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Sweden: cancer statistics from IARC GlobalCan (2012)

Population in 2012: 9.5m
People newly diagnosed with cancer (excluding NMSC) / yr: 50,500
Age-standardised rate, incidence per 100,000 people/yr: 270.0
Risk of getting cancer before age 75:27.8%
People dying from cancer /yr: 22,100

Menu: Swedish Cancer Resources

Swedish Cancer Organisations
Cancer Centres in Sweden
Latest Research Publications from Sweden

Swedish Cancer Organisations (16 links)

Cancer Centres in Sweden (6 links)

Latest Research Publications from Sweden

Floodeen H, Lindgren R, Hallböök O, Matthiessen P
Evaluation of long-term anorectal function after low anterior resection: a 5-year follow-up of a randomized multicenter trial.
Dis Colon Rectum. 2014; 57(10):1162-8 [PubMed] Related Publications
BACKGROUND: Anorectal function after rectal surgery with low anastomosis is often impaired. Outcome of long-term anorectal function is poorly understood but may improve over time.
OBJECTIVE: We evaluated anorectal function 5 years after low anterior resection for cancer with regard to whether patients had a temporary stoma at initial resection. The objective of this study was to assess changes in anorectal function over time by comparing the results with anorectal function 1 year after rectal resection.
DESIGN: This study was a secondary end point of a randomized, multicenter controlled trial.
SETTINGS: The study was conducted at 21 Swedish hospitals performing rectal cancer surgery from 1999 to 2005.
PATIENTS: Patients included were those operated on with low anterior resection.
INTERVENTIONS: Patients were randomly assigned to receive or not receive a defunctioning stoma.
MAIN OUTCOME MEASURES: We evaluated anorectal function in patients who were initially randomly assigned to the defunctioning stoma or no stoma group, who had been free of stoma for 5 years, by means of using a standardized patient questionnaire. Questions addressed stool frequency, urgency, fragmentation of bowel movements, evacuation difficulties, incontinence, lifestyle alterations, and patient preference regarding permanent stoma formation. Results were compared with the same patient cohort at 1-year follow-up.
RESULTS: A total of 123 patients answered the bowel function questionnaire (65 in the no-stoma group and 58 in the stoma group). No differences were found between groups regarding the number of passed stools, need for medication to open the bowel, evacuation difficulties, incontinence, and urgency. General well-being was significantly better in the no-stoma group (p = 0.033). Comparison with anorectal function at 1 year showed no further changes over time.
LIMITATIONS: The study was based on a limited sample size (n = 123) and formed a secondary end point of a randomized trial.
CONCLUSIONS: Anorectal function was impaired for many patients, but the temporary presence of a defunctioning stoma after rectal resection did not affect long-term outcome. Anorectal function did not change between 1-year and 5-year follow-up.
1Department of Surgery, Örebro University Hospital, Örebro, Sweden 2Department of Surgery, Linköping University Hospital, Linköping, Sweden 3Örebro University, Örebro, Sweden.

Holme Ø, Løberg M, Kalager M, et al.
Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: a randomized clinical trial.
JAMA. 2014; 312(6):606-15 [PubMed] Related Publications
IMPORTANCE: Colorectal cancer is a major health burden. Screening is recommended in many countries.
OBJECTIVE: To estimate the effectiveness of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality in a population-based trial.
DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 100,210 individuals aged 50 to 64 years, identified from the population of Oslo city and Telemark County, Norway. Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 31, 2011. Of those selected, 1415 were excluded due to prior colorectal cancer, emigration, or death, and 3 could not be traced in the population registry.
INTERVENTIONS: Participants randomized to the screening group were invited to undergo screening. Within the screening group, participants were randomized 1:1 to receive once-only flexible sigmoidoscopy or combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT). Participants with positive screening test results (cancer, adenoma, polyp ≥10 mm, or positive FOBT) were offered colonoscopy. The control group received no intervention.
MAIN OUTCOMES AND MEASURES: Colorectal cancer incidence and mortality.
RESULTS: A total of 98,792 participants were included in the intention-to-screen analyses, of whom 78,220 comprised the control group and 20,572 comprised the screening group (10,283 randomized to receive a flexible sigmoidoscopy and 10,289 to receive flexible sigmoidoscopy and FOBT). Adherence with screening was 63%. After a median of 10.9 years, 71 participants died of colorectal cancer in the screening group vs 330 in the control group (31.4 vs 43.1 deaths per 100,000 person-years; absolute rate difference, 11.7 [95% CI, 3.0-20.4]; hazard ratio [HR], 0.73 [95% CI, 0.56-0.94]). Colorectal cancer was diagnosed in 253 participants in the screening group vs 1086 in the control group (112.6 vs 141.0 cases per 100,000 person-years; absolute rate difference, 28.4 [95% CI, 12.1-44.7]; HR, 0.80 [95% CI, 0.70-0.92]). Colorectal cancer incidence was reduced in both the 50- to 54-year age group (HR, 0.68; 95% CI, 0.49-0.94) and the 55- to 64-year age group (HR, 0.83; 95% CI, 0.71-0.96). There was no difference between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups.
CONCLUSIONS AND RELEVANCE: In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and FOBT reduced colorectal cancer incidence and mortality on a population level compared with no screening. Screening was effective both in the 50- to 54-year and the 55- to 64-year age groups.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00119912.

Related: Colorectal (Bowel) Cancer Cancer Screening and Early Detection
Department of Medicine, Sorlandet Hospital Kristiansand, Kristiansand, Norway2Institute of Health and Society, University of Oslo, Oslo, Norway3Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts4Department of Biostatistics Harvard School of Public Health, Boston, Mas...
Research funded by:

Norström MM, Rådestad E, Stikvoort A, et al.
Novel method to characterize immune cells from human prostate tissue.
Prostate. 2014; 74(14):1391-9 [PubMed] Related Publications
BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common benign adenoma and prostate cancer is the most frequent malignancy in men over 50 years of age in the Western world, where it remains a significant health problem. Prostate lesions are known to contain immune cells, which may contribute to the immune control of tumor progression. However, due to their low numbers and restricted access to necessary material it is difficult to isolate immune cells from prostate tissue to characterize their immunological features.
METHODS: An efficient and robust method was developed to process prostate tissue and isolate immune cells for phenotypic analysis by multicolor flow cytometry as downstream application. Fresh prostate tissue from 11 patients undergoing surgery for bladder outlet obstruction due to BPH was processed to evaluate the number, viability, yield, and frequency of various immune cell types.
RESULTS: The presented method does not include enzymatic digestion nor incubation steps at 37 °C, increasing cellular viability and avoiding possible phenotypic modification. Various immune cell populations were detected in all patient samples and the median cellular viability was 90%. The number of detected events of individual cell populations varied between patients. The median frequency of different immune cell populations also varied, being 87% for the CD3- and 15% for the CD3+ cell population.
CONCLUSIONS: This novel method will allow the phenotypic characterization of immune cell populations present in tumor tissue of prostate cancer patients and promote development of novel approaches to immunotherapy of the disease.

Related: Prostate Cancer
Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.

Arab K, Park YJ, Lindroth AM, et al.
Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A.
Mol Cell. 2014; 55(4):604-14 [PubMed] Related Publications
DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.

Related: Cancer Prevention and Risk Reduction
Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Tjörnstrand A, Gunnarsson K, Evert M, et al.
The incidence rate of pituitary adenomas in western Sweden for the period 2001-2011.
Eur J Endocrinol. 2014; 171(4):519-26 [PubMed] Related Publications
OBJECTIVE: The number of studies on the incidence of pituitary adenomas (PAs) is limited. The aim of this study was to evaluate the standardised incidence rate (SIR) of PAs in western Sweden.
DESIGN, SUBJECTS AND METHODS: Data from adult patients diagnosed with PAs in 2001-2011, living in the Västra Götaland County, were collected from the Swedish Pituitary Registry (SPR). In addition, medical records on all patients diagnosed with PAs at the six hospitals in the region were reviewed. In total, 592 patients were included in the study.Age-SIR, given as rate/100 000 inhabitants (95% CI), was calculated using the WHO 2000 standard population as a reference.
RESULTS: The total SIR for PAs was 3.9/100 000 (3.6-4.3); 3.3/100 000 (2.9-3.7) for men and 4.7/100 000 (4.1-5.3) for women. In men, SIR increased with age, while in women SIR peaked at 25-34 years, mainly due to prolactinomas. Non-functioning PA (NFPA) was the most common PA (54%, 1.8/100 000 (1.6-2.0)) followed by prolactinomas (32%, 1.6/100 000 (1.3-1.9)), acromegaly (9%, 0.35/100 000 (0.25-0.45)), Cushing's disease (4%, 0.18/100 000 (0.11-0.25)) and TSH-producing PA (0.7%, 0.03/100 000 (0.00-0.05)). The proportion of macroadenomas for NFPA was 82%, prolactinomas 37%, GH-producing PA 77%, ACTH-producing PA 28% and TSH-producing PA 100%. The lifetime risk for PAs was 0.27% (0.24-0.31) in men and 0.29% (0.26-0.33) in women.
CONCLUSION: This study provides a reliable estimate on the overall incidence of PAs and confirms an increased incidence of PAs compared with studies conducted in the pre-magnetic resonance imaging era. The lower proportion of prolactinomas compared with previous studies is probably explained by the different criteria used.

Related: Pituitary Tumors
Sahlgrenska AcademyDepartment of OncologyInstitute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenDepartment of EndocrinologySahlgrenska University Hospital, Gothenburg, Sweden

Boussemart L, Malka-Mahieu H, Girault I, et al.
eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.
Nature. 2014; 513(7516):105-9 [PubMed] Related Publications
In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.

Related: EIF4E Melanoma BRAF gene Signal Transduction Thyroid Cancer Vemurafenib (Zelboraf)
1] Inserm UMR981, Villejuif F-94805, France [2] Université Paris-Sud XI, Kremlin-Bicêtre F-94276, France [3] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France [4].

Hemdan T, Lindén M, Lind SB, et al.
The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer.
Br J Cancer. 2014; 111(6):1180-7 [PubMed] Related Publications
BACKGROUND: The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target.
METHODS: Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA.
RESULTS: In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA.
CONCLUSIONS: STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer.

Related: MKI67 TP53 Bladder Cancer Bladder Cancer - Molecular Biology
Department of Surgical Sciences, Uppsala University, Uppsala 751 85, Sweden.

Blom J, Kilpeläinen S, Hultcrantz R, Törnberg S
Five-year experience of organized colorectal cancer screening in a Swedish population - increased compliance with age, female gender, and subsequent screening round.
J Med Screen. 2014; 21(3):144-50 [PubMed] Related Publications
OBJECTIVE: To evaluate compliance by age, gender, and screening round in the population based Stockholm/Gotland colorectal cancer screening programme.
METHODS: All individuals aged between 60 and 69 living in the counties of Stockholm and Gotland (Sweden) have, since 2008, successively been included in a colorectal cancer screening programme using biennial faecal occult blood tests (Hemoccult®). Personal invitations including test kits have been sent to home addresses, and individuals with a positive test result have been called to a defined clinic for an assessment colonoscopy. Descriptive statistics have been used to evaluate different aspects of compliance.
RESULTS: Over the five-year period 2008-2012, more than 200,000 individuals from nine different birth cohorts have been invited, with a compliance rate of approximately 60%, which increased by age, female gender, and subsequent screening round. In total, 4,300 individuals (2.1%) with positive tests were referred to assessment colonoscopy, where 213 colorectal cancers were diagnosed. The compliance with the follow-up colonoscopies varied by year, and ranged from 85.6-92.4%.
CONCLUSION: The strong organization of the programme contributed to a high compliance rate, that increased by screening round. The lower participation rate among men and among individuals at younger ages needs further attention.

Related: Colorectal (Bowel) Cancer Screening for Colorectal (Bowel) Cancer Cancer Screening and Early Detection
Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Boele J, Persson H, Shin JW, et al.
PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.
Proc Natl Acad Sci U S A. 2014; 111(31):11467-72 [PubMed] Article available free on PMC after 05/02/2015 Related Publications
Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3' end, and moreover that the 3' end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3'-to-5' direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases.

Related: Cancer Prevention and Risk Reduction DICER1 miR-21
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Department of Systems Bioinformatics, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, 1081 HV, Amsterdam, The Netherlands;
Research funded by:

Cao Y
VEGF-targeted cancer therapeutics-paradoxical effects in endocrine organs.
Nat Rev Endocrinol. 2014; 10(9):530-9 [PubMed] Related Publications
Systemic administration of antiangiogenic drugs that target components of the vascular endothelial growth factor A (VEGF-A; VEGF) signal transduction pathway has become a viable therapeutic option for patients with various types of cancer. Nevertheless, these drugs can drive alterations in healthy vasculatures, which in turn are associated with adverse effects in healthy tissues. VEGF is crucial for vascular homeostasis and the maintenance of vascular integrity and architecture in endocrine organs. Given these critical physiological functions, systemic delivery of drugs that target VEGF signalling can block VEGF-mediated vascular functions in endocrine organs, such as the thyroid gland, and lead to endocrine dysfunction, including hypothyroidism, adrenal insufficiency and altered insulin sensitivity. This Review discusses emerging evidence from preclinical and clinical studies that contributes to understanding the mechanisms that underlie the vascular changes and subsequent modulations of endocrine function that are induced by targeted inhibition of VEGF signalling. Understanding these mechanisms is crucial for the design of antiangiogenic drugs with minimal associated adverse effects that will enable effective treatment of patients with cancer.

Related: Angiogenesis Inhibitors Cancer Prevention and Risk Reduction Signal Transduction VEGFA
Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Nobels vag 16, 17177 Stockholm, Sweden.

Northcott PA, Lee C, Zichner T, et al.
Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
Nature. 2014; 511(7510):428-34 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.

Related: Chromosome 9 Childhood Medulloblastoma / PNET GFI1
1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2].
Research funded by:

Tuomi L, Andréll P, Finizia C
Effects of voice rehabilitation after radiation therapy for laryngeal cancer: a randomized controlled study.
Int J Radiat Oncol Biol Phys. 2014; 89(5):964-72 [PubMed] Related Publications
BACKGROUND: Patients treated with radiation therapy for laryngeal cancer often experience voice problems. The aim of this randomized controlled trial was to assess the efficacy of voice rehabilitation for laryngeal cancer patients after having undergone radiation therapy and to investigate whether differences between different tumor localizations with regard to rehabilitation outcomes exist.
METHODS AND MATERIALS: Sixty-nine male patients irradiated for laryngeal cancer participated. Voice recordings and self-assessments of communicative dysfunction were performed 1 and 6 months after radiation therapy. Thirty-three patients were randomized to structured voice rehabilitation with a speech-language pathologist and 36 to a control group. Furthermore, comparisons with 23 healthy control individuals were made. Acoustic analyses were performed for all patients, including the healthy control individuals. The Swedish version of the Self Evaluation of Communication Experiences after Laryngeal Cancer and self-ratings of voice function were used to assess vocal and communicative function.
RESULTS: The patients who received vocal rehabilitation experienced improved self-rated vocal function after rehabilitation. Patients with supraglottic tumors who received voice rehabilitation had statistically significant improvements in voice quality and self-rated vocal function, whereas the control group did not.
CONCLUSION: Voice rehabilitation for male patients with laryngeal cancer is efficacious regarding patient-reported outcome measurements. The patients experienced better voice function after rehabilitation. Patients with supraglottic tumors also showed an improvement in terms of acoustic voice outcomes. Rehabilitation with a speech-language pathologist is recommended for laryngeal cancer patients after radiation therapy, particularly for patients with supraglottic tumors.

Related: Cancer of the Larynx Laryngeal Cancer - Molecular Biology
Department of Otorhinolaryngology, Head and Neck Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address:

Epstein JI, Egevad L, Humphrey PA, et al.
Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference.
Am J Surg Pathol. 2014; 38(8):e6-e19 [PubMed] Related Publications
The following are the International Society of Urological Pathology (ISUP) recommendations for the use of immunohistochemistry (IHC) in prostate specimens. Either high-molecular weight cytokeratin (34βE12 or CK5/6 or others) or p63 or a combination of the 2 with AMACR either in a double or triple cocktail is recommended for the workup of small foci of atypical glands suspicious for adenocarcinoma of the prostate (PCa). ERG is optional as it is present in only 40% to 50% of prostate cancers and also positive in high-grade prostatic intraepithelial neoplasia. In the setting of obvious carcinoma or benign glands, there is no justification to do basal cell stains and AMACR. If there is a Gleason score of 3+4=7 or a higher-grade cancer on at least 1 part, the workup of other parts with an atypical focus suspicious for Gleason score 3+3=6 cancer is not recommended. In the setting of Gleason score 4+3 or 4+4=8 cancer on at least 1 part, the extent of high-grade cancer could affect clinical treatment such that workup of other atypical possible high-grade cancer foci is justified. In the setting of Gleason score 4+3 or higher-grade cancer on at least 1 part, given that intraductal carcinoma in the vast majority of cases is considered extension of high-grade cancer into prostatic ducts and acini, it is not recommended in the setting of definitive invasive high-grade cancer that workup of additional cribriform lesions be pursued. In the setting of Gleason score 3+3 on at least 1 part, the number of positive cores and/or their location could possibly affect subsequent therapy in terms of suitability for active surveillance or focal therapy, such that unless one knows with certainty that it would not affect therapy, it is justified to perform an IHC workup of additional atypical foci. In the differential diagnosis of high-grade PCa versus urothelial carcinoma (UC), the primary option is to use prostate-specific antigen (PSA) as a first test to identify PCa and GATA3 to identify UC. If GATA3 is not available, then HMWCK and p63 can be used. If the tumor is PSA positive with intense staining and HMWCK and p63 negative, the findings are diagnostic of PCa. If the tumor is equivocal/weak/negative for PSA and negative/focal for p63 and HMWCK, then one needs to perform staining for P501S, NKX3.1, and GATA3. Some experts also include PAP in this second round of staining. If the tumor is negative for PSA and diffusely strongly positive for p63 and HMWCK, the findings are diagnostic of UC. If the tumor is negative for PSA and moderately to strongly positive for GATA3, it is diagnostic of UC. Laboratories should be encouraged to use GATA3 for UC and add P501S and NKX3.1 as prostate markers in addition to PSA, p63, and HMWCK. If GATA3, p501S, and NKX3.1 are not available in equivocal cases, the case should be sent out for consultation to laboratories with these antibodies. The article also covers the use of IHC in: (1) high-grade PCa versus bladder adenocarcinoma; (2) prostatic small cell carcinoma versus high-grade PCa; (3) metastatic carcinoma of unknown primary: rule out PCa; (4) nonspecific granulomatous prostatitis/xanthoma versus high-grade PCa; (5) adult prostate sarcoma versus sarcomatoid PCa; (6) colorectal adenocarcinoma versus high-grade PCa; and (7) prognostic IHC markers.

Related: Prostate Cancer
*Departments of Pathology, Urology, and Oncology, The John Hopkins Medical Institutions, Baltimore, MD ‡Department of Pathology, Yale University School of Medicine, New Haven, CT †Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden ...

Marino AM, Frijhoff J, Calero R, et al.
Effects of epigenetic modificators in combination with small molecule inhibitors of receptor tyrosine kinases on medulloblastoma growth.
Biochem Biophys Res Commun. 2014; 450(4):1600-5 [PubMed] Related Publications
Epigenetic alterations and aberrant expression of genes controlling epigenetic mechanisms have been identified in several cancers, including medulloblastoma, the most common brain tumor in children. Here we show that combining drugs that inhibit two of the most important epigenetic factors, gene methylation and post-translational modifications of protein histone-associated DNA, with small molecule inhibitors of receptor tyrosine kinases induces apoptosis. The histone deacetylation inhibitor, 4-phenylbutyrate (4-PB) and the demethylation agent, 5-Aza-2'deoxycytidine (5-Aza-dC) had minor effects on medulloblastoma cell cytotoxity in single agent treatment whereas a significant enhancement in cell cytotoxity was seen when these drugs were combined with Gleevec. Triple treatment of medulloblastoma cells with 4-PB, 5-Aza and Gleevec were associated with reduced DNA methyltransferase activity, reduced global methylation and induction of apoptosis. Taken together these results suggest that a combination of these drugs may be beneficial in the treatment of medulloblastoma.

Related: Childhood Medulloblastoma / PNET
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Rosin G, de Boniface J, Karthik GM, et al.
Oestrogen receptors β1 and βcx have divergent roles in breast cancer survival and lymph node metastasis.
Br J Cancer. 2014; 111(5):918-26 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: The expression of oestrogen receptor (ER) α characterises a subset of breast cancers associated with good response to endocrine therapy. However, the clinical significance of the second ER, ERβ1, and its splice variant ERβcx is still unclear.
METHODS: We here report an assessment of ERα, ERβ1 and ERβcx by immunohistochemistry using quantitative digital image analysis of 340 primary tumours and corresponding sentinel lymph nodes.
RESULTS: No differences were seen in ER levels in primary tumours vs lymph node metastases. ERβ1 and ERβcx were equally distributed among age groups and tumour histological grades. Loss of ERβ1 in the primary tumour was strongly associated with poor survival. Its prognostic impact was particularly evident in young patients and in high-grade tumours. The worst outcome was seen in the tumours lacking both ERα and ERβ1. ERβcx expression in the primary tumour correlated with a higher risk of lymph node metastasis, and with poor survival when expressed in sentinel node lymphocytes.
CONCLUSIONS: Our study reveals highly significant although antagonising roles of ERβ1 and ERβcx in breast cancer. Consequently, we suggest that the histopathological assessment of ERβ1 is of value as a prognostic and potentially predictive biomarker.

Related: Breast Cancer
1] Department of Oncology and Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden [2] Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 14183 Huddinge, Sweden.

Amin MB, Epstein JI, Ulbright TM, et al.
Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the International Society of Urological Pathology consensus conference.
Am J Surg Pathol. 2014; 38(8):1017-22 [PubMed] Related Publications
Members of the International Society of Urological Pathology (ISUP) participated in a half-day consensus conference to discuss guidelines and recommendations regarding best practice approaches to use of immunohistochemistry (IHC) in differential diagnostic situations in urologic pathology, including bladder, prostate, testis and, kidney lesions. Four working groups, selected by the ISUP leadership, identified several high-interest topics based on common or relevant challenging diagnostic situations and proposed best practice recommendations, which were discussed by the membership. The overall summary of the discussions and the consensus opinion forms the basis of a series of articles, one for each organ site. This Special Article summarizes the overall recommendations made by the four working groups. It is anticipated that this ISUP effort will be valuable to the entire practicing community in the appropriate use of IHC in diagnostic urologic pathology.
*Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA †Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD ‡Department of Pathology, Indiana University School of Medicine, Indianapolis, IN §Department of Pathology & ...

Lim K, Stewart J, Kelly V, et al.
Dosimetrically triggered adaptive intensity modulated radiation therapy for cervical cancer.
Int J Radiat Oncol Biol Phys. 2014; 90(1):147-54 [PubMed] Related Publications
PURPOSE: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload.
METHODS AND MATERIALS: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small PTV margin of only 3 mm to account for setup and internal interfractional motion: (1) a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT).
RESULTS: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients.
CONCLUSIONS: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost.

Related: Cervical Cancer
Department of Radiation Oncology, Liverpool Hospital, Sydney, Australia.
Research funded by:

Yu M, Bardia A, Aceto N, et al.
Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility.
Science. 2014; 345(6193):216-20 [PubMed] Related Publications
Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor-positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease.

Related: Breast Cancer ESR1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Research funded by:

Mollbrink A, Jawad R, Vlamis-Gardikas A, et al.
Expression of thioredoxins and glutaredoxins in human hepatocellular carcinoma: correlation to cell proliferation, tumor size and metabolic syndrome.
Int J Immunopathol Pharmacol. 2014 Apr-Jun; 27(2):169-83 [PubMed] Related Publications
Thioredoxins (Trx) and glutaredoxins (Grx) are thiol oxidoreductases that are ubiquitously expressed, and are involved in several biological processes. The expression of thioredoxins and glutaredoxins is induced in many neoplasms, and correlates with prognosis in gallbladder and colorectal carcinoma. The aim of the present study was to examine the expression pattern of these proteins (redoxins) in hepatocellular carcinoma (HCC) and to correlate their levels with clinical features. Paraffin-embedded tissues from 25 patients resected for HCC and 15 patients resected for colorectal carcinoma (CRC) liver metastases were analyzed with immunohistochemistry. Our results showed that Trx1, Trx2 and Grx5 were upregulated in HCCs as compared to the respective surrounding liver. In comparison, almost all redoxins were upregulated in CRC liver metastases, with Trx1 and Grx3 being significantly more increased in the CRC liver metastases than in the primary HCC tumors. In HCC, Trx1 correlated significantly with cell proliferation, and with a trend towards increased levels with micro-vascular invasion, while expression of Trx2 decreased with tumor size. Trx1 levels were lower in tumors of males, smokers, and patients with high alcohol consumption. Grx2 levels were significantly higher in patients with metabolic syndrome. In conclusion, this study illustrates specific correlations of individual redoxins to clinical features of HCC, and implicates the redoxins in the pathogenesis of HCC.

Related: Colorectal (Bowel) Cancer
Division of Gastroenterology and Hepatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Martin-Liberal J, Gil-Martín M, Sáinz-Jaspeado M, et al.
Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.
Br J Cancer. 2014; 111(5):858-65 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine.
METHODS: Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted.
RESULTS: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment.
CONCLUSIONS: Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.

Related: Cancer Prevention and Risk Reduction Gemcitabine
The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

Vaccarella S, Franceschi S, Engholm G, et al.
50 years of screening in the Nordic countries: quantifying the effects on cervical cancer incidence.
Br J Cancer. 2014; 111(5):965-9 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: Nordic countries' data offer a unique possibility to evaluate the long-term benefit of cervical cancer screening in a context of increasing risk of human papillomavirus infection.
METHODS: Ad hoc-refined age-period-cohort models were applied to the last 50-year incidence data from Denmark, Finland, Norway and Sweden to project expected cervical cancer cases in a no-screening scenario.
RESULTS: In the absence of screening, projected incidence rates for 2006-2010 in Nordic countries would have been between 3 and 5 times higher than observed rates. Over 60,000 cases or between 41 and 49% of the expected cases of cervical cancer may have been prevented by the introduction of screening in the late 1960s and early 1970s.
CONCLUSIONS: Our study suggests that screening programmes might have prevented a HPV-driven epidemic of cervical cancer in Nordic countries. According to extrapolations from cohort effects, cervical cancer incidence rates in the Nordic countries would have been otherwise comparable to the highest incidence rates currently detected in low-income countries.

Related: Cancer Screening and Early Detection Cervical Cancer Cervical Cancer Screening
International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon cedex 08, France.

Hallqvist Everhov A, Bergmark K, Smedby KE, et al.
Anti-Müllerian hormone in premenopausal women following treatment of uterine cervical cancer.
Acta Obstet Gynecol Scand. 2014; 93(9):949-53 [PubMed] Related Publications
In this longitudinal study we prospectively enrolled 32 premenopausal women (ages 23-44 years) with stage I-III uterine cervical cancer undergoing surgery and/or chemoradiation. Serum levels of anti-Müllerian hormone, follicle-stimulating hormone and estradiol were examined at baseline and 1 year after treatment. As expected, serum anti-Müllerian hormone was undetectable after salpingo-oophorectomy or chemoradiation. After radical hysterectomy and pelvic lymphadenectomy with ovarian preservation serum anti-Müllerian hormone declined from a mean value of 2.0 ± 1.4 μg/L to 1.1 ± 0.8 μg/L (p = 0.01), representing a 45% reduction, whereas there was no significant change in serum levels of follicle-stimulating hormone and estradiol. This implies that ovarian function may be affected not only by castrating treatment but also by radical hysterectomy with ovarian preservation. The risk of premature menopause and the potential need of hormone replacement therapy among these women may be overlooked since they no longer menstruate.

Related: Cervical Cancer
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.

Flejmer AM, Josefsson D, Nilsson M, et al.
Clinical implications of the ISC technique for breast cancer radiotherapy and comparison with clinical recommendations.
Anticancer Res. 2014; 34(7):3563-8 [PubMed] Related Publications
PURPOSE: The present project studied the implications of using the irregular surface compensator (ISC) technique in comparison to three-dimensional conformal radiation therapy (3D-CRT) for breast cancer treatment. ISC is an electronic compensation algorithm that modulates the fluence across the radiation fields to compensate for irregularly-shaped surfaces and deliver a homogeneous dose to a compensation plane.
PATIENTS AND METHODS: Ten breast cancer patients (five left- and five right-sided) were planned with both techniques. The planning was done for 50 Gy in 25 fractions with 2 Gy per fraction in all patients. Physical parameters such as doses to the clinical target volume (CTV-T) and the planned target volume (PTV), heterogeneity index and doses to lung and heart were determined and compared for the treatment plans.
RESULTS: The ISC technique led to significantly better coverage of the CTV-T and PTV in almost all patients with statistically significant better homogeneity of the dose distribution. The contralateral lung and the heart receive the same dose with both ISC and 3D-CRT plans. However, ISC showed a trend towards decreasing the volumes of the ipsilateral lung irradiated with high doses.
CONCLUSION: The ISC technique leads to an improvement of the target coverage and the radiation burden of the ipsilateral lung thus allowing better compliance with the national recommendations for breast radiotherapy and increasing the potential for improved quality of life for breast cancer patients. It should therefore be preferred over 3D-CRT for breast cases with difficult dose homogeneity to the PTV or CTV-T.

Related: Breast Cancer
Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

Helleday T, Eshtad S, Nik-Zainal S
Mechanisms underlying mutational signatures in human cancers.
Nat Rev Genet. 2014; 15(9):585-98 [PubMed] Related Publications
The collective somatic mutations observed in a cancer are the outcome of multiple mutagenic processes that have been operative over the lifetime of a patient. Each process leaves a characteristic imprint--a mutational signature--on the cancer genome, which is defined by the type of DNA damage and DNA repair processes that result in base substitutions, insertions and deletions or structural variations. With the advent of whole-genome sequencing, researchers are identifying an increasing array of these signatures. Mutational signatures can be used as a physiological readout of the biological history of a cancer and also have potential use for discerning ongoing mutational processes from historical ones, thus possibly revealing new targets for anticancer therapies.

Related: Cancer Prevention and Risk Reduction
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
Research funded by:

Leblanc S, Battista MC, Noll C, et al.
Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome.
Endocrinology. 2014; 155(9):3684-93 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 μU/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g·min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km (P = .009), which were strongly correlated together in all PCOS/cp rats (ρ = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.
Division of Endocrinology (S.L., M.-C.B., C.N., N.G.-P., A.C.C., J.-P.B.), Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4; Department of Medicinal Chemistry (A.H.), Biomedicinska Centrum, Uppsala University, Uppsala...
Research funded by:

Lundgren-Nilsson A, Dencker A, Jakobsson S, et al.
Construct validity of the Swedish version of the revised piper fatigue scale in an oncology sample--a Rasch analysis.
Value Health. 2014; 17(4):360-3 [PubMed] Related Publications
OBJECTIVES: Fatigue is a common and distressing symptom in cancer patients due to both the disease and its treatments. The concept of fatigue is multidimensional and includes both physical and mental components. The 22-item Revised Piper Fatigue Scale (RPFS) is a multidimensional instrument developed to assess cancer-related fatigue. This study reports on the construct validity of the Swedish version of the RPFS from the perspective of Rasch measurement.
METHODS: The Swedish version of the RPFS was answered by 196 cancer patients fatigued after 4 to 5 weeks of curative radiation therapy. Data from the scale were fitted to the Rasch measurement model. This involved testing a series of assumptions, including the stochastic ordering of items, local response dependency, and unidimensionality. A series of fit statistics were computed, differential item functioning (DIF) was tested, and local response dependency was accommodated through testlets.
RESULTS: The Behavioral, Affective and Sensory domains all satisfied the Rasch model expectations. No DIF was observed, and all domains were found to be unidimensional. The Mood/Cognitive scale failed to fit the model, and substantial multidimensionality was found. Splitting the scale between Mood and Cognitive items resolved fit to the Rasch model, and new domains were unidimensional without DIF.
CONCLUSIONS: The current Rasch analyses add to the evidence of measurement properties of the scale and show that the RPFS has good psychometric properties and works well to measure fatigue. The original four-factor structure, however, was not supported.

Related: Cancer Prevention and Risk Reduction
Centre for Person-centred Care, Institute of Health and Care Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Swed...

Pacheva I, Panov G, Gillberg C, Neville B
A girl with tuberous sclerosis complex presenting with severe epilepsy and electrical status epilepticus during sleep, and with high-functioning autism and mutism.
Cogn Behav Neurol. 2014; 27(2):88-95 [PubMed] Related Publications
Most patients with tuberous sclerosis complex (TSC) suffer from epilepsy, and many have cognitive and behavioral problems like severe intellectual disability, autism, and hyperactivity. Only rare patients with TSC and autism have a normal intelligence quotient. We report a 13-year-old girl with definite TSC who had early-onset severe epilepsy, autistic behavior, and moderate developmental delay. By school age, however, she had normal intelligence; her intelligence quotient was at least 70 based on a Stanford-Binet test that she refused to complete. She showed good reading, writing, and language comprehension skills, and the special abilities of hyperlexia, hypermnesia, and hypercalculia. However, she did not speak. Criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and her Childhood Autism Rating Scale score of 36 indicated mild to moderate autism. She had severe electroencephalographic abnormalities: hypsarrhythmia, multifocal or generalized epileptiform discharges, and electrical status epilepticus during sleep, with a continuous left temporal focus. Magnetic resonance imaging showed many cortical tubers in all brain lobes, and subependymal nodules. We discuss possible explanations for her lack of speech. Considered as speech apraxia, her mutism could be either a symptom of her TSC or a component of her autism. Another possibility is that long-lasting electrical status epilepticus during sleep led to her autistic behavior and language arrest. Still another possibility is that a disinhibited mammalian target of rapamycin (mTOR) pathway was at the root of all of her neuropsychiatric symptoms.

Related: Signal Transduction
*Department of Pediatrics and Medical Genetics, Medical University, Plovdiv, Bulgaria †Neurology and Neurophysiology Unit, Hospital Stoyan Kirkovich, Stara Zagora, Bulgaria ‡Department of Child and Adolescent Psychiatry, Gothenburg University, Gothenburg, Sweden §Neurosciences Unit...

Drake I, Wallström P, Hindy G, et al.
TCF7L2 type 2 diabetes risk variant, lifestyle factors, and incidence of prostate cancer.
Prostate. 2014; 74(12):1161-70 [PubMed] Related Publications
BACKGROUND: Variation in transcription factor 7-like 2 (TCF7L2), the strongest genetic risk factor for type 2 diabetes (T2D), may play a role in prostate cancer (PCa) depending on lifestyle factors. The aims of this study were to determine if TCF7L2 rs7903146 is associated with risk of PCa and if the association is modified by lifestyle factors independently of T2D status.
METHODS: We prospectively followed 8,558 men in the Malmö Diet and Cancer Study from baseline 1991-1996 until end of 2009. Cox regression models were used to assess the association between rs7903146 T2D-risk allele (T) and PCa. Effect modification by incident T2D status, fasting glucose levels, dietary, and lifestyle risk factors were tested.
RESULTS: During follow-up 855 incident PCa cases were registered. We observed a non-significant tendency for the TCF7L2 variant to associate with higher risk of PCa, which was unaffected by adjustment for incident T2D (HR = 1.24; 95% CI: 0.96, 1.60; P = 0.079) but more pronounced among subjects who developed T2D (HR = 1.91, 95% CI: 0.88, 4.14; P = 0.064). In a sub-sample of hyperglycemic men we observed an increased risk of PCa among T-allele carriers (HR = 2.72, 95% CI: 1.22, 6.04; P = 0.014; P(interaction)  = 0.056). T-allele carriers with higher number of lifestyle risk factors had an increased risk of PCa (P(interaction)  = 0.006).
CONCLUSIONS: We found no independent association between TCF7L2 rs7903146 and PCa risk. However, among hyperglycemic men we observed that the risk allele may increase risk of PCa. The association between rs7903146 and PCa risk may also be modified by lifestyle factors.

Related: Prostate Cancer
Department of Clinical Sciences in Malmö, Research Group in Nutritional Epidemiology, Lund University, Lund, Sweden.

Sclafani F, Gonzalez D, Cunningham D, et al.
TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial.
J Natl Cancer Inst. 2014; 106(7) [PubMed] Related Publications
In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P < .05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS.

Related: TP53 Cetuximab (Erbitux)
Affiliations of authors: Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey, UK (FS, DG, DC, SHW, SP, AD, AW, GB, DT, JO, IC); Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain (JT); Department of ...

Testa A, Kaijser J, Wynants L, et al.
Strategies to diagnose ovarian cancer: new evidence from phase 3 of the multicentre international IOTA study.
Br J Cancer. 2014; 111(4):680-8 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
BACKGROUND: To compare different ultrasound-based international ovarian tumour analysis (IOTA) strategies and risk of malignancy index (RMI) for ovarian cancer diagnosis using a meta-analysis approach of centre-specific data from IOTA3.
METHODS: This prospective multicentre diagnostic accuracy study included 2403 patients with 1423 benign and 980 malignant adnexal masses from 2009 until 2012. All patients underwent standardised transvaginal ultrasonography. Test performance of RMI, subjective assessment (SA) of ultrasound findings, two IOTA risk models (LR1 and LR2), and strategies involving combinations of IOTA simple rules (SRs), simple descriptors (SDs) and LR2 with and without SA was estimated using a meta-analysis approach. Reference standard was histology after surgery.
RESULTS: The areas under the receiver operator characteristic curves of LR1, LR2, SA and RMI were 0.930 (0.917-0.942), 0.918 (0.905-0.930), 0.914 (0.886-0.936) and 0.875 (0.853-0.894). Diagnostic one-step and two-step strategies using LR1, LR2, SR and SD achieved summary estimates for sensitivity 90-96%, specificity 74-79% and diagnostic odds ratio (DOR) 32.8-50.5. Adding SA when IOTA methods yielded equivocal results improved performance (DOR 57.6-75.7). Risk of Malignancy Index had sensitivity 67%, specificity 91% and DOR 17.5.
CONCLUSIONS: This study shows all IOTA strategies had excellent diagnostic performance in comparison with RMI. The IOTA strategy chosen may be determined by clinical preference.

Related: Ovarian Cancer
Department of Gynaecologic Oncology, Catholic University of the Sacred Heart, Largo Francesco Vito 8, Rome 00165, Italy.

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