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Malta

Cancer Statistics
Population in 2012: 0.4m
People newly diagnosed with cancer (excluding NMSC) / yr: 1,900
Age-standardised rate, incidence per 100,000 people/yr: 242.9
Risk of getting cancer before age 75:23.7%
People dying from cancer /yr: 800
Data from IARC GlobalCan (2012)
Malta Cancer Organisations and Resources
Latest Research Publications Related to Malta

Malta Cancer Organisations and Resources (2 links)


Latest Research Publications Related to Malta

Gevers EF, Meredith S, Shah P, et al.
Cushing syndrome in a child due to pro-opiomelanocortin (POMC) secretion from a yolk sac tumor.
Eur J Endocrinol. 2017; 176(2):K1-K7 [PubMed] Related Publications
CONTEXT: Pituitary microadenomas and adrenal tumours are the most common causes for endogenous Cushing syndrome (CS) in children.
CASE DESCRIPTION: We describe a two-year old girl with Cushing syndrome due to ectopic pro-opiomelanocortin (POMC) production from an abdominal yolk sac tumor. Cortisol concentrations were elevated but adrenocorticotropic hormone (ACTH) concentrations were equivocal. The use of antibodies specifically detecting ACTH precursors revealed that plasma ACTH precursors were elevated. Additionally, an ACTH assay with a low cross-reactivity for precursors showed low concentrations of ACTH. Immunohistochemistry suggested POMC but not ACTH production by the tumour.
CONCLUSION: We describe a yolk sac tumour as a novel source of ectopic POMC production leading to CS in a young girl.

Grech G, Baldacchino S, Saliba C, et al.
Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options.
Tumour Biol. 2016; 37(9):11691-11700 [PubMed] Related Publications
The complexity of the phosphatase, PP2A, is being unravelled and current research is increasingly providing information on the association of deregulated PP2A function with cancer initiation and progression. It has been reported that decreased activity of PP2A is a recurrent observation in many types of cancer, including colorectal and breast cancer (Baldacchino et al. EPMA J. 5:3, 2014; Cristobal et al. Mol Cancer Ther. 13:938-947, 2014). Since deregulation of PP2A and its regulatory subunits is a common event in cancer, PP2A is a potential target for therapy (Baldacchino et al. EPMA J. 5:3, 2014). In this review, the structural components of the PP2A complex are described, giving an in depth overview of the diversity of regulatory subunits. Regulation of the active PP2A trimeric complex, through phosphorylation and methylation, can be targeted using known compounds, to reactivate the complex. The endogenous inhibitors of the PP2A complex are highly deregulated in cancer, representing cases that are eligible to PP2A-activating drugs. Pharmacological opportunities to target low PP2A activity are available and preclinical data support the efficacy of these drugs, but clinical trials are lacking. We highlight the importance of PP2A deregulation in cancer and the current trends in targeting the phosphatase.

Golubnitschaja O, Debald M, Yeghiazaryan K, et al.
Breast cancer epidemic in the early twenty-first century: evaluation of risk factors, cumulative questionnaires and recommendations for preventive measures.
Tumour Biol. 2016; 37(10):12941-12957 [PubMed] Related Publications
Rapidly increasing incidence of breast cancer is a new social challenge resulting from a spectrum of internal and external risk factors which appear to be well accepted as an attribute of the early twenty-first century, being, however, new for female sub-populations compared to the past. These include altered socio-economical conditions such as occupational exposure, rotating shift work, specific environmental factors (increased pollution and environmental toxicity, altered dietary habits, quality and composition of meal) as well as consequently shifted and/or adapted physiologic factors such as lower age at menarche, late age of first full-term pregnancy, if any, shorter periods of breastfeeding and later menopause. Consolidated expert statements suggest that over 50 % of all breast cancer cases may be potentially prevented by risk reduction strategy such as regulation of modifiable risk factors. Currently available risk assessment models may estimate potential breast cancer predisposition, in general; however, they are not able to predict the disease manifestation individually. Further, current deficits in risk assessment and effective breast cancer prevention have been recently investigated and summarised as follows: gaps in risk estimation, preventive therapy, lifestyle prevention, understanding of the biology of breast cancer risk and implementation of known preventive measures. This paper overviews the most relevant risk factors, provides recommendations for improved risk assessment and proposes an extended questionnaire for effective preventive measures.

Asciak R, Gouder C, Bilocca D, Montefort S
A diagnostic dilemma in a case of pulmonary inflammatory myofibroblastic tumour.
BMJ Case Rep. 2016; 2016:10.1136/bcr-2016-215168 [PubMed] Related Publications
An 18-year-old man presented to the local hospital in Malta, with dyspnoea, cough, mild haemoptysis, chest pain and night sweats. CT revealed a right hilar mass. Pleural tap, bronchoscopy and open lung biopsy were inconclusive. Biopsies obtained at repeat bronchoscopy and endobronchial ultrasound (EBUS) revealed a likely diagnosis of inflammatory myofibroblastic tumour (IMT). The patient subsequently underwent right pneumonectomy, and histology revealed the presence of two further nodules apart from the main tumour. Follow-up with positron emission tomography (PET)/CT showed the development of a right basal paracardial lesion due to recurrence and the presence of lymph node, pleural and skeletal disease. Despite radiotherapy to the recurrent nodule and chemotherapy, there was skeletal disease progression. Treatment with an anaplastic lymphoma kinase inhibitor, ceritinib, resulted in very good metabolic response. This case report highlights the importance of keeping IMT in mind when the diagnosis of lung tumours is difficult, as delayed diagnosis may lead to worsened prognosis.

Gauci D, Allemani C, Woods L
Population-level cure of colorectal cancer in Malta: An analysis of patients diagnosed between 1995 and 2004.
Cancer Epidemiol. 2016; 42:32-8 [PubMed] Related Publications
AIM: The aim of this study was to estimate the population-level 'cure' of Maltese colorectal cancer patients diagnosed between 1995 and 2004, and to estimate the median survival time for the 'uncured' patients.
METHODS AND STUDY POPULATION: Analysis was conducted on 1470 cases registered by the Malta National Cancer Register between 1995 and 2004 and followed up to end of 2010. The mean age of the patients was 66.4 (95%CI 65.8-67.1), and the number of men and women were equal. Background mortality for 1995-2010 was extracted from publicly available life tables. A mixture model with Weibull survival distribution and identity link was used to model 'cure'.
RESULTS: The overall 'cured' proportion for the patients diagnosed in 1995-1999 was 45.3% (95%CI 40.2-50.5) while the 'cured' proportion for the patients diagnosed in 2000-2004 was 52.3% (95%CI 47.2-57.5). Median survival time for the 'uncured' patients increased in the second calendar period from 1.25 years (95%CI 1.04-1.45) to 1.42 years (95%CI 1.15-1.76).
CONCLUSION: In Malta, as in the rest of Europe, improvements have been made in short- and long-term survival over the 15-year period under study. To continue this improvement, differences by age that still persist must be investigated and efforts focused to reduce any gaps between Malta and other European countries.

Trakatelli M, Barkitzi K, Apap C, et al.
Skin cancer risk in outdoor workers: a European multicenter case-control study.
J Eur Acad Dermatol Venereol. 2016; 30 Suppl 3:5-11 [PubMed] Related Publications
BACKGROUND: Exposure to ultraviolet radiation (UVR) is the most important external risk factor for skin cancer. Outdoor workers, who are exposed to high ambient UVR levels are at increased risk.
OBJECTIVE: To compare outdoor with indoor workers in terms of: (i) skin cancer risk factors, and (ii) risk of developing skin cancer.
METHODS: Using descriptive methods and a large multicenter European case-control study, we compared risk factor patterns between outdoor (N = 1416) and indoor workers (N = 1863). Risk of developing basal cell carcinoma (BCC), squamous cell carcinoma (SCC), melanoma and actinic keratosis (AK) were analysed by type of work using multivariate logistic regression models, for three categories of work: indoor; farming/construction; other outdoor work.
RESULTS: Although skin phototype was equally distributed by type of work, significantly less outdoor than indoor workers used sunscreen in their own country (44.3% vs. 60.2%), but had more outdoor hobbies (66.2% vs. 58.2%). Outdoor workers had lower educational levels, and felt less confident in understanding medical information and filling medical forms (all P < 0.001). Outdoor workers had more signs of photodamage (78.1% vs. 65.5%) and among the skin cancer patients, 37.7% of outdoor workers vs. 28.6% of indoor workers had ≥2 skin cancers diagnosed during their lifetime. Multivariate logistic regression models showed significantly increased risk of outdoor vs. indoor work for AK (ORother outdoor = 1.55, ORfarming/construction = 2.58), SCC (ORother outdoor = 1.32, ORfarming/construction = 2.77) and BCC (ORother outdoor = 1.53, ORfarming/construction = 1.83). No significant associations were found for melanoma. The risk of all types of skin cancer and AK was significantly increased for workers with ≥5 years of outdoor work.
CONCLUSIONS: Outdoor workers had more risk behaviour with similar constitutional skin cancer risk factors: more UV exposure (both occupational and leisure) and less sunscreen use and lower health literacy. This results in higher exposure, more photodamage and an increased risk of developing AK, BCC and SCC.

Okkalides D
The Result of Multiple I-131 Treatments on the Effective Half-Life of Retained Radioactivity in Patients Ablated for Differentiated Thyroid Cancer: Possible Evidence for Thyroid Remnant Function Impairment.
Cancer Biother Radiopharm. 2016; 31(2):58-64 [PubMed] Related Publications
The ablation of differentiated thyroid cancer by ingested I-131 depends on the activity absorbed by the remnant. This depends on the function of the thyroid cells and on the rate that radioactivity is excreted from the blood. The reduction of radioiodine is described by the effective half-life (EHL), which is the time taken to half the retained radioactivity. If the tumor recurs, more treatments are prescribed, often with escalating activities. Patients may receive several treatments during the evolution of the disease, and the total radioactivity administered (TRA) is the sum of all such activities. The patients' archived information permitted the calculation of EHL and TRA. The patient cohort processed here comprised 274 females and 101 males treated during 1997 to 2015. The TRA to the patients ranged between 1.1 and 129.5 GBq (average = 7.93 ± 9.9 GBq) and the EHL varied between 5.06 and 43.87 hours (average = 14.13 ± 5.7 hours). The data were processed as follows: (a) the EHL corresponding to the last treatment of each patient was plotted against TRA to patients who were treated once and to those treated several times for comparison and (b) using a small subgroup of 16 patients who were treated at least 5 times, the EHL and TRA corresponding to each treatment of each patient were plotted. A function of the form y = p-k·ln(x) was fitted on the data in all graphs and k was calculated. For patients treated once, EHL was independent of TRA. A decrease was seen in (a) multitreated patients, with the gradient (k) ranging between -0.541 and -13.880 and (b) 13 out of 16 patients, with the gradient (k) ranging between -5.55 and -31.17, both indicating an impairment of the remnant function, perhaps identified as "stunning." Since this is not avoidable, the uptake may be boosted by splitting the prescribed activity into low radioactivity fractions, which will also reduce patient hospitalization.

Lanciotti A, Brignone MS, Visentin S, et al.
Megalencephalic leukoencephalopathy with subcortical cysts protein-1 regulates epidermal growth factor receptor signaling in astrocytes.
Hum Mol Genet. 2016; 25(8):1543-58 [PubMed] Related Publications
Mutations in the MLC1 gene, which encodes a protein expressed in brain astrocytes, are the leading cause of MLC, a rare leukodystrophy characterized by macrocephaly, brain edema, subcortical cysts, myelin and astrocyte vacuolation. Although recent studies indicate that MLC1 protein is implicated in the regulation of cell volume changes, the exact role of MLC1 in brain physiology and in the pathogenesis of MLC disease remains to be clarified. In preliminary experiments, we observed that MLC1 was poorly expressed in highly proliferating astrocytoma cells when compared with primary astrocytes, and that modulation of MLC1 expression influenced astrocyte growth. Because volume changes are key events in cell proliferation and during brain development MLC1 expression is inversely correlated to astrocyte progenitor proliferation levels, we investigated the possible role for MLC1 in the control of astrocyte proliferation. We found that overexpression of wild type but not mutant MLC1 in human astrocytoma cells hampered cell growth by favoring epidermal growth factor receptor (EGFR) degradation and by inhibiting EGF-induced Ca(+) entry, ERK1/2 and PLCγ1 activation, and calcium-activated KCa3.1 potassium channel function, all molecular pathways involved in astrocyte proliferation stimulation. Interestingly, MLC1 did not influence AKT, an EGFR-stimulated kinase involved in cell survival. Moreover, EGFR expression was higher in macrophages derived from MLC patients than from healthy individuals. Since reactive astrocytes proliferate and re-express EGFR in response to different pathological stimuli, the present findings provide new information on MLC pathogenesis and unravel an important role for MLC1 in other brain pathological conditions where astrocyte activation occurs.

Clark E, Boffa M, Magri C, Muscat V
Chlorambucil-Induced Radiation Recall Dermatitis.
Skinmed. 2015 Jul-Aug; 13(4):317-9 [PubMed] Related Publications
A 65-year-old woman was diagnosed with low-grade non-Hodgkin lymphoma (Figure 1). She was treated with six cycles of cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), and prednisolone (CHOP) and three cycles of fludarabine and mitoxantrone. Ten months later she received radiotherapy to the left groin (total dose of 50 Gy in 25 fractions over 5 weeks) without complications.

Cserni G, Wells CA, Kaya H, et al.
Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers.
Virchows Arch. 2016; 468(4):473-81 [PubMed] Related Publications
Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100% agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.

Barbaric J, Sekerija M, Agius D, et al.
Disparities in melanoma incidence and mortality in South-Eastern Europe: Increasing incidence and divergent mortality patterns. Is progress around the corner?
Eur J Cancer. 2016; 55:47-55 [PubMed] Related Publications
INTRODUCTION: Most countries in South-Eastern Europe (SEE) have lower incidence, but higher mortality rates of malignant melanoma (MM) of the skin compared to North-Western Europe (NWE). We explored trends in MM incidence and mortality in SEE countries by sex and age and compared them with the trends in NWE.
METHODS: We obtained data on incident cases and deaths from MM (ICD-10 code C43) from 11 population-based cancer registries in Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Malta, Romania, Serbia, Slovakia, Slovenia and Turkey. We calculated age-specific rates for 25-49 ('young'), 50-69 ('middle aged') and 70+ years ('older') and estimated the average annual percent of change in incidence and mortality trends 2000-2010 according to age group and sex, using joinpoint regression analysis.
FINDINGS: The incidence rates of MM across the region were uniformly increasing. Significant increases in mortality rates were observed in middle aged men in Serbia and Bulgaria, middle aged women in Slovenia, older men in the Czech Republic, Serbia and Turkey, and older women in Slovenia and Serbia.
INTERPRETATION: While MM incidence rates were still increasing across SEE, mortality trends diverged and were less favourable than in NWE. Empowering cancer registration and improving the quality of incidence and mortality data will be essential for monitoring progress in MM control. In the context of prevention of melanoma, disparities in early detection appear to be widening the gap between SEE and NWE, while the provision of care to patients with advanced disease is likely to prove a challenge for regional healthcare budgets.

Bartolo K, Fsadni P
Stridor: a rare presentation of oesophageal malignancy.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
A middle-aged ex-smoker, with a history of curative surgery for oesophageal squamous cell carcinoma 7 years earlier, presented to the casualty department at Mater Dei Hospital with stridor and a 2-week history of progressively worsening dyspnoea. A thoracic CT scan showed the presence of a posterior mediastinal mass involving the upper half of the stomach and posterior wall of the trachea. Histology of an exophytic ulcerating lesion at 25 cm of the oesophagus was that of squamous cell carcinoma. Bronchoscopy performed to ascertain the cause of the stridor showed the trachea to be 70% occluded. The patient showed symptomatic improvement with radiotherapy and intravenous dexamethasone; however, he passed away a few weeks later due to respiratory failure secondary to tracheal occlusion.

Pchejetski D, Alfraidi A, Sacco K, et al.
Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer.
J Cancer Res Clin Oncol. 2016; 142(8):1659-71 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the non-specific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets.
METHODS: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription.
RESULTS AND CONCLUSION: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies.

Alshaker H, Sacco K, Alfraidi A, et al.
Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma.
Oncotarget. 2015; 6(34):35556-63 [PubMed] Free Access to Full Article Related Publications
The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited.Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive.Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies.

Karalexi MA, Papathoma P, Thomopoulos TP, et al.
Childhood central nervous system tumour mortality and survival in Southern and Eastern Europe (1983-2014): Gaps persist across 14 cancer registries.
Eur J Cancer. 2015; 51(17):2665-77 [PubMed] Related Publications
AIM: Childhood central nervous system (CNS) tumour registration and control programs in Southern and Eastern Europe remain thin, despite the lethal nature of the disease. Mortality/survival data were assembled to estimate the burden of malignant CNS tumours, as well as the potential role of sociodemographic survival determinants across 14 cancer registries of this region.
METHODS: Average age-adjusted mortality rates were calculated, whereas time trends were quantified through Poisson and Joinpoint regressions. Kaplan-Meier curves were derived for the maximum and the more recent (10 and 5 year) registration periods. Multivariate Cox regression models were used to assess demographic and disease-related determinants.
RESULTS: Variations in mortality (8-16 per million) and survival (5-year: 35-69%) were substantial among the participating registries; in most registries mortality trend was stable, whereas Bulgaria, having the highest starting rate, experienced decreasing annual mortality (-2.4%, p=0.001). A steep decrease in survival rates was evident before the second year of follow-up. After controlling for diagnostic subgroup, age, gender and diagnostic year, Greece seemed to present higher survival compared with the other contributing registries, although the follow-up period was short. Irrespective of country, however, rural residence was found to impose substantial adverse repercussions on survival (hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.1-1.4).
CONCLUSION: Cross-country mortality and survival variations possibly reflect suboptimal levels of health care delivery and cancer control in some regions of Southern and Eastern Europe, notwithstanding questionable death certification patterns or follow-up procedures. Continuous childhood cancer registration and linkage with clinical data are prerequisite for the reduction of survival inequalities across Europe.

Pace JL
Acne - a potential skin marker of internal disease.
Clin Dermatol. 2015 Sep-Oct; 33(5):572-8 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in adult women. Hyperandrogenism is the crux of the pathogenesis of both acne and hirsutism, the most frequent clinical presentations of the syndrome. The chronic anovulation that may occur, often but not always associated with enlarged cystic ovaries, has long been recognized as an important feature of PCOS. In recent years major changes have occurred with regard to PCOS: Although management of the common cutaneous manifestations, mainly acne, hirsutism, alopecia, and acanthosis nigricans, remains strictly within the realm of daily dermatologic practice, the pendulum is shifting toward greater awareness of the longer-term systemic implications of PCOS, with emphasis on the unique opportunity and privileged position of the dermatologist to diagnose this potentially serious problem at an early stage, when effective long-term treatment can be instituted. Patients need to be advised that PCOS cannot be cured but can be controlled. Management should involve a multidisciplinary team with emphasis on lifestyle change, insulin sensitizing agents, androgen blockers, and attention to specific cutaneous manifestations.

Buhagiar A, Ayers D
Chemoresistance, cancer stem cells, and miRNA influences: the case for neuroblastoma.
Anal Cell Pathol (Amst). 2015; 2015:150634 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma is a type of cancer that develops most often in infants and children under the age of five years. Neuroblastoma originates within the peripheral sympathetic ganglia, with 30% of the cases developing within the adrenal medulla, although it can also occur within other regions of the body such as nerve tissue in the spinal cord, neck, chest, abdomen, and pelvis. MicroRNAs (miRNAs) regulate cellular pathways, differentiation, apoptosis, and stem cell maintenance. Such miRNAs regulate genes involved in cellular processes. Consequently, they are implicated in the regulation of a spectrum of signaling pathways within the cell. In essence, the role of miRNAs in the development of cancer is of utmost importance for the understanding of dysfunctional cellular pathways that lead to the conversion of normal cells into cancer cells. This review focuses on highlighting the recent, important implications of miRNAs within the context of neuroblastoma basic research efforts, particularly concerning miRNA influences on cancer stem cell pathology and chemoresistance pathology for this condition, together with development of translational medicine approaches for novel diagnostic tools and therapies for this neuroblastoma.

Jeremic B, Fidarova E, Sharma V, et al.
The International Atomic Energy Agency (IAEA) randomized trial of palliative treatment of incurable locally advanced non small cell lung cancer (NSCLC) using radiotherapy (RT) and chemotherapy (CHT) in limited resource setting.
Radiother Oncol. 2015; 116(1):21-6 [PubMed] Related Publications
BACKGROUND: To optimize palliation in incurable locally advanced non-small cell lung cancer (NSCLC), the International Atomic Energy Agency conducted a prospective randomized study (NCT00864331) comparing protracted palliative radiotherapy (RT) course with chemotherapy (CHT) followed by short-course palliative RT.
METHODS AND MATERIALS: Treatment-naive patients with histologically confirmed NSCLC, stage IIIA/IIIB, received either 39Gy in 13 fractions as RT alone (arm A, n=31) or 2-3 platinum-based CHT cycles followed by 10Gy in a single fraction or 16Gy in 2 fractions separated by one week (arm B, n=34). Primary outcome was overall survival.
RESULTS: Treatment groups were balanced with respect to various variables. Median survival for all 65 patients was 8months, while median survival was 7.1 and 8.1months for the two arms, respectively (log-rank p=0.4 by study arm, and p=0.6 by Cox regression and stratified by country and sub-stage). One and three year survival rates for the two arms were 29%, and 9% and 41%, and 6%, respectively. There were no differences in any of the following endpoints: any failure, local failure, regional failure, contralateral thoracic failure, and distant failure between the two arms. High-grade (⩾3) toxicity was similar between the two arms. Symptoms, adverse events of any kind, KPS and body-mass index, were not different during treatment and during follow-up. There was no grade 5 toxicity.
CONCLUSIONS: This incomplete and underpowered trial only hinted similar outcome between the treatment arms. Therefore, combined CHT-RT can perhaps be considered, in limited resource setting, where access to RT remains inadequate.

Rizzo C, Vella S, Cachia MJ
Refractory hypocalcaemia complicating metastatic prostatic carcinoma.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
A 72-year-old man with a background of ischaemic heart disease was referred to the accident and emergency department with a 1-week history of worsening dyspnoea and lethargy. A chest X-ray revealed a right-sided lobar pneumonia and a prolonged corrected QT interval was noted on his ECG at presentation. Laboratory investigations confirmed severe hypocalcaemia, significant vitamin D deficiency and relative hypoparathyroidism. A markedly elevated prostate-specific antigen was also identified. Bone scintigraphy demonstrated widespread osteoblastic bone metastases. Severe hypocalcaemia persisted despite treatment and he succumbed after 60 days of hospitalisation.

Sladden D, Yamagata K, Pllaha E, Busuttil W
Squamous cell carcinoma of unknown origin metastasising to the right atrium causing acute heart failure.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
We describe a case of metastasis to the heart, which was initially suspected to be a myxoma, causing acute right heart failure. Emergency surgery was carried out by opening the right atrium and superior vena cava, and debulking the tumour in a piecemeal fashion, providing temporary relief of symptoms. The histology showed this to be metastatic squamous cell carcinoma possibly of head and neck origin. This is extremely rare, with few published cases. Full endoscopic and CT, including positron emission tomography CT, investigation of the head and neck was performed with no primary findings. Only two such cases of squamous cell carcinoma of unknown origin metastasising to the heart have been described, and, in both cases, the patients died within several weeks of diagnosis. This patient remains alive 2 months postoperatively and is receiving radiotherapy to the chest, but his prognosis remains poor.

Karageorgos I, Mizzi C, Giannopoulou E, et al.
Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach.
Hum Genomics. 2015; 9:12 [PubMed] Free Access to Full Article Related Publications
Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance.

Baron B, Wang Y, Maehara S, et al.
Resistance to gemcitabine in the pancreatic cancer cell line KLM1-R reversed by metformin action.
Anticancer Res. 2015; 35(4):1941-9 [PubMed] Related Publications
BACKGROUND/AIM: The pancreatic cancer cell line KLM1 can gain chemoresistance following gemcitabine (GEM) treatment. Metformin was found to be a useful sensitising agent towards GEM treatment following gain of chemoresistance.
MATERIALS AND METHODS: The proliferation of GEM-sensitive and -resistant cells was investigated over a range of metformin concentrations from 0.005 to 5 mM. The intra- and extra-cellular energetic profiles of these two cell types under metformin exposure were investigated through adenosine triphosphate (ATP) and L-lactate assays.
RESULTS: There was an unexpected decrease in intracellular L-lactate following gain of chemoresistance, despite observable medium acidification. At the biochemical level, a marked effect on phosphorylated proteins upstream of Akt, along the mTOR pathway, was observed at 6 h. These changes followed a time-dependent pattern linked closely to the changes in the energetic profile.
CONCLUSION: Together, these results indicate that metformin indirectly blocks protein phosphorylation, including that of heat shock protein 27 (HSP27).

Baron B, Fujioka T, Kitagawa T, et al.
Comparative proteomic analysis of two stress-management strategies in pancreatic cancer.
Cancer Genomics Proteomics. 2015 Mar-Apr; 12(2):83-7 [PubMed] Related Publications
BACKGROUND: It is known that cancers adopt different strategies to cope with stress and overcome adverse micro-environmental conditions. Such strategies are also applicable to chemo-therapeutic treatment, which could subsequently result in chemo-resistance.
MATERIALS AND METHODS: In order to investigate known stress-evasion strategies observed in pancreatic cancer, the stress-resistant KLM1-derived cell lines KLM1-R (Gemcitabine (GEM)-induced stress) and KLM1-S (growth factor restriction-induced stress) were employed. Comparative proteomics were employed between for the two cell lines that were also compared against the parent cell line KLM1.
RESULTS: Proteomic analysis revealed changes in the expression levels of 6 proteins, namely: transitional endoplasmic reticulum ATPase, lamin A/C, PDZ and LIM protein 1, calmodulin, heat shock protein 60 and alpha enolase. Resistance to GEM of KLM1-R and KLM1-S was found to be comparable, with KLM1-S cells exhibiting close to 1.5-fold higher half-maximal inhibitory concentration (IC50) compared to KLM1-R cells.
CONCLUSION: These results suggest that KLM1-R can be used as a model of directly-acquired chemoresistance (responding directly to evade GEM treatment), while KLM1-S is a good model of indirectly-acquired chemoresistance (formed in response to having to survive with less availability of growth factors), additionally gaining a selective advantage upon GEM treatment.

Baron B, Kitagawa T, Nakamura K, Kuramitsu Y
Isolation of a growth factor stress-induced pancreatic cancer sub-population: insight into changes due to micro-environment.
Cancer Genomics Proteomics. 2015 Mar-Apr; 12(2):49-55 [PubMed] Related Publications
BACKGROUND: Micro-environment plays a crucial role in determining the phenotypes within a tumor.
MATERIALS AND METHODS: In order to understand how the micro-environment affects pancreatic cancer, KLM1 cells were cultured under growth factor stress by culturing in foetal bovine serum (FBS)-free and reduced (1%) medium over several passages to mimic the core of a solid tumor with low vascularisation.
RESULTS: Proteomic analysis on these conditioned pancreatic cancer cells, called KLM1-S, compared to the parent cell line KLM1 revealed that a number of proteins including α-enolase, GAPDH, GRP78, HSP60 and STIP-1 were dysregulated. Additionally, KLM1-S cells exhibited a 250-fold increase in half-maximal inhibitory concentration (IC50) over the parent cell line KLM1.
CONCLUSION: By decreasing their replication rate and levels of intracellular reactive oxygen species (ROS), KLM1-S cells are able to resist gemcitabine (GEM). The results obtained suggest that in KLM1 different phenotypes are a result of cellular plasticity rather than a committed transformation.

Micallef S, Micallef D, Schembri-Wismayer P, et al.
Chemoprevention of breast cancer among women at elevated risk as defined by Gail Score.
Minerva Ginecol. 2015; 67(4):335-52 [PubMed] Related Publications
The risk of an individual woman to develop breast cancer over a 5-year period can be estimated using the Gail Model. The risk factors included in this model effectively classify patients into two different subgroups. One subgroup comprises patients at increased risk because of increased exposure to estrogen. These women are more likely to benefit from endocrine chemopreventive therapies, namely selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The second subgroup comprises women who have inherited genetic mutations that predispose them to breast cancer. Chemoprevention in these patients is more likely to be achieved by novel agents, such as lapatinib, gefitinib, fenretinide, rexinoids and poly(ADP-ribose) polymerase (PARP)-inhibitors.

Buttigieg EL, Grima KB, Cortis K, et al.
An evaluation of the use of oral contrast media in abdominopelvic CT.
Eur Radiol. 2014; 24(11):2936-44 [PubMed] Related Publications
OBJECTIVES: To evaluate the diagnostic efficacy of different oral contrast media (OCM) for abdominopelvic CT examinations performed for follow-up general oncological indications. The objectives were to establish anatomical image quality criteria for abdominopelvic CT; use these criteria to evaluate and compare image quality using positive OCM, neutral OCM and no OCM; and evaluate possible benefits for the medical imaging department.
METHODS: Forty-six adult patients attending a follow-up abdominopelvic CT for general oncological indications and who had a previous abdominopelvic CT with positive OCM (n = 46) were recruited and prospectively placed into either the water (n = 25) or no OCM (n = 21) group. Three radiologists performed absolute visual grading analysis (VGA) to assess image quality by grading the fulfilment of 24 anatomical image quality criteria.
RESULTS: Visual grading characteristics (VGC) analysis of the data showed comparable image quality with regards to reproduction of abdominal structures, bowel discrimination, presence of artefacts, and visualization of the amount of intra-abdominal fat for the three OCM protocols.
CONCLUSION: All three OCM protocols provided similar image quality for follow-up abdominopelvic CT for general oncological indications.
KEY POINTS: • Positive oral contrast media are routinely used for abdominopelvic multidetector computed tomography • Experimental study comparing image quality using three different oral contrast materials • Three different oral contrast materials result in comparable CT image quality • Benefits for patients and medical imaging department.

Gatt A, Bonello F, Buttigieg R, et al.
Flow cytometry and thromboelastography to assess platelet counts and coagulation in patients with haematological malignancies.
Blood Transfus. 2014; 12(4):479-84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accurate platelet counts (PC) are necessary in order to follow recommendations for prophylactic platelet transfusion. We carried out a study comparing the standard way of counting platelets using a routine analyser and compared it with PC determined by flow cytometry (FC) and haemostatic data obtained with thromboelastography (TEG).
MATERIALS AND METHODS: The study was carried out on 24 patients with haematological malignancies, all given one adult dose of platelets. The PC was determined before and after transfusion using an automated blood cell counter and FC. Citrated, "native" whole blood TEG was carried out before and after platelet transfusion to assess global haemostasis.
RESULTS: No bleeding was observed in any of the subjects. Thirty-one assessments were performed in the 24 patients. The mean pre-transfusion PC were 9.8 and 13×10(9)/L with the automated counter and FC, respectively with a difference of 3.7 (p=0.0011). Excellent correlation was observed between the two counts (r=0.89; p<0.0001). Mean post-transfusion increments were 23 and 29×10(9)/L for the routine counter and FC, respectively. Using the immunological PC, patients would not have qualified for transfusion in 18.2% of cases since their PC was >20×10(9)/L. TEG showed a shortened reaction time in 69.6% of cases and a normal mean K time of 6.7 min. Only 9% had a low α angle signifying hypocoagulability. The maximum amplitude was reduced in the majority of cases but normal in 25% despite PC<20×10(9)/L. Mean activated partial thromboplastin time, prothrombin time and fibrinogen were normal prior to transfusion.
DISCUSSION: Although higher PC as assessed by FC could potentially have an impact on platelet transfusion practices, TEG was sensitive enough to detect PC<10×10(9)/L and some between 10-20×10(9)/L. Whether patients with the latter PC are more prone to bleeding remains to be verified in larger studies.

Formosa R, Vassallo J
cAMP signalling in the normal and tumorigenic pituitary gland.
Mol Cell Endocrinol. 2014; 392(1-2):37-50 [PubMed] Related Publications
cAMP signalling plays a key role in the normal physiology of the pituitary gland, regulating cellular growth and proliferation, hormone production and release. Deregulation of the cAMP signalling pathway has been reported to be a common occurrence in pituitary tumorigenesis. Several mechanisms have been implicated including somatic mutations, gene-gene interactions and gene-environmental interactions. Somatic mutations in G-proteins and protein kinases directly alter cAMP signalling, while malfunctioning of other signalling pathways such as the Raf/MAPK/ERK, PI3K/Akt/mTOR and Wnt pathways which normally interact with the cAMP pathway may mediate indirect effects on cAMP and varying downstream effectors. The aryl hydrocarbon receptor signalling pathway has been implicated in pituitary tumorigenesis and we review its role in general and specifically in relation to cAMP de-regulation.

Miglio U, Oldani A, Mezzapelle R, et al.
KRAS mutational analysis in ductal adenocarcinoma of the pancreas and its clinical significance.
Pathol Res Pract. 2014; 210(5):307-11 [PubMed] Related Publications
Mutations of KRAS are detectable in 70-90% of pancreatic duct adenocarcinomas (PDAC), using direct sequencing. We used a highly sensitive molecular method in order to investigate: (a) the frequency and prognostic significance of different KRAS mutations and, (b) whether the presence of KRAS mutations in histologically-negative resection margins of PDAC could explain local tumor recurrence after surgery. Twenty-seven patients with histologic diagnosis of PDAC, radical pancreaticoduodenectomy and histologically-negative margins were evaluated. KRAS mutations were searched for mutant-enriched PCR in tumor and negative resection margins. KRAS mutations were detected in 85.2% of the cases; the most frequent mutation was G12D (48.1%). Shorter OS was found in patients with G12D (25 months; 95% CI, 20.5-29.5), vs patients with other mutations (31.5 months; 95% CI, 25.6-37.1) (N.S.). KRAS mutation in histologically-negative margins was detected in one patient who died of locoregional recurrence; six patients had tumor recurrence but no mutations in surgical margins. The high frequency of KRAS mutations suggests a search for KRAS status to improve the diagnosis in suspected cases; the G12D mutation could be related to poor prognosis, but without statistical significance. No correlation was found between the frequency of cancer recurrence and KRAS mutations in surgical margins.

Torpiano P, Borg E, Cassar PJ, Manche' A
Intrathoracic schwannoma with Horner syndrome.
BMJ Case Rep. 2013; 2013 [PubMed] Free Access to Full Article Related Publications
Horner syndrome (HS) results from the interruption of the sympathetic pathway to the eye and face, and describes a collection of signs consisting of ipsilateral miosis, partial ptosis, anhidrosis and apparent enophthalmos. It is a clinical observation, and has a plethora of possible causes, ranging from the benign to the malignant. Involvement of the stellate ganglion on the sympathetic chain by malignant tumours of the lung is a well-recognised cause of HS. On the other hand, HS secondary to the excessive growth of a benign intrathoracic neoplasm is a very rare finding, with only a few cases described in the literature. Our patient was found to have such a diagnosis when he presented to medical attention with a 1-month history of cough that was associated with features of HS that he had ignored for the preceding 9 years.

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