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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 23 Αυγούστου 2016
Penicillium spp.: prolific producer for harnessing cytotoxic secondary metabolites.
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Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma
Abstract
PIK3CA mutation represents a clinical subset of diverse carcinomas. We explored the status of PIK3CA mutation and evaluated its genetic variability, treatment, and prognosis in patients with lung adenocarcinoma. A total of 810 patients with completely resected lung adenocarcinoma were recruited between 2008 and 2013. The status of PIK3CA mutation and other three genes, that is, EGFR mutation, KRAS mutation and ALK fusion were examined by reverse transcription-polymerase chain reaction (RT-PCR). Survival curves were plotted with the Kaplan–Meier method and log-rank for comparison. Cox proportional hazard model was performed for multivariate analysis. Among the 810 patients, 23 cases of PIK3CA mutation were identified with a frequency of 2.8%. There were 14 men and 9 women with a median age of 61 years. Seventeen tumors revealed concurrent gene abnormalities of EGFR mutation (n = 12), KRAS mutation (n = 3), and ALK fusion (n = 2). Seven patients with EGFR & PIK3CA mutations recurred and administrated of EGFR-TKIs yielded a median progression free-survival of 6.0 months. Among four eviromous-treated patients, stable disease was observed in three patients with a median Progression-free survival (PFS) of 3.5 months. Patients with and without PIK3CA mutation had different overall survivals (32.2 vs. 49.6 months, P = 0.003). Multivariate analysis revealed that PIK3CA mutation was an independent predictor of poor overall survival (HR = 2.37, P = 0.017). The frequency of PIK3CA mutation was around 2.8% in the Chinese patients of lung adenocarcinoma. PIK3CA mutation was associated with reduced PFS of EGFR-TKIs treatment and shorter overall survival.
PIK3CA mutation of lung adenocarcinoma was commonly concurrent with other driver genes. PIK3CA mutation was associated with reduced progression-free survival of EGFR-TKIs treatment and shorter overall survival.
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HPV-16 infection modifies overall survival of Puerto Rican HNSCC patients
Abstract
Background
HPV-16 modifies the overall survival (OS) of patients with oropharyngeal cancer (OPSCC). HPV-16 has been established as risk factor for OPSCC, but HPV-16 infection may also reside in the larynx and oral cavity. We evaluated HPV-16 status on OS of Head and Neck Squamous Cell Carcinoma (HNSCC) patients.
Methods
HPV-16 infection was confirmed by amplification of E6 and E7 viral oncogenes through PCR assay and E6 IHC in 185 HNSCC samples. Associations between HPV-16 status and clinicopathological parameters were performed using Fisher's exact test and x2. Survival analysis was completed using Kaplan-Meier estimator and multivariate Cox regression analysis.
Results
OS of HPV-16 positive patients was longer compared to HPV-16 negative patients (P = 0.002). HPV-16 positive tumors of the larynx (LSCC) and pharynx (PSCC) showed improved OS compared to HPV-16 negative tumors. Also, HPV-16 positive patients exposed to radiotherapy presented a better survival.
Conclusions
HPV-16 status has a positive prognostic value in HNSCC. Addition of HPV-16 status to the TNM staging can provide better assessment in prognosis and guide treatment for HNSCC patients.
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Efficacy of PI3K-mTOR inhibition in high-grade glioma
Purpose: The PI3K-AKT-mTOR signaling pathway is frequently activated in glioblastoma (GBM) and offers several drugable targets. However, clinical efficacy of PI3K/mTOR inhibitors in GBM has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against GBM. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood-brain barrier (BBB) restricts the brain penetration of many drugs. Experimental design: We used in vitro drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wildtype and ABC-transporter knockout mice.. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models. Results: The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1 whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055 but not ZSTK474 or rapamycin. Concordantly, Abcb1a/b-/-;Abcg2-/- mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold) and NVP-BEZ235 (4.5-fold) but not ZSTK474 relative to WT mice. Importantly, ABC-transporters limited rapamycin brain penetration to sub-therapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition. NVP-BEZ235 and ZSTK474 demonstrated antitumor efficacy with improved survival against U87 orthotopic gliomas, although the effect of ZSTK474 was more pronounced. Lastly, ZSTK474 prolonged overall survival in Cre-LoxP conditional transgenic Pten;p16Ink4a/p19Arf;K-Rasv12;LucR mice, mainly by delaying tumor onset. Conclusions: PI3K/mTOR-inhibitors with weak affinities for ABC-transporters can achieve target inhibition in brain (tumors), but have modest single agent efficacy and combinations with (BBB penetrable) inhibitors of other activated pathways may be required.
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Exportin-5 is an oncogene in colorectal cancer
ABSTRACT Objective: Dysregulated expression of microRNAs (miRNAs) has emerged as a hallmark feature in human cancers. Exportin-5 (XPO5), a karyopherin family member, is a key protein responsible for transporting precursor miRNAs from the nucleus to the cytoplasm. While XPO5 is one of the key regulators of miRNA biogenesis, its functional role and potential clinical significance in colorectal cancer (CRC) remains unclear. Design: The expression levels of XPO5 were initially assessed in three genomic datasets, followed by determination and validation of the relationship between XPO5 expression and clinicopathological features in two independent CRC patient cohorts. A functional characterization of XPO5 in CRC was examined by targeted gene silencing in colorectal cancer cell lines and a xenograft animal model. Results: XPO5 is upregulated, both at mRNA and protein levels, in CRCs compared with normal tissues. High-XPO5 expression associated with worse clinicopathological features and poor survival in CRC patient cohorts. The siRNA knockdown of XPO5 resulted in reduced cellular proliferation, attenuated invasion, induction of G1/S cell-cycle arrest, and downregulation of key oncogenic miRNAs in CRC cells. These findings were confirmed in a xenograft animal model wherein silencing of XPO5 resulted in the attenuation of tumor growth. Conclusion: XPO5 acts like an oncogene in CRC by regulating the expression of miRNAs and may be a potential therapeutic target in CRC.
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HHLA2 in lung cancer
Purpose: Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small-cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC. Experimental Design: We performed immunohistochemistry with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinico-pathological characteristics of these patients. Results: Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR-mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P=0.01) and validation cohorts (89% vs. 69%, P=0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared to squamous and large cell histology, non-Hispanic White vs. Hispanics, and tumors with high tumor infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma. Conclusion: HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy.
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Definitive chemoradiotherapy for squamous head and neck cancer: cisplatin versus carboplatin? A meta-analysis
Future Oncology Ahead of Print.
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Impact of obesity and exercise on chemotherapy-related fatigue
Abstract
Introduction
Breast cancer patients undergoing adjuvant chemotherapy often develop fatigue from their treatment that may persist for months. While the positive effects of physical activity in cancer patients are increasingly recognized, the impact of obesity on chemotherapy-induced fatigue has not been well studied.
Methods
Female age 35–75 years with stage I-III breast cancer receiving adjuvant chemotherapy were enrolled in an IRB-approved study. Patient fatigue was self-reported using a 14-question fatigue symptom inventory. Patients were queried about fatigue and their level of exercise before, during, and after completion of chemotherapy. BMI was measured prior to their first cycle of chemotherapy.
Results
Of the 47 evaluable patients, 37 reported performing exercise on a regular basis. Following chemotherapy, 53 % of the exercise group and 80 % of the non-exercise group displayed a worsening of their FS. In patients with a BMI < 25, the fatigue score (FS) after chemotherapy was 27.6 in the exercise group versus 40.5 in the non-exercise group. In patients with a BMI > 25, the FS after chemotherapy was 25.96 in the exercise group versus 32.6 in the non-exercise group.
Conclusion
Our study indicates a trend towards fatigue reduction with exercise even in patients who are overweight. Thus, an elevated BMI at diagnosis does not preclude a breast cancer patient from experiencing the same positive effects from exercise on chemotherapy-related fatigue as patients with normal BMIs. This indicates an important role of physicians in the primary care setting to encourage patients to initiate physical activity when offering cancer-screening services.
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Chamomile infusion cryotherapy to prevent oral mucositis induced by chemotherapy: a pilot study
Abstract
Purpose
The aim of this study is to compare cryotherapy made only with water and cryotherapy made with chamomile infusion for prevention and reduction of intensity of oral mucositis in patients with cancer receiving 5-fluorouracil and leucovorin.
Method
This is a randomized pilot study with two groups: cryotherapy made only with water (control group, n = 18) and cryotherapy made with chamomile infusion (chamomile group, n = 20). Both groups were instructed to swish the ice around in their oral cavity for at least 30 min during chemotherapy. Assessment of oral mucosa occurred on days 8, 15, and 22 after the first day of chemotherapy.
Results
Fifty percent of the patients in the control and 30 % in the chamomile group developed oral mucositis. Mouth pain score was higher in patients in the control group on all evaluations (p = 0.02 for day 8, p = 0.09 for day 15, and p = 0.14 for day 22). Patients in the chamomile group never developed mucositis with grade 2 or higher. Presence of ulceration was statistically significant on day 8 (16 % in the control vs. 0 % in the chamomile group, p = 0.10), but not in days 15 and 22, although 11 % still had ulcerations in the control group and none in the chamomile group.
Conclusion
The occurrence of oral mucositis was lower in patients in the chamomile group than in the control group. When compared to the controls, the chamomile group presented less mouth pain and had no ulcerations. Cryotherapy was well tolerated by both groups, and no toxicity related to chamomile was identified.
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The palatability of oral nutritional supplements: before, during, and after chemotherapy
Abstract
Purpose
Oral nutritional supplements (ONS) are commonly prescribed to malnourished patients to improve their nutritional status. Taste and smell changes in patients with cancer can affect the palatability of ONS. The present study investigated: (1) the palatability of six ONS in testicular cancer patients before, during the first two cycles, and after chemotherapy; (2) the relation between the palatability and taste and smell function; (3) the metallic taste of these ONS.
Methods
Twenty-one testicular cancer patients undergoing first-line cisplatin-based chemotherapy participated. Two milk-based (vanilla; strawberry), two juice-based (apple; orange), and two yoghurt-based (vanilla-lemon; peach-orange) ONS were tested. A questionnaire was used to assess the palatability of ONS and to which extent the attribute 'metallic' was applicable. Taste and smell function were measured using taste strips and 'Sniffin' Sticks', respectively.
Results
The palatability of ONS was highly variable among patients. The milk-based strawberry ONS was preferred most before, during, and after chemotherapy. The liking of the milk-based vanilla ONS tended to decrease over time (p = 0.053), whereas the liking of the other ONS remained stable. A higher smell threshold and a lower sour taste threshold were correlated to a decreased liking of the milk-based vanilla ONS. The two juice-based ONS tended to taste more metallic during than before chemotherapy.
Conclusion
Health care professionals and patients should be aware that the palatability of ONS can change over time. Regular structured contact between health care professionals and patients regarding the choice of ONS seems warranted.
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Impact of intravenous magnesium infusion rate during ambulatory replacements on serum magnesium concentrations after allogeneic stem cell transplant
Abstract
Purpose
For an outpatient cancer center to operate efficiently, optimizing the use of chair time is essential. Allogeneic hematopoietic cell transplant (allo-HCT) recipients are seen frequently in this setting after hospital discharge and regularly for several months thereafter. Aggressive electrolyte replacement is commonly required in these patients, primarily due to renal wasting with calcineurin inhibitor use. Frequent intravenous (IV) magnesium repletion, requiring several hours of infusion time, is often needed in these patients to adequately manage their magnesium deficiencies. The purpose of this study is to explore the impact of extending the infusion rate of intravenous magnesium sulfate on the frequency and degree of IV magnesium replacements required in allo-HCT recipients.
Methods
We conducted a retrospective study to compare two cohorts of patients administered IV magnesium sulfate at a rate of 4 g/1 h versus 4 g/2 h.
Results
A total of 103 continuous patients were assessed in two groups as cohort 1 at the 4 g/1 h rate and cohort 2 at the 4 g/2 h rate. Cohort 1 required less IV magnesium per outpatient visit (median 2.2 vs. 2.9 g/visit, P = 0.0211) and less total IV magnesium replacement through day +100 (median 68 vs. 85 g, P = 0.0479) than cohort 2.
Conclusion
These data suggest that there is no apparent benefit of prolonging magnesium infusion from 1 to 2 h in our outpatient allo-HCT population.
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Change in bone mineral density during adjuvant chemotherapy for early-stage breast cancer
Abstract
Purpose
Adjuvant chemotherapy has been associated with loss of bone mineral density (BMD) either as a direct effect or due to glucocorticoids used as supportive care medication. A prospective cohort study was conducted to evaluate changes in BMD from baseline to right after completion of chemotherapy, i.e., 4 months.
Methods
Dual-imaging X-ray absorptiometry (DXA) was performed at baseline and after completing anthracycline- and taxane-based chemotherapy to measure BMD in the spine, hip, and forearm in early-stage breast cancer patients. High-dose prednisolone was used at three weekly intervals to reduce nausea and vomiting. Patients were advised a daily calcium/vitamin D supplement. Linear regression was used to assess mean percentage change in BMD and 95 % confidence intervals (95 % CI) according to doses of prednisolone, menopausal status, smoking, and BMI.
Results
Eight patients were excluded: seven because of initiation of bisphosphonate treatment due to osteoporosis at baseline, and one had non-interpretable DXA. The final cohort included 97 patients with a mean age of 53 years (range 34–72). Mean cumulative prednisolone dose was 1308 mg (95 % CI 1255; 1362). BMD increased 1.36 % (95 % CI 0.7; 2.0, p < 0.001) in the spine and 1.27 % (95 % CI 0.9; 1.7, p < 0.001) in the hip. Forearm BMD did not change. Postmenopausal women had increases in spine BMD of 2.35 % (95 % CI 1.1; 3.6, p < 0.001) compared to premenopausal women. The spine BMD of current smokers decreased 1.67 % (95 % CI −3.3; −0.1, p = 0.04) compared to never/former smokers.
Conclusions
Adjuvant chemotherapy supplemented with prednisolone was not associated with loss of BMD. Postmenopausal women gained bone mass, whereas current smokers lost bone mass.
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Breast cancer and bone metastases: a call for appropriate treatment
Abstract
Purpose
The aim of this study is to provide an overview of the potential barriers to uptake of bone-targeted agents for the prevention of skeletal-related events (SREs) in patients with breast cancer and bone metastases.
Methods
A top-line literature review was conducted to identify trends in and barriers to initiating bone-targeted therapy in patients with metastatic breast cancer.
Results
The majority of patients with bone metastases that are secondary to breast cancer clearly benefit from treatment with a bone-targeted agent such as the RANK ligand inhibitor denosumab or the bisphosphonate zoledronic acid, because both delay the onset of SREs. Evidence suggests, however, that these agents are not being used in these patients as per European guideline recommendations.
Conclusions
Adoption of a number of behavioral changes may help to overcome barriers to earlier initiation of treatment with bone-targeted agents in these patients. This includes raising awareness of the guidelines that are available for bone-targeted therapies, providing physician and patient education on the appropriate use of these agents, and highlighting to physicians the importance of early treatment and regular monitoring for adverse events. Earlier initiation of treatment should help to reduce the risk of SREs and thus lessen the burden that these debilitating skeletal complications place on patients and healthcare systems.
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Mechanisms of skin aging induced by EGFR inhibitors
Abstract
Background
The mechanisms of skin aging have not been completely elucidated. Anecdotal data suggests that EGFR inhibition accelerates aging-like skin changes.
Objective
The objective of the study was to evaluate the clinical characteristics and investigate the cellular and molecular mechanisms underlying skin changes associated with the use of EFGRIs.
Patients and methods
Patients during prolonged treatment with EGFRIs (>3 months) were analyzed for aging-like skin changes. Baseline EGFR expression was compared in young (<25 years old) vs. old (> 65 years old) skin. In addition, the regulation of extracellular matrix, senescence-associated genes, and cell cycle status was measured in primary human keratinocytes treated with erlotinib in vitro.
Results
There were progressive signs of skin aging, including xerosis cutis, atrophy, rhytide formation, and/or actinic purpura in 12 patients. Keratinocytes treated with erlotinib in vitro showed a significant down-modulation of hyaluronan synthases (HAS2 and HAS3), whereas senescence-associated genes (p21, p53, IL-6, maspin) were upregulated, along with a G1 cell cycle arrest and stronger SA β-Gal activity. There was significantly decreased baseline expression in EGFR density in aged skin, when compared to young controls.
Conclusions
EGFR inhibition results in molecular alterations in keratinocytes that may contribute to the observed skin aging of patients treated with respective targeted agents.
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Capacity of the Edmonton Symptom Assessment System and the Canadian Problem Checklist to screen clinical insomnia in cancer patients
Abstract
Purpose
Insomnia is highly prevalent in cancer patients. Efficacious treatments exist for this condition but, for these interventions to be offered, an effective screening needs to be carried out beforehand. The pan-Canadian practice guidelines on sleep disturbances provide recommendations on how to use the Edmonton Symptom Assessment System (ESAS) and the Canadian Problem Checklist (CPC) to screen for sleep difficulties in cancer. However, empirical evidence to support these recommendations is lacking. The goal of this study was to assess the capacity of the ESAS (drowsiness and "other" items) and the CPC (sleep item) to screen for clinical insomnia in cancer patients.
Methods
As part of routine care, 615 patients with various cancer types completed the ESAS, the CPC, and the Insomnia Severity Index, used as the standard for establishing the presence of clinical insomnia.
Results
None of the criteria provided an effective screening when used alone. No patient used the ESAS-other item to report sleep difficulties. The sensitivity and specificity rates of the CPC-sleep item alone were 60.4 and 89.6 %, respectively. A score ≥2 on the ESAS-drowsiness item had a sensitivity of 61.5 % and a specificity of 75.4 %. When used in combination, the best option was scoring positively on the CPC-sleep item OR a score ≥2 on the ESAS-drowsiness item (sensitivity 84.2 %; specificity 69.7 %).
Conclusions
When used alone, the CPC-sleep and the ESAS-drowsiness items yielded insufficient sensitivity rates for a first screening, but when used in combination, they provided a good balance between sensitivity and specificity.
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Effectiveness of tapentadol prolonged release for the management of painful mucositis in head and neck cancers during intensity modulated radiation therapy
Abstract
Purpose
To evaluate the effectiveness and tolerability profile of tapentadol prolonged release (PR) in a cohort of head and neck cancer (HNC) patients affected by background pain due to painful mucositis during intensity modulated radiation therapy with or without cisplatin with definitive and adjuvant intent.
Materials and methods
Tapentadol PR was administered at the moment of pain onset in opioid-naive patients at the dosage of 50 mg BID. The dosage was increased 50 mg twice a day until the optimal dose of no more than 500 mg/day of tapentadol PR. Primary endpoint of the analysis was the evaluation of improved assessment using the numerical rating scale (NRS). Secondary endpoints were as follows: (1) assessment of the treatment received using the patients' global impression of change (PGIC) scale; (2) weight increase/stability; (3) sleep quality; and (4) tolerability. The period of observation was 90 days from the start of antineoplastic treatment.
Results
Between September 2014 and May 2015, 30 HNC patients were observed. The average age was 64.9 years (range, 36–80). Twenty-two days after the start of antineoplastic treatment, tapentadol PR was administered to 25 % of patients. This percentage was increased to 50 % after 39 days and to 75 % after 43 days. Considering the efficacy of tapentadol PR on daily pain, there was a reduction of 30 % (95 % C.I. 69.3 ÷ 96.2 %) in the pain score in 26 patients (86.7 %), and a reduction of 50 % (95 % C.I. 57.7 ÷ 90.1 %) in 23 patients (76.7 %).
Conclusion
The use of tapentadol PR is feasible and well tolerated in HNC patients affected by background pain due to painful mucositis during intensity modulated radiotherapy with or without cisplatin. Further studies are needed to enhance current findings.
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Characteristics and predictors of fatigue among men receiving androgen deprivation therapy for prostate cancer: a controlled comparison
Abstract
Purpose
Although fatigue is a common problem for men with prostate cancer undergoing androgen deprivation therapy (ADT), there has been little systematic research on this issue. The present study examined changes in fatigue among prostate cancer patients receiving ADT compared to controls and predictors of heightened fatigue in ADT patients.
Methods
Prostate cancer patients treated with ADT (ADT+ group, n = 60) completed assessments of fatigue prior to or just after ADT initiation (baseline) and 6 and 12 months later. Prostate cancer patients treated with prostatectomy only (ADT− group, n = 85) and men without cancer (CA− group, n = 86) matched on age and education completed assessments at similar intervals.
Results
Group-by-time interactions for fatigue severity, interference, and duration were observed when comparing the ADT+ group to the controls. Groups did not differ at baseline; however, the ADT+ group reported worse fatigue at 6 and 12 months. The same pattern was observed for changes in the prevalence of clinically meaningful fatigue and the extent of clinically meaningful change in fatigue. Within the ADT+ group, higher baseline comorbidity scores were associated with greater increases in fatigue interference, and higher baseline Gleason scores were associated with greater increases in fatigue duration.
Conclusions
Prostate cancer patients receiving ADT demonstrate a trajectory of worsened fatigue during the first 12 months following treatment initiation relative to the controls. Greater comorbidities and higher Gleason scores at baseline appear to be risk factors for heightened fatigue during the first year following ADT initiation. Results highlight important time points for implementation of interventions aimed at fatigue reduction.
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Knowledge, attitudes, and influencing factors of cancer patients toward approving advance directives in China
Abstract
Purpose
Many cancer patients do not have advance directives (ADs), which may lead to unwanted excessive or aggressive care when patients have lost decision-making capacity. The aim of this study was to investigate knowledge and attitudes of approving ADs and explore factors associated with willing to designate ADs among cancer patients in China.
Methods
We conducted semi-structured interview method investigating 753 in-patients with cancer in two cancer centers.
Results
Of those subjects, none of the cancer patients had an AD. Only 22.4 % (118 of 526) approved ADs. Comparing with the disapproved ADs group, the approved ADs group were more likely to discuss the AD with oncologist or nurse (χ 2 = 180.4, p < 0.001) in the cancer center (χ 2 = 244.1, p < 0.001), and they chose more comfort care (χ 2 = 18.8, p < 0.001). Most of cancer patients in the two groups wanted to die at home (72.8 %, 73.7 %, respectively). The older patients (OR, 1.04, 95 % CI, 1.02–1.07, p = 0.001), female (OR, 0.55, 95 % CI, 0.35–0.88, p = 0.013), with higher education levels (OR, 3.38, 95 % CI, 1.92–5.96, p < 0.001), with religious beliefs (OR, 2.91, 95 % CI, 1.71–4.94, p < 0.001), and with higher scores of ECOG (OR, 1.46, 95 % CI, 1.17–1.82, p = 0.001) were associated with desiring for ADs.
Conclusions
Our findings indicate that there was a dearth of knowledge and different attitudes toward approving ADs among cancer patients, and some factors of demographic and clinical characteristics influenced their willing to designate ADs. This research highlights the importance of propagandizing the ADs to the public, especially to the patients, and further discussing with them when the time is ripe.
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Impact of early palliative interventions on the outcomes of care for patients with non-small cell lung cancer
Abstract
Purpose
The aim of this study is to address the question "does early palliative care in addition to standard oncology care or late additional palliative care improve patterns of terminal care in patients who died from non-small cell lung cancer (NSCLC)?"
Methods
We performed retrospective single-institution study of 286 patients. Palliative care was provided by a dedicated multidisciplinary palliative care team (PCT). An arbitrarily defined cutoff of 3 months before death was chosen to distinguish between early and late additional palliative care. Referral was at the discretion of the treating physicians who provided standard anticancer treatments.
Results
Patients who received early (8 %) or late (27 %) additional palliative care were significantly younger than those who did not receive additional palliative care. The likelihood of active anticancer treatment in the last month of life was lowest in the early additional palliative care group, p = 0.03. Patients who received early or late additional palliative care were significantly less likely to lack a documented resuscitation preference, p = 0.0001. Patients who received early additional palliative care were significantly less likely to become hospitalized in the last 3 months of life, p = 0.003. Place of death was also numerically different, with hospital death occurring in 33 % of patients who received early additional palliative care, as compared to 48 % in the late and 50 % in the no PCT group, p = 0.35. Anticancer treatment intensity was not reduced if the PCT contributed to the overall management.
Conclusion
Early additional palliative care resulted in relevant improvements. The optimal timing of this intervention should be examined prospectively.
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Transition journey from hospital to home in patients with cancer and their caregivers: a qualitative study
Abstract
Background
The National Cancer Institute Singapore initiated the NUH2 Home program in January 2014, referred to as "Caring Across the Cancer Continuum," a nurse-led cancer transitional care service (CTCS) that provides home care to patients with cancer and their caregivers. The study aimed to explore the transition experiences of patients with cancer and their caregivers.
Method
Using a purposive sampling, 12 patients with cancer and 12 caregivers were recruited. Audiotape interviews were conducted until data saturation was achieved. Each interview was transcribed verbatim, and thematic analyses were performed to extract significant themes and subthemes.
Results
Four themes emerged from the data including (1) ongoing concerns, (2) needing timely help, (3) resuming control and normality of life, and (4) appreciating the transition care. The transition journey of patients and caregivers provided them with an ability to regain control and normality in their lives, be reassured and confident in being able to care for themselves and manage the physiological and psychological strains associated with the multiple vicissitudes associated with having cancer and its treatment while at home.
Conclusion
Our study addressed the nature, patterns, conditions, and responses to transition care. Our findings provided relevant contextual knowledge to further improve the transition care service based on the recommendations of the patients with cancer and their caregivers who first experienced the new service.
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Exceptional patients and communication in cancer care—are we missing another survival factor?
Abstract
Objective
There is increased awareness of the issue of exceptional survival beyond expectations among cancer patients with poor prognosis, and researchers are starting to look closely at this phenomenon. In this study, we explored the perceptions of these "exceptional patients" as to their understanding and insight into their unusual experience.
Methods
We used a qualitative approach consisting of in-depth, open-ended interviews with exceptional patients in two locations, Texas and Israel, from 2007 to 2014. The interviews were audio-recorded and qualitatively analyzed, and gave rise to illness narratives entailing detailed descriptions of patients experience over the course of their disease and treatment. A qualitative content analysis focusing on contextual meaning was utilized.
Results
Twenty-nine patients participated in our study. The mean years since diagnosis was 9.55 years (range, 4–23 years). All patients had received conventional treatment, including surgery, chemotherapy, and radiation therapy. One of the prevailing themes in these interviews was related to the patient-doctor relationship. Most participants mentioned that the support they received from one or more physicians was a crucial factor for their exceptional survival.
Conclusion
The significance of patient-doctor relationship in cancer survival requires further research. This research is especially important as it adds to the current trend of patient centered care and points to the added value of relationship between health providers and patients. This relationship, as perceived by these exceptional patients, can be a factor that adds to improved survival in cancer care.
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Evaluation of quality of life using a tablet PC-based survey in cancer patients treated with radiotherapy: a multi-institutional prospective randomized crossover comparison of paper and tablet PC-based questionnaires (KROG 12–01)
Abstract
Purpose
This study compared a tablet PC questionnaire with a paper method for reliability and patient preferences in the acquisition of patient-reported outcomes (PROs) for patients treated with radiotherapy. By comparing the two modes of PRO administration, we aimed to evaluate the adequacy of using tablet PC questionnaires in future clinical use.
Methods
Patients were randomized in a crossover study design using two different methods for PRO entry. A group of 89 patients answered a paper questionnaire followed by the tablet PC version, whereas 89 patients in another group completed the tablet PC questionnaire followed by the paper version. Surveys were performed four times per patient throughout the course of the radiotherapy. The Korean versions of the M.D. Anderson Symptom Inventory (MDASI-K) and the Brief Fatigue Inventory (BFI-K) were used. The primary endpoint of our current study was an assessment of patient preference for the survey method. The proportions of patients preferring each mode of questionnaire were evaluated.
Results
The proportion of patients who preferred the tablet PC version, paper form, or who had no preference was 52.2, 22.1, and 25.7 %, respectively. More than half of the patients preferred the tablet PC to the paper version in all four surveys. Age, gender, educational status, prior experience of using a tablet PC, and the order of paper to tablet PC administration did not impact patient preferences. Inter-class correlation coefficients (ICCs) between the modes were 0.92 for MDASI-K and 0.94 for BFI-K and ranged from 0.91 to 0.96 on both instruments during the four surveys.
Conclusions
A tablet PC-based PRO is an acceptable and reliable method compared with paper-based data collection for Korean patients receiving radiotherapy.
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Impact of metastasectomy on prognosis in patients treated with targeted therapy for metastatic renal cell carcinoma
Abstract
Purpose
We evaluated the value of metastasectomy in patients treated with targeted therapy for metastatic renal cell carcinoma (mRCC).
Methods
The medical records of 325 patients who presented with mRCC were reviewed; among these patients, 33 underwent complete metastasectomy followed by targeted therapy (complete metastasectomy group), 29 underwent incomplete metastasectomy followed by targeted therapy (incomplete metastasectomy group), and 263 treated with targeted therapy alone (non-metastasectomy group). We estimated progression-free and overall survivals using Kaplan–Meier curves. A Cox proportional hazards regression model was used to estimate the prognostic significance of metastasectomy.
Results
Clinicopathological variables did not differ among the three groups except for age, history of nephrectomy, type of metastasis, the International Metastatic Renal Cell Carcinoma Database Consortium risk groups, histology, and bone metastasis. The median progression-free survivals were 29.5, 18.8, and 14.8 months in the complete, incomplete, and non-metastasectomy groups (p < 0.001). Complete metastasectomy (hazard ratio 0.431, p = 0.001) was an independent predictor of disease progression, along with targeted agents, risk groups, sarcomatoid feature, and number of metastatic sites. The median overall survivals were 92.5, 29.6, and 23.5 months in the complete, incomplete, and non-metastasectomy groups (p < 0.001). Complete metastasectomy (hazard ratio 0.378, p = 0.001) was an independent predictor of overall survival, along with targeted agents, type of metastasis, risk groups, sarcomatoid feature, and number of metastatic sites.
Conclusions
Complete metastasectomy performed before targeted therapy might improve progression-free and overall survivals in patients with mRCC.
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Immunological evaluation of personalized peptide vaccination for patients with histologically unfavorable carcinoma of unknown primary site
Abstract
The immunological characteristics of carcinoma of unknown primary site (CUP) are not well established due to inclusion of heterogeneous types of metastatic tumors with the absence of any detectable primary site. We evaluated the immune responses in patients with histologically unfavorable CUP during personalized peptide vaccination (PPV). Ten patients with histologically unfavorable CUP who had been treated by PPV after chemotherapy failure were analyzed. In PPV treatment, up to four human leukocyte antigen-matched peptides of a total 31 peptides were selected according to preexisting host immunity before vaccination and administered subcutaneously. Peptides derived from the Lck antigen were most often chosen for use among all patients. CTL responses were increased in 8 of the 10 and 5 of the five patients tested at the end of the first and second PPV cycles, respectively. Increases in humoral responses after vaccination, including IgG, IgG1, IgG3, IgA, and IgM, were observed against not only the vaccinated peptides but also the non-vaccinated peptides. Severe adverse events due to PPV were not observed. Median overall survival was 13.9 months (95 % CI 4.0–22.5 months). PPV activated both cellular and humoral immune responses to short peptides derived from CTL epitopes in the majority of CUP patients. PPV with Lck-derived peptides may be a feasible, new treatment modality for histologically unfavorable CUP patients due to its safety and strong ability to boost immune responses, although its clinical efficacy remains to be investigated in larger-scale trials.
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BRCA1-associated protein 1 deficiency in lung adenocarcinoma predicts poor outcome and increased tumor invasion
Abstract
Background
The major pathological type of non-small cell lung cancer is lung adenocarcinoma (LAC), which has a poor prognosis. BRCA1-associated protein-1 (BAP1) is a newly identified tumor suppressor that regulates a number of cellular functions in somatic malignancies. However, the impact of BAP1 expression in LAC has not been investigated.
Methods
A total of 112 cases of LAC and 101 cases of non-neoplastic lung diseases were included in this study. The study focused on BAP1 expression in lung tissues and its relationship to patients' clinical and pathological features. BAP1 expression was detected by immunohistochemistry. A human LAC cell line NCI-H1299 was transfected with lipofectamine p3xFLAG-BAP1. BAP1 gene expression was silenced in another LAC cell line NCI-H1650, in order to test the inhibitory effect of BAP1 on cell migration and invasion, as well as cell cycle regulation.
Results
BAP1 expression showed a negative correlation with tumorigenesis of LAC (p <0.001) and lymph node metastasis (p = 0.010). High expression of BAP1 predicted longer disease free survival (p = 0.040) and overall survival (p = 0.021) of LAC patients. In functional assays, BAP1 was found to inhibit the migration and invasion of LAC cells, and promoted their apoptosis and necrosis.
Conclusions
We identify BAP1 as a LAC precursor as well as a robust prognostic indicator in LAC patients. This study provides in vitro rationale for the further investigation of BAP1 in preclinical studies.
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Performance and prognostic utility of the 92-gene assay in the molecular subclassification of ampullary adenocarcinoma
Abstract
Background
Ampullary adenocarcinoma is a rare gastrointestinal cancer associated with diverse outcomes due to clinical and pathological heterogeneity. Standardized methods to better prognosticate and inform therapeutic selection for ampullary adenocarcinoma are needed. This study explored the novel use and potential prognostic utility of a 92-gene cancer classifier in ampullary adenocarcinomas.
Methods
In this prospectively-defined, blinded study of ampullary adenocarcinoma [N =54; stage T3 or higher (57 %); Grade III (44 %); Node positive (55 %)], the performance of a 92-gene classifier was examined to predict the ampullary subtype that was derived from histomorphological examination of resected ampullary samples. Outcome data for relapse-free survival (RFS) and overall survival (OS) were plotted to compare the prognostic utility of histological subtyping, histomolecular phenotyping, and the 92-gene classifier. Multivariate analysis was used to determine clinicopathological variables that were independently associated with overall survival.
Results
The 92-gene classifier demonstrated sensitivities and specificities of 85 % [95 % CI, 66–94] and 68 % [95 % CI, 48–84] and 64 % [95 % CI, 46–79] and 88 % [95 % CI, 70–98] for the pancreaticobiliary and intestinal histological subtypes, respectively. For the 92-gene classifier, improved outcomes were observed for the intestine versus the pancreaticobiliary prediction (median OS 108.1 v 36.4 months; HR, 2.17; 95 % CI, 0.98 to 4.79; P = 0.05). Similar results were seen for ampullary adenocarcinoma stratification by histological subtype (P = 0.04) and histomolecular phenotype (P = 0.02). Within poorly differentiated ampullary adenocarcinomas only the 92-gene classifier demonstrated statistically significant differences in RFS and OS (P < 0.05).
Conclusions
Prognostic stratification of ampullary adenocarcinoma was similar for the 92-gene classifier, histological subtype, and histomolecular phenotype. The 92-gene classifier provides an unbiased standardized molecular-based approach to stratify ampullary tumors.
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Antemortem diagnosis of pulmonary tumor thrombotic microangiopathy in a patient with recurrent breast cancer: a case report
Abstract
Background
Pulmonary tumor thrombotic microangiopathy (PTTM), a rare complication of advanced cancer, is histologically characterized by tumor embolisms and fibrocellular intimal proliferation of small pulmonary arteries and arterioles. PTTM usually has an extremely poor prognosis, and antemortem diagnosis is very difficult.
Case presentation
A 65-year-old woman with a 5-year history of clinical stage IIA (T2N0M0) invasive ductal carcinoma of the left breast was hospitalized for worsening shortness of breath, hemoptysis, and cough since 2 months. She had previously received neoadjuvant chemotherapy and left mastectomy. Because the cancer cells were positive for human epidermal growth factor receptor 2 (HER2), four cycles of trastuzumab had been administered as adjuvant chemotherapy. On admission, chest computed tomography (CT) showed peripheral consolidations in both the lower lobes and a mediastinal mass. Specimens obtained on video-assisted thoracoscopic surgical biopsy revealed tumor cell embolism, intimal fibrocellular proliferation of small arteries, fibrin thrombi, recanalization, and infarction in the left lower lobe, as well as metastasis to the mediastinal pleura. Immunohistochemical staining of the tumor cells revealed positivity for HER2, and a diagnosis of recurrent breast cancer with PTTM was made. Four cycles of trastuzumab resulted in rapid improvement of her symptoms and CT findings of peripheral consolidations and the mediastinal mass.
Conclusion
An antemortem diagnosis of PTTM was made in a patient with HER2-positive recurrent breast cancer. Trastuzumab was effective for not only breast cancer but also PTTM.
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Effect of diagnostic delay on survival in patients with colorectal cancer: a retrospective cohort study
Abstract
Background
Disparate and contradictory results make studies necessary to investigate in more depth the relationship between diagnostic delay and survival in colorectal cancer (CRC) patients. The aim of this study is to analyse the relationship between the interval from first symptom to diagnosis (SDI) and survival in CRC.
Methods
Retrospective study of n = 942 CRC patients. SDI was calculated as the time from the diagnosis of cancer and the first symptoms of CRC.
Cox regression was used to estimate five-year mortality hazard ratios as a function of SDI, adjusting for age and gender. SDI was modelled according to SDI quartiles and as a continuous variable using penalized splines.
Results
Median SDI was 3.4 months. SDI was not associated with stage at diagnosis (Stage I = 3.6 months, Stage II-III = 3.4, Stage IV = 3.2; p = 0.728). Shorter SDIs corresponded to patients with abdominal pain (2.8 months), and longer SDIs to patients with muchorrhage (5.2 months) and rectal tenesmus (4.4 months).
Adjusting for age and gender, in rectum cancers, patients within the first SDI quartile had lower survival (p = 0.003), while in colon cancer no significant differences were found (p = 0.282). These results do not change after adjusting for TNM stage.
The splines regression analysis revealed that, for rectum cancer, 5-year mortality progressively increases for SDIs lower than the median (3.7 months) and decreases as the delay increases until approximately 8 months. In colon cancer, no significant relationship was found between SDI and survival.
Conclusions
Short diagnostic intervals are significantly associated with higher mortality in rectal but not in colon cancers, even though a borderline significant effect is also observed in colon cancer. Longer diagnostic intervals seemed not to be associated with poorer survival. Other factors than diagnostic delay should be taken into account to explain this "waiting-time paradox".
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Expression of EIF5A2 associates with poor survival of nasopharyngeal carcinoma patients treated with induction chemotherapy
Abstract
Background
Nasopharyngeal carcinoma (NPC) is a type of head-neck cancer with a distinguishable geographic and racial distribution worldwide. Increasing evidence supports that the accumulation of additional genetic and epigenetic abnormalities is important in driving the NPC tumorigenic process. In this study, we aim to investigate the association between EIF5A2 (Eukaryotic translation initiation factor 5A2) expression status and NPC clinical outcomes.
Methods
The expression status of EIF5A2 was investigated in the NPC tissue microarray. Tissues were from 166 NPC patients staging II-IV, collected between 1999 and 2005. All patients were administered 2–3 cycles of DDP (cisplatin) + 5-Fu (5-fluorouracil) induction therapy and then treated with a uniform conventional two-dimensional radiotherapy. Cell motility assay, tumor growth assay and cytotoxicity assay were performed on the EIF5A2 overexpressed cells and control cells. siRNA was also used in the in vitro studies.
Results
Positive staining of EIF5A2 was observed in 85.4 % (105/123) informative tumor cases. Multivariate analyses demonstrated that EIF5A2 was an independent prognostic marker of poor overall survival (OS) (P = 0.041), failure-free survival (FFS) (P = 0.029), and distant failure-free survival (D-FFS) (P = 0.043) in patients with locoregionally advanced NPC patients treated with cisplatin + 5-Fu chemoradiotherapy. The forced expression of EIF5A2 in NPC cells enhanced the cells' motility and growth ability. Knock-down of EIF5A2 in NPC cells decreased the cell's motility and growth ability. Our results also demonstrated that EIF5A2 overexpression induced chemoresistance of NPC cells to 5-Fu.
Conclusions
Our findings suggested that EIF5A2 expression, as examined by immunohistochemistry, could function as an independent prognostic factor of outcomes in NPC patients with cisplatin + 5-Fu chemoradiotherapy. EIF5A2 might be a novel therapeutic target for the inhibition of NPC progress.
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Interleukin 12 shows a better curative effect on lung cancer than paclitaxel and cisplatin doublet chemotherapy
Abstract
Background
Interleukin 12 (IL-12) is a cytokine that has been reported to exhibit potent tumoricidal effects in animal tumor models. A combined approach using Paclitaxel and platinum-based doublet chemotherapy is the most commonly used backbone regimen for treating lung cancer. Despite numerous studies regarding the anti-tumor effects of IL-12 and the widespread use of conventional chemotherapy, few direct comparisons of IL-12 and conventional chemotherapy in the treatment of lung cancer have been performed.
Methods
We compared IL-12 to paclitaxel and cisplatin doublet chemotherapy in terms of efficacy against lung cancer in mouse models. The antitumor effect was measured by survival assays, histological analyses and imaging analyses. The cytokine levels were assessed using enzyme linked immunosorbent assay (ELISA) and flow cytometry (FACS). The spleen sizes were measured. CD31, CD105 and Vascular endothelial growth factor receptor 3 (VEGFR3) were analyzed using immunofluorescence. Matrix metalloprotein-9 (MMP-9) and cadherin 1 (CDH1) transcript levels were measured by quantitative PCR. Tumor cells apoptosis were examined by Tunel assay.
Results
The results showed that IL-12 treatment inhibited lung tumor growth, resulting in the long-term survival of lung cancer-bearing mice. Further examination revealed that IL-12 rapidly activated NK cells to secrete IFN-γ, resulting in the inhibition of tumor angiogenesis. In contrast, paclitaxel and cisplatin doublet chemotherapy did not show the expected efficacy in orthotopic lung cancer models; the IFN-γ levels were not increased after this treatment, and the number of peripheral lymphocytes was reduced.
Conclusion
Together, these animal model data indicate that IL-12 shows a better curative effect than PTX + CDDP doublet chemotherapy.
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Histone deacetylase inhibitors induce invasion of human melanoma cells in vitro via differential regulation of N-cadherin expression and RhoA activity
Abstract
Background
Histone deacetylase inhibitors (HDACi) exert multiple cytotoxic actions on cancer cells. Currently, different synthetic HDACi are in clinical use or clinical trials; nevertheless, since both pro-invasive and anti-invasive activities have been described, there is some controversy about the effect of HDACi on melanoma cells.
Methods
Matrigel and Collagen invasion assays were performed to evaluate the effect of several HDACi (Butyrate, Trichostatin A, Valproic acid and Vorinostat) on two human melanoma cell line invasion (A375 and HT-144). The expression of N- and E-Cadherin and the activity of the RhoA GTPase were analyzed to elucidate the mechanisms involved in the HDACi activity.
Results
HDACi showed a pro-invasive effect on melanoma cells in vitro. This effect was accompanied by an up-regulation of N-cadherin expression and an inhibition of RhoA activity. Moreover, the down-regulation of N-cadherin through blocking antibodies or siRNA abrogated the pro-invasive effect of the HDACi and, additionally, the inhibition of the Rho/ROCK pathway led to an increase of melanoma cell invasion similar to that observed with the HDACi treatments.
Conclusion
These results suggest a role of N-cadherin and RhoA in HDACi induced invasion and call into question the suitability of some HDACi as antitumor agents for melanoma patients.
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Immunological evaluation of personalized peptide vaccination for patients with histologically unfavorable carcinoma of unknown primary site
Abstract
The immunological characteristics of carcinoma of unknown primary site (CUP) are not well established due to inclusion of heterogeneous types of metastatic tumors with the absence of any detectable primary site. We evaluated the immune responses in patients with histologically unfavorable CUP during personalized peptide vaccination (PPV). Ten patients with histologically unfavorable CUP who had been treated by PPV after chemotherapy failure were analyzed. In PPV treatment, up to four human leukocyte antigen-matched peptides of a total 31 peptides were selected according to preexisting host immunity before vaccination and administered subcutaneously. Peptides derived from the Lck antigen were most often chosen for use among all patients. CTL responses were increased in 8 of the 10 and 5 of the five patients tested at the end of the first and second PPV cycles, respectively. Increases in humoral responses after vaccination, including IgG, IgG1, IgG3, IgA, and IgM, were observed against not only the vaccinated peptides but also the non-vaccinated peptides. Severe adverse events due to PPV were not observed. Median overall survival was 13.9 months (95 % CI 4.0–22.5 months). PPV activated both cellular and humoral immune responses to short peptides derived from CTL epitopes in the majority of CUP patients. PPV with Lck-derived peptides may be a feasible, new treatment modality for histologically unfavorable CUP patients due to its safety and strong ability to boost immune responses, although its clinical efficacy remains to be investigated in larger-scale trials.
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DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses
Abstract
Radiotherapy resistance is one of the major factors limiting the efficacy of radiotherapy in lung cancer patients. The extensive investigations indicate the diversity in the mechanisms underlying radioresistance. Here, we revealed that DNA damage binding protein 2 (DDB2) is a potential regulator in the radiosensitivity of non-small cell lung cancer (NSCLC) cells. DDB2, originally identified as a DNA damage recognition factor in the nucleotide excision repair, promotes the survival and inhibits the apoptosis of NSCLC cell lines upon ionizing radiation (IR). Mechanistic investigations demonstrated that DDB2 is able to facilitate IR-induced phosphorylation of Chk1, which plays a critical role in the cell cycle arrest and DNA repair in response to IR-induced DNA double-strand breaks (DSBs). Indeed, knockdown of DDB2 compromised the G2 arrest in the p53-proficient A549 cell line and reduced the efficiency of homologous recombination (HR) repair. Taken together, our data indicate that the expression of DDB2 in NSCLC could be used as a biomarker to predict radiosensitivity of the patients. Targeting Chk1 can be used to increase the efficacy of radiotherapy in patients of NSCLC possessing high levels of DDB2.
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