell surface. Apparently, this cross-presentation was TAP-independent, as it was conducted not only by B cells but in addition by TAP-deficient T2-cells. This is intriguing, as soluble PD-L1 has been detected in the sera from patients with cancer. PD-L1-specific CTL may boost immunity by the killing of immunosuppressive tumor cells as well as regulatory cells. However, PD-L1-specific CTLs may as well suppress immunity by the elimination of normal immune cells especially PD-L1 expressing mature dendritic cells.

Validity and Reliability of the Swedish Version of the Memorial Symptom Assessment Scale (MSAS): An Instrument for the Evaluation of Symptom Prevalence, Characteristics, and Distress

ContextThere are few scales in Swedish that assess symptoms in the dimensions of frequency, severity, and distress. ObjectivesThe purpose of this study was to translate and determine the validity and reliability of the Memorial Symptom Assessment Scale (MSAS) in a Swedish population of postmenopausal women newly diagnosed with primary or recurrent breast cancer. MethodsThe original 32-item MSAS, a self-report measure for assessing symptom distress and frequency in cancer patients, was translated and administered to 206 patients (primary, n = 150 and recurrent, n = 56). ResultsThe MSAS psychological symptom subscale correlated with the emotional and cognitive functioning subscales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and showed the highest correlation with the EORTC QLQ-C30 emotional functioning subscale (r = −0.78; P < 0.01). The psychological symptom subscale also correlated with the Hospital Anxiety and Depression Scale (HADS) within values for anxiety (r = 0.68; P < 0.01) and with the EORTC QLQ-C30 within cognitive functioning values (r = −0.58; P < 0.01). The Global Distress Index (GDI)-MSAS showed satisfactory correlations with the EORTC QLQ-C30 emotional functioning subscale (r = −0.75; P < 0.01), whereas the correlation between the GDI-MSAS and the EORTC QLQ-C30 cognitive functioning subscale was somewhat lower (r = −0.54; P < 0.01). Correlations between the GDI-MSAS and the HADS anxiety subscale were confirmed (r = 0.62; P < 0.01), and a correlation between the MSAS physical symptom items and symptom items in the EORTC-QLQ-C30 was evident (r = 0.60–0.85; P < 0.01). Cronbach's alpha coefficients for the MSAS and MSAS subscales based on symptom scores ranged from 0.80 to 0.89. The internal consistency at different time points was satisfactory, ranging from 0.86 (baseline) to 0.90 (follow-up). ConclusionThe Swedish version of the MSAS presents as a valid and reliable measure for assessing symptom distress, severity, and frequency in Swedish patients diagnosed with primary and recurrent breast cancer.

Neoplastic leptomeningitis presenting in a melanoma patient treated with dabrafenib (a V600EBRAF inhibitor): a case report.

IntroductionLeptomeningeal metastases are occurring at higher frequency in cancer patients. The prognosis of leptomeningeal metastases is poor and standard treatment, which includes radiotherapy and chemotherapy, is mostly ineffective. Melanoma represents one of the tumors with the highest incidence of leptomeningeal metastases. For such a disease, the BRAF inhibitors have recently been demonstrated to be effective on melanoma brain metastases harboring the V600EBRAF mutation.Case presentationWe report a case of a 39-year-old Italian woman with advanced melanoma with brain, lung and peritoneum metastases harboring the V600EBRAF mutation. In August 2010 she was enrolled into the BRIM3 trial and after the randomization process she received dacarbazine. After two cycles, there was evidence of disease progression in her peritoneum and lung. For this reason, she was enrolled into another clinical trial with the GSK2118436 BRAF inhibitor, dabrafenib, as a second line of therapy. She had a partial response that was maintained until 13 weeks of treatment. In January 2011 she developed symptoms typical for brain metastases and received a diagnosis of leptomeningeal involvement of melanoma cells after an examination of her cerebral spinal fluid; magnetic resonance imaging was negative for meningitis or brain metastases. Analysis of her cerebral spinal fluid sample confirmed that the melanoma cells still carried the V600EBRAF mutation. After a few days, our patient went into a coma and died.ConclusionStarting with a clinical case, we discuss the pathogenesis of leptomeningeal metastases and whether the leptomeninges may represent a sanctuary where melanoma cells may generate resistance and/or BRAF inhibitors cannot reach an adequate concentration for significant activity. We assess whether treatment with BRAF inhibitors in melanoma patients should be interrupted as soon as disease progression appears or continued beyond progression, through the administration of additional compounds.

Characterization of the Immunoregulatory Function of Human TCRαβ+ CD4-CD8- Double-Negative T Cells

AbstractAbstract 2776Regulatory T (Treg) cells have been shown to be involved in downregulating immune responses in autoimmunity, transplant rejection, and graft-versus-host disease. Moreover, the important role of Treg cells in tumor progression has also been extensively investigated and Treg-mediated immune suppression has emerged as a crucial mechanism of tumor evasion. Recently, a novel subset of TCRαβ+ CD4−CD8− (double-negative, DN) T cells has been characterized to specifically suppress immune responses in mice. Here we demonstrate that human DN T cells belong to the family of inducible Treg cells with potent suppressor activity towards CD4+ and CD8+ T-cell responses. Resting DN T cells failed to suppress responder cells, whereas antigen presenting cell (APC)-stimulated DN T-cells and freshly isolated CD4+CD25+ Treg cells revealed a strong suppressive activity. Of importance, when more potent stimulators such as allogeneic dendritic cells were used for activation of responder T cells, CD4+CD25+ Treg cells were unable to mediate any suppressor function, while APC-primed DN T cells were still able to suppress. The suppressive activity of DN T cells is neither mediated indirectly by modulation of APCs nor by competition for T-cell growth factors. Furthermore, DN T-cell mediated suppression towards responder T cells requires cell-cell contact and is TCR dependent. Based on the importance of Treg cells in tumor immunity, we determined the frequency of circulating DN T cells in patients with malignant diseases. Of interest, the DN T-cell pool revealed an increased frequency in cancer patients compared to healthy controls, indicating that these suppressor cells might limit tumor-specific T-cell responses and thereby impair tumor immunosurveillance. Taken together, our results demonstrate that human DN T cells are a new subset of inducible Treg cells exerting a very potent suppressive activity towards cellular immune responses. Further understanding of the mechanisms involved in human DN T-cell suppression may have important implications for novel immunotherapies. Disclosures:No relevant conflicts of interest to declare.

Zoledronic acid and atrial fibrillation in cancer patients

Treatment with a bisphosphonate was found to be associated with a significantly increased risk for atrial fibrillation (AF) in a few studies. A recent study showed that once-yearly infusions of intravenous zoledronic acid (ZA) significantly increased the risk of serious AF in postmenopausal women with osteoporosis. This study was conducted to determine the frequency of atrial fibrillation among cancer patients receiving the standard treatment of ZA. Patients with bone metastases who presented to our outpatient clinic for any reason (routine control, chemotherapy, or ZA administration) were included in the study. All patients had been receiving 4 mg ZA at 4-week intervals, with each dose administered over 15 min. A short survey was completed and standard 12-lead ECG recordings were obtained. One hundred and twenty-four cancer patients with documented bone metastases were evaluated. Mean age of the patients was 55 ± 13.0 years, 60% of the patients were female. Forty-one percent of the patients had breast cancer, 18% had non-small cell lung cancer, and the remainder had other solid tumors. Mean duration of ZA administration was 13.4 ± 15.0 months. Mean total cumulative dose was 54 ± 15.0 mg per patient. Sixty patients (48%) had previously been treated with anthracycline-containing regimens, and 37 (30%) had received chest radiotherapy that might affect the heart. Twenty-three percent of the patients had hypertension, 10% had diabetes mellitus, 3.7% had myocardial infarction history, 1.9% had congestive heart failure, and 1% had valvular disease; 10.5% were current smokers and 32% ex-smokers. On ECG evaluation, we observed normal sinus rhythm in 58%, sinus tachycardia in 15%, sinus bradicardia in 3.2%, and ventricular extrasystole in 5.7% of the patients. There was no AF in any of the cases. There was no increase in the risk of AF frequency in cancer patients who were treated with intravenous ZA, although most of the patients had additional risk factors including previous treatment with cardiotoxic agents or with chest radiotherapy. We believe that the risk of AF is negligible in this patient population and does not affect treatment decisions.

High Micronucleus Frequency in Peripheral Blood Lymphocytes of Untreated Cancer Patients Irrespective of Gender, Smoking and Cancer Sites

Chromosomal instability could be one of primary causes for malignant cell transformation. The objective of the present study was to evaluate the spontaneous genetic damages in circulated lymphocytes of newly diagnosed cancer patients by using cytokinesis-block micronucleus (CBMN) assay, with respect to the factors that might affect micronucleus frequency (i.e. age, gender, smoking habits and cancer sites). Micronuclei (MN) are small nuclei that are originated from chromosome fragments or whole chromosomes. The analyzed samples included 44 untreated cancer patients (19 females and 25 males with mean age of 60.89 years) with different cancer sites (12 patients with breast cancer, 5 with uterine cancer and 27 with cancer of pharynx). Control group included 40 healthy donors (28 females and 12 males with mean age of 43.95 years). The mean baseline MN frequency was significantly higher (p < 0.001) in cancer patients (15.18 +/- 5.05 MN/1000 BN cells ranging from 4 to 27) than the baseline frequency in healthy controls (6.45 +/- 2.75 MN/1000 BN cells, ranging from 1 to 11). There was no gender difference in baseline MN frequency in cancer patients and healthy controls. Moreover, the MN frequency did not significantly differ among cancer sites, and between smokers and non-smokers in both patient and control samples. In conclusion, untreated cancer patients may be associated with an increase of chromosomal instability in peripheral blood lymphocytes, irrespective of gender, cigarette smoking and cancer sites.

Characteristics and Outcomes of Pulmonary Embolism IN CANCER PATIENTS and IN PATIENTS without CANCER.

Abstract 5065 BackgroundVenous thromboembolism (VTE), a frequent complication in cancer and, occasionally, a harbinger of occult cancer, is one of the leading causes of death in cancer patients. VTE recurs with a three-fold greater frequency in cancer patients than in patients who do not have cancer, and requires long-term anticoagulation. There is a two-fold greater risk of bleeding complications in these patients compared to patients who do not have cancer. Because pulmonary embolism (PE) is a life-threatening sequel of VTE, we sought to evaluate the hypothesis that cancer patients suffer from extensive pulmonary embolism (involving central pulmonary artery or bilateral pulmonary arteries) and to determine if we could detect differences in two clinical outcomes, length of stay (LOS) and mortality. Patients and MethodsThis retrospective cohort of subjects with pulmonary embolism (PE) was developed using data beginning in January 2003 to December 2007 at a 680 bed, urban teaching hospital. The cohort of 118 patients with PE diagnosed with CT angiogram yielded 41 patients in cancer group (20 males and 21 females) and 47 (23 males and 24 females) patients in non cancer group. Other baseline characteristics gathered for the two groups included age, gender, race, co-morbidities, ambulatory status and therapeutic interventions. Criteria for being assigned to the “central PE” were a filling defect in the pulmonary arteries or the main stem. Patients who showed filling defects in both central and peripheral vessels were also assigned to the “central PE”. All other patients with filling defects in one or more peripheral vessels were assigned to the “peripheral PE” group. ResultsThe baseline characteristics did not show significant differences between the groups. Our data demonstrated that central PE was strongly associated with the cancer group (26/41; 63.4%) compared with 15 of 47 (31.9%) in the non-cancer group (OR = 3.70; 95% CI: 1.53 to 8.95; p = 0.0051). The common cancers associated with VTE were genito–urinary (13) followed by gastro-intestinal (10), then lung and breast (6 in each group). LOS was significantly greater in the cancer group (median: 9d; IQR: 7-19d) compared to non-cancer group (median: 7d; IQR: 5-11d; p = 0.032. We detected no significant difference in overall mortality between the two groups (p = 0.11). Kaplan-Meier analysis of survival, similarly, demonstrated no significant difference (95% CI of HR: 0.62 to 3.18; p = 0.42) ConclusionCancer patients appear to be at a higher risk for central PE and have longer stay in the hospital after diagnosis than patients without cancer. However, in this study we did not detect increased mortality over a twelve-month observation period. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Zoledronic acid and atrial fibrillation in cancer patients with bone metastases

e20591 Background: Treatment with a bisphosphonate was linked with a significantly increased risk for atrial fibrillation (AF) in a few studies. Once-yearly infusions of intravenous zoledronic acid (ZA) was also significantly increased serious AF in postmenopausal women with osteoporosis. This study was conducted to determine the frequency of atrial fibrillation among cancer patients receiving the standard treatment of ZA. Methods: One hundred and twenty-four cancer patients who had bone metastasis receiving ZA were included in this study. All patients have been receiving 4 mg ZA at 4-week intervals; with each dose administered over 15 minutes. Patients who presented outpatient clinic for any reason (routine control, chemotherapy, ZA administration) a short survey completed and standard 12-lead ECG recordings were obtained. Results: One hundred and twenty-four cancer patients with documented bone metastases were evaluated. Mean age of the patients was 55 ± 13.0 years, 60% of the patients were female. Forty-one percent of the patients had breast cancer and 17% non-small cell lung cancer and the remainder had other solid tumors. Mean duration of ZA administration was 13.4 ± 15.0 months/patients. Mean total cumulative dose was 54 ± 15.0 mg per patients. 60 (48%) of the patients were treated with antracycline including regimens, and 37 (30%) were treated with mediastinal radiotherapy that might effect the heart. Twenty-three percent of the patients had hypertension, 10% diabetes mellitus, 7% currently smoker and 32% exsmoker, 3.7% myocardial infarction history, 1.9% congestive heart failure, and 1% valvular disease. On ECG evaluation; we observed sinus rhythm in 58%, sinus tachycardia in 15%, sinus bradicardia in 3.2%, ventricular exracystole in 5.7% of the patients. There were no AF. Conclusions: Although most of the patients were also having potentially cardiotoxic treatment, there was no increase in AF frequency in cancer patients who were treated with intravenous ZA. We believe that the risk of AF is small and may increase with age and comorbidity. No significant financial relationships to disclose.