A study of microRNAs as new prognostic biomarkers in anal cancer patients.

BACKGROUND: MicroRNA (MiR) influences the growth of cancer by regulation of mRNA for 50-60% of all genes. We present as per our knowledge the first global analysis of microRNA expression in anal cancer patients and their prognostic impact. METHODS: Twenty-nine patients with T1-4 N0-3 M0 anal cancer treated with curative intent from September 2003 to April 2011 were included in the study. RNA was extracted from fresh frozen tissue and sequenced using NGS. Differentially expressed microRNAs were identified using the R-package DEseq2 and the endpoints were time to progression (TTP) and cancer specific survival (CSS). RESULTS: Five microRNAs were significantly associated with 5-year progression free survival (PFS): Low expression of two microRNAs was associated with higher PFS, miR-1246 (100% vs. 55.6%, p = 0.008), and miR-135b-5p (92.9% vs. 59.3%, p = 0.041). On the other hand, high expressions of three microRNAs were associated with higher PFS, miR-148a-3p (93.3% vs. 53.6%, p = 0.025), miR-99a-5p (92.9% vs. 57.1%, p = 0.016), and let-7c-3p (92.9% vs. 57.1%, p = 0.016). Corresponding findings were documented for CSS. INTERPRETATION: Our study identified five microRNAs as prognostic markers in anal cancer. MiR-1246 and microRNA-135b-5p were oncoMiRs (miRs with oncogene effects), while miR-148a-3p, miR- 99a-5p, and let-7c-3p acted as tumour suppressors in anal cancer patients.

Prognostic role of tumour-infiltrating lymphocytes and macrophages in relation to MSI, CDX2 and BRAF status: a population-based study of metastatic colorectal cancer patients.

BACKGROUND: Tumour-infiltrating CD3, CD8 lymphocytes and CD68 macrophages are associated with favourable prognosis in localised colorectal cancer, but the effect in metastatic colorectal cancer (mCRC) is not established. METHODS: A Scandinavian population-based cohort of non-resectable mCRC patients was studied. Tissue microarrays (n = 460) were stained with CD3, CD8 and CD68 using fluorescence-based multiplex immunohistochemistry. Associations with clinicopathological variables, overall survival (OS) and progression-free survival were estimated. RESULTS: Two-thirds of microsatellite instable (MSI) and one-fourth of microsatellite stable (MSS) tumours displayed the highest quartile density of CD8. For CD3 high vs low cases, median OS was 20 vs 16 months (HR: 0.76, 95% CI: 0.59, 0.76, p = 0.025) with 3-year OS of 27 vs 13%. For CD68 high vs low cases, median OS was 23 vs 15 months (HR: 0.69, 95% CI: 0.54, 0.88, p = 0.003) with 3-year OS of 28 vs 12%. MSI, BRAF mutation and CDX2 loss were negative prognostic markers independent of tumour immune infiltration. CONCLUSIONS: In mCRC, high lymphocyte infiltration was found in proportions of MSI and MSS tumours-potential subgroups of immunotherapy response. Tumour-infiltrating CD3 lymphocytes and CD68 macrophages were associated with median and long-term survival. MSI was a significant negative prognostic marker despite high immunogenicity.

Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II-III colon cancer.

Mismatch repair (MMR) deficiency is an indicator of good prognosis in localized colon cancer but also associated with lack of expression of caudal-type homeobox transcription factor 2 (CDX2) and high tumor grade; markers that in isolation indicate a poor prognosis. Our study aims to identify clinically relevant prognostic subgroups by combining information about tumor grade, MMR phenotype, and CDX2 expression. Immunohistochemistry for MMR proteins and CDX2 was performed in 544 patients with colon cancer stage II-III, including a cohort from a randomized trial. In patients with proficient MMR (pMMR) and CDX2 negativity, hazard ratio (HR) for cancer death was 2.93 (95% CI 1.23-6.99, p = 0.015). Cancer-specific survival for pMMR/CDX2-negative cases was 35.8 months (95% CI 23.4-48.3) versus 52.1-53.5 months (95% CI 45.6-58.6, p = 0.001) for the remaining cases (CDX2-positive tumors or deficient MMR (dMMR)/CDX2-negative tumors). In our randomized cohort, high tumor grade was predictive of response to adjuvant fluorouracil-levamisole in pMMR patients, with a significant interaction between tumor grade and treatment (p = 0.036). For pMMR patients, high tumor grade was a significant marker of poor prognosis in the surgery-only group (HR 4.60 (95% CI 1.68-12.61), p = 0.003) but not in the group receiving chemotherapy (HR 0.66 (95% CI 0.15-3.00), p = 0.587). To conclude, patients with pMMR and CDX2 negativity have a very poor prognosis. Patients with pMMR and high-graded tumors have a poor prognosis but respond well to adjuvant chemotherapy. CDX2 expression and tumor grade did not impact prognosis in patients with dMMR.

Evaluation of the stage classification of anal cancer by the TNM 8th version versus the TNM 7th version.

Background: The UICC TNM 7th edition introduced stage groups for anal cancer which in 2019 has not yet come into general use. The new TNM 8th edition from 2016 defines 7 sub-stages. Background data for these changes are lacking. We aimed to investigate whether the new classification for anal cancer reliably predict the prognosis in the different stages.Patients and methods: The Nordic Anal Cancer Group (NOAC) conducted a large retrospective study of all anal cancers in Norway, Sweden and most of Denmark in 2000-2007. From the Nordic cohort 1151 anal cancer patients with follow-up data were classified by the TNM 4th edition which has identical T, N and M definitions as the TNM 7th edition, and therefore also can be classified by the TNM 7th stage groups. We used the Nordic cohort to translate the T, N and M stages into the TNM 8th stages and sub-stages. Overall survival for each stage was assessed.Results: Although the summary stage groups for TNM 8th edition discriminates patients with different prognosis reasonably well, the analyses of the seven sub-stages show overlapping overall survival: HR for stage IIA 1.30 (95%CI 0.80-2.12) is not significantly different from stage I (p = .30) and HR for stage IIB 2.35 (95%CI 1.40-3.95) and IIIA 2.48 (95%CI 1.43-4.31) are also similar as were HRs for stage IIIB 3.41 (95%CI 1.99-5.85) and IIIC 3.22 (95%CI 1.99-5.20). Similar overlapping was shown for local recurrence and distant spread.Conclusion: The results for the sub-stages calls for a revision of the staging system. We propose a modification of the TNM 8th edition for staging of anal cancer into four stages based on the T, N and M definitions of the TNM 8th classification.

B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Objective: To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS. Design: Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942). Setting: 4 university hospitals and 1 general hospital in Norway. Patients: 151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years. Intervention: Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74). Measurements: Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures. Results: Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, -5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, -0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events. Limitation: Self-reported primary outcome measures and possible recall bias. Conclusion: B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS. Primary Funding Source: The Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association.

Rationale for combination of radiation therapy and immune checkpoint blockers to improve cancer treatment.

Radiation therapy for cancer is considered to be immunosuppressive. However, the cellular response after radiation therapy may stimulate or suppress an immune response. The effect may vary with the tumor type and occasionally tumor regressions have been observed outside the irradiated volume, both in animal studies and in the clinic. A renewed interest in the role of immunity for the observed effect of radiation came with the current recognized role of immune checkpoint blockers (ICBs) for control of selected cancer types. We therefore here review preclinical studies and clinical reports on the interaction of ICBs and radiation as a basis for further clinical trials. Some tumor types where the combination of these modalities seems especially promising are also proposed.

Rare genetic variation in mitochondrial pathways influences the risk for Parkinson's disease.

BACKGROUND: Mitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein-altering variation in nuclear genes controlling mitochondrial structure and function. OBJECTIVE: The objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD. METHODS: We employed whole-exome sequencing data from 2 independent cohorts of clinically validated idiopathic PD and controls, the Norwegian ParkWest cohort (n = 411) and the North American Parkinson's Progression Markers Initiative (n = 640). We applied burden-based and variance-based collapsing methods to assess the enrichment of rare, nonsynonymous, and damaging genetic variants on genes, exome-wide, and on a comprehensive set of mitochondrial pathways, defined as groups of genes controlling specific mitochondrial functions. RESULTS: Using the sequence kernel association test, we detected a significant polygenic enrichment of rare, nonsynonymous variants in the gene-set encoding the pathway of mitochondrial DNA maintenance. Notably, this was the strongest association in both cohorts and survived multiple testing correction (ParkWest P = 6.3 × 10-3 , Parkinson's Progression Markers Initiative P = 6.9 × 10-5 , metaanalysis P = 3.2 × 10-6 ). CONCLUSIONS: Our results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD. We propose that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explains part of the disorder's "missing heritability." © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Hearing loss before and after cisplatin-based chemotherapy in testicular cancer survivors: a longitudinal study.

BACKGROUND: Hearing loss is a well-known long-term effect after cisplatin-based chemotherapy (CBCT) in testicular cancer survivors (TCS), but longitudinal data are sparse. We evaluate hearing loss and the impact of age in TCS treated with CBCT in this longitudinal study. MATERIAL AND METHODS: Forty-six TCS treated with CBCT 1980-1994 with audiograms (0.25-8 kHz) pre-chemotherapy (PRE) and at a follow-up survey (SURV) after median 10 years were included (cases). Audiograms at SURV from 46 age-matched TCS without CBCT were included as controls. Linear regression was performed to evaluate predictors for change in the hearing threshold level (HTL) from PRE to SURV. Two definitions of a audiogram-defined hearing loss was applied if: (1) mean HTL for both ears exceeded 20 dB at any frequency 0.25-8 kHz (American Speech-Language-Hearing Association (ASHA) definition) and (2) average HTL for the frequencies 0.5, 1, 2 and 4 kHz exceeded 20 dB (WHO-M4 definition). Self-reported hearing impairment (SURV) was assessed by a questionnaire. RESULTS: Age and cisplatin dose was significantly associated with a greater change in HTL for the frequencies 2-8 kHz. For the 8 kHz frequency, each 100 mg increase in cumulative cisplatin dose was associated with a deterioration of 3.6 dB (95% CI 1.8-5.3, p < .001). The prevalence of hearing loss (ASHA) among cases was 33% PRE, 70% at SURV and 65% among controls at SURV (cases vs. controls, p = .66). According to M4, the prevalence of hearing loss among cases was 6.5% PRE, 13% at SURV and 2.2% among controls at SURV (cases vs. controls, p = .049). Twenty-nine percent of cases, and 33% of controls (p = .70) reported hearing impairment at SURV. CONCLUSION: Cisplatin is associated with a hearing loss particularly at higher frequencies. Age appear to be an important factor for hearing loss regardless of treatment. The ASHA definition overestimates the hearing problem.

Multimodal therapy is feasible in elderly anal cancer patients.

BACKGROUND: Many patients are diagnosed with an anal cancer in high ages. We here present the outcome after oncological therapy for patients above 80 years compared with younger patients. MATERIALS AND METHODS: A series of 213 consecutive patients was diagnosed and treated at a single institution from 1984 to 2009. The patients received similar radiation doses but with different techniques, thus progressively sparing more normal tissues. The majority of patients also had simultaneous [5-fluorouracil (5FU) and mitomycin C] or induction chemotherapy (cisplatin and 5FU). The patients were stratified by age above or below 80 years. Despite that the goal was to offer standard chemoradiation treatment to all, the octo- and nonagenarians could not always be given chemotherapy. RESULTS: In our series 35 of 213 anal cancer patients were above 80 years. After initial therapy similar complete response was observed, 80% above and 87% below 80 years. Local recurrence rate was also similar in both groups, 21% versus 26% (p = .187). Cancer-specific survival and relative survival were significantly lower in patients above 80 years, 60% and 50% versus 83% and 80%, (p = .015 and p = .027), respectively. CONCLUSION: Patients older than 80 years develop anal cancer, but more often marginal tumors. Even in the oldest age group half of the patients can tolerate standard treatment by a combination of radiation and chemotherapy, and obtain a relative survival of 50% after five years. Fragile patients not considered candidates for chemoradiation may be offered radiation or resection to control local disease.

Linear energy transfer distributions in the brainstem depending on tumour location in intensity-modulated proton therapy of paediatric cancer.

BACKGROUND: For tumours near organs at risk, there is concern about unintended increase in biological dose from elevated linear energy transfer (LET) at the distal end of treatment fields. The objective of this study was therefore to investigate how different paediatric posterior fossa tumour locations impact LET and biological dose to the brainstem during intensity-modulated proton therapy (IMPT). MATERIAL AND METHODS: Multiple IMPT plans were generated for four different simulated tumour locations relative to the brainstem for a five-year-old male patient. A prescribed dose of 59.4 Gy(RBE) was applied to the planning target volumes (PTVs). Plans with two lateral and one posterior non-coplanar fields were created, along with plans with modified field arrangements. The dose-averaged LET (LETd) and the physical dose × RBELET (D × RBELET), where RBELET=1+c × LETd, were calculated using the FLUKA Monte Carlo code. A scaling parameter c was applied to make the RBELET represent variations in the biological effect due to LET. RESULTS: High LETd values surrounded parts of the PTV and encompassed portions of the brainstem. Mean LETd values in the brainstem were 3.2-6.6 keV/µm. The highest absolute brainstem LETd values were seen with the tumour located most distant from the brainstem, whereas lower and more homogeneous LETd values were seen when the tumour invaded the brainstem. In contrast, the highest mean D × RBELET values were found in the latter case (54.0 Gy(RBE)), while the case with largest distance between tumour and brainstem had a mean D × RBELET of 1.8 Gy(RBE). CONCLUSIONS: Using IMPT to treat posterior fossa tumours may result in high LETd values within the brainstem, particularly if the tumour volume is separated from the brainstem. However, the D × RBELET was greater for tumours that approached or invaded the brainstem. Changing field angles showed a reduction of LETd and D × RBELET in the brainstem.

CXCR4, CXCL12 and the relative CXCL12-CXCR4 expression as prognostic factors in colon cancer.

The CXCL12-CXCR4 axis is proposed to mediate metastasis formation. In this study, we examined CXCL12, CXCR4 and the relative CXCL12-CXCR4 expression as prognostic factors in two cohorts of colon cancer patients. Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to study CXCR4, CXCL12 and relative CXCL12-CXCR4 expression in tissue microarrays. Our study included totally 596 patients, 290 in cohort 1 and 306 in cohort 2. For tumour, node, metastasis (TNM) stage III, low nuclear expression of CXCR4 was a positive prognostic factor for 5-year disease-free survival (DFS) in cohort 1 (P = 0.007) and cohort 2 (P = 0.023). In multivariate analysis for stage III, nuclear expression of CXCR4 in cohort 1 was confirmed as a prognostic factor for DFS (hazard ratio (HR), 0.27; 95 % CI, 0.09 to 0.77). For TNM stage III, high cytoplasmic expression of CXCL12 was associated with better 5-year DFS in both cohorts (P = 0.006 and P = 0.006, respectively). We further validated the positive prognostic value of CXCL12 expression for 5-year DFS in stage III with ISH (P = 0.022). For TNM stage III, the relative CXCL12-CXCR4 expression (CXCL12 > CXCR4 vs CXCL12 = CXCR4 vs CXCL12 < CXCR4) was a prognostic factor for 5-year DFS in cohort 1 (92 % vs 46 % vs 31 %, respectively; P < 0.001) and cohort 2 (92 % vs 66 % vs 30 %, respectively; P = 0.006). In conclusion, CXCL12 and relative CXCL12-CXCR4 expression are independent prognostic factors for 5-year DFS in TNM stage III colon cancer.

LGR5 and CD133 as prognostic and predictive markers for fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer.

BACKGROUND: Expression of leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) gene is associated with a metastatic phenotype and poor prognosis in colorectal cancer (CRC). CD133 expression is a putative cancer stem cell marker and a proposed prognostic marker in CRC, whereas the predictive value of CD133 expression for effect of adjuvant chemotherapy in CRC is unclear. MATERIAL AND METHODS: For the study of LGR5 mRNA and CD133 expression, tissue microarrays from 409 primary CRC stage II and III tumors, where patients had been randomized to adjuvant chemotherapy or surgery only, were available. LGR5 mRNA and CD133 expression were assessed by in situ hybridization (ISH) and immunohistochemistry (IHC), respectively. LGR5 mRNA and CD133 expression as prognostic and predictive markers were evaluated by univariate and multivariate analyses. RESULTS: For all CRC patients, positive LGR5 mRNA and CD133 expression were associated with classic adenocarcinoma histology type (p = 0.001 and p = 0.014, respectively). Positive LGR5 mRNA expression was also associated with smaller tumor diameter for CRC stage II (p = 0.005), but not for CRC stage III (p = 0.054). For CRC stage II, lack of LGR5 mRNA expression was associated with longer time to recurrence (TTR) in Kaplan-Meier (p = 0.045) and in multivariate Cox analysis (HR 0.27, 95% CI 0.08-0.95, p = 0.041). For colon cancer stage III patients, lack of CD133 expression was associated with better effect of adjuvant chemotherapy (p = 0.016) in Kaplan-Meier univariate analysis, but the interaction between CD133 and adjuvant chemotherapy was not statistically significant in multivariate analysis (HR 0.59, 95% CI 0.18-1.89, p = 0.374). CONCLUSION: LGR5 mRNA expression is a prognostic factor for CRC stage II patients, whereas the value of CD133 expression as prognostic and predictive biomarker is inconclusive.

Investigation of six testicular germ cell tumor susceptibility genes suggests a parent-of-origin effect in SPRY4.

Recent genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with testicular germ cell tumor (TGCT) risk in the genes ATF7IP, BAK1, DMRT1, KITLG, SPRY4 and TERT. In the present study, we validate these associations in a Scandinavian population, and explore effect modification by parental sex and differences in associations between the major histological subtypes seminoma and non-seminoma. A total of 118 SNPs in the six genes were genotyped in a population-based Swedish-Norwegian sample comprising 831 TGCT case-parent triads, 474 dyads, 712 singletons and 3919 population controls. Seven hundred and thirty-four additional SNPs were imputed using reference haplotypes from the 1000 genomes project. SNP-TGCT association was investigated using a likelihood-based association test for nuclear families and unrelated subjects implemented in the software package UNPHASED. Forward stepwise regression within each gene was applied to determine independent association signals. Effect modifications by parent-of-origin and effect differences between histological subtypes were explored. We observed strong association between SNPs in all six genes and TGCT (lowest P-value per gene: ATF7IP 6.2 × 10(-6); BAK1 2.1 × 10(-10); DMRT1 6.7 × 10(-25); KITLG 2.1 × 10(-48); SPRY4 1.4 × 10(-29); TERT 1.8 × 10(-18)). Stepwise regression indicated three independent signals for BAK1 and TERT, two for SPRY4 and one each for DMRT1, ATF7IP and KITLG. A significant parent-of-origin effect was observed for rs10463352 in SPRY4 (maternal odds ratio = 1.72, paternal odds ratio = 0.99, interaction P = 0.0013). No significant effect differences between seminomas and non-seminomas were found. In summary, we validated previously reported genetic associations with TGCT in a Scandinavian population, and observed suggestive evidence of a parent-of-origin effect in SPRY4.

Nuclear maspin expression as a predictive marker for fluorouracil treatment response in colon cancer.

BACKGROUND: Maspin is a member of the serpin family of protease inhibitors whose function in colorectal cancer is not fully understood. The objective of this study was to determine whether level of maspin expression could have prognostic or predictive value in colorectal cancer. MATERIAL AND METHODS: Maspin expression was assessed using immunohistochemistry on tissue microarrays obtained from 380 patients with stage II and III colorectal cancer randomized to adjuvant chemotherapy with fluorouracil and levamisole (5-FU/Lev) or to surgery only (control), with scores (0-300) based on presence (0-100) and intensity (0-3) of maspin expression. Associations with disease-free survival (DFS), cancer-specific survival (CSS) and prognostic factors were determined. RESULTS: Maspin expression was predominantly nuclear and present in tumor tissue in 99% of the cases. No associations with clinicopathological factors were identified. In colon cancer patients receiving adjuvant chemotherapy, maspin expression level was significantly associated with CSS [HR 1.43 per 50 points increase in maspin score (p = 0.021)] in multivariate analyses, and a significant interaction between treatment status and maspin expression (p = 0.045) was found. Kaplan-Meier plots from colon cancer patients showed a significant treatment benefit in patients with low maspin expression, but not for individuals with medium/high expression. Level of maspin expression was not significantly related to clinical outcome in rectal cancer or in any of the control groups. CONCLUSIONS: In patients with colon cancer a low nuclear maspin expression was an independent predictor of benefit from adjuvant chemotherapy with 5-FU/Lev. A prognostic value of maspin expression was not found in this material.

Validity of Norwegian Rectal Cancer Registry data at a major university hospital 1997-2005.

BACKGROUND: The Norwegian Rectal Cancer Registry (NRCR) has been used extensively to monitor patient treatment and outcomes since its establishment in 1993. Control of data validity is crucial to ensure reliable information, but an audit of the NRCR data validity has not been performed so far. This study aims to validate NRCR data on patients diagnosed in the period 1997-2005, Department of Surgery, Haukeland University Hospital. MATERIAL AND METHODS: The material comprises NRCR data on all 482 patients diagnosed with rectal cancer in the period 1997-2005 at a major Norwegian university hospital. We checked 50 variables for discrepancies by comparing NRCR data with the medical records. All erroneous registrations were recorded. RESULTS: One hundred patients (21%) had one or more data discrepancies in the registry, and 131 errors (0.5%) were noted in total. Sixteen variables (32%) had no erroneous registrations. Pre-operative CT and type of surgical procedure had the highest proportion of erroneous registrations (2.1%). Recorded errors were grouped into five variable categories: Pre-operative evaluation and adjuvant treatment (40 errors), surgical treatment (44 errors), pathological evaluation (20 errors), complications (7 errors) and oncological outcomes (20 errors). The majority of erroneous registrations (45%) were considered minor in severity, 27% were moderate and 28% were major. CONCLUSION: Assessment of the NRCR data from a nine-year period showed a good data validity in this hospital cohort.

Bilateral testicular germ cell tumors in patients treated for clinical stage I non-seminoma within two risk-adapted SWENOTECA protocols.

BACKGROUND: A contralateral tumor occurs in 3.5-5% of men diagnosed with testicular germ cell cancer (TGCC). Biopsy of the contralateral testis may detect intratubular germ cell neoplasia ITGCNU, a precursor of TGCC. Biopsy of the contralateral testis to detect ITGCNU is controversial. If adjuvant chemotherapy (ACT) protects against bilateral cancer is debated. MATERIAL AND METHODS: A total of 1003 patients with clinical stage I (CS I) non-seminomatous testicular germ cell cancer (NSGCT) were included in two prospective, population-based protocols. Fifteen patients were excluded. Treatment was either adjuvant chemotherapy (n = 494), or surveillance (n = 494). Contralateral testicular biopsy was recommended for all patients, but was performed only in 282 patients. In case of ITGCNU radiotherapy (RT) to 16 Gy was recommended. RESULTS: During a follow-up of 8.3 years, 31 (3.6%) patients developed contralateral TGCC. ITGCNU was detected in 3.2% (9/282) of biopsied patients. The incidence of bilateral TGCC was similar following ACT, 2.5% (11/494), and surveillance, 3.4% (13/494), p = 0.41. Young age was a risk factor for metachronous TGCC (HR 0.93; 95% CI 0.88-0.99, p = 0.02). In total 2.2% (6/273) of patients without ITGCNU in the biopsy developed contralateral TGCC. One irradiated patient developed contralateral cancer, and one developed contralateral tumor before RT was given. CONCLUSION: ACT did not reduce the incidence of contralateral TGCC. Young patients had the highest risk of developing contralateral TGCC. The proportion of false negatives biopsies was higher than reported in earlier trials, but this may in part be related to patient selection, single biopsies and lack of mandatory immunohistochemistry.

Nationwide improvement of rectal cancer treatment outcomes in Norway, 1993-2010.

BACKGROUND: The Norwegian Rectal Cancer Project was initated in 1993 with the aims of improving surgery, decreasing local recurrence rates, improving survival, and establishing a national rectal cancer registry. Here we present results from the Norwegian Colorectal Cancer Registry (NCCR) from 1993 to 2010. MATERIAL AND METHODS: A total of 15 193 patients were diagnosed with rectal cancer in Norway 1993-2010, and were registered with clinical data regarding diagnosis, treatment, locoregional recurrences and distant metastases. Of these, 10 796 with non-metastatic disease underwent tumour resection. The results were stratified into five time periods, and the treatment outcomes were compared. Recurrence rates are presented for the 9785 patients who underwent curative major resection (R0/R1). RESULTS: Among all 15 193 patients, relative five-year survival increased from 54.1% in 1993-1997 to 63.4% in 2007-2010 (p < 0.001). Among the 10 796 patients with stage I-III disease who underwent tumour resection, from 1993-1997 to 2007-2010, relative five-year survival improved from 71.2% to 80.6% (p < 0.001). An increasing proportion of these patients underwent surgery at large-volume hospitals; and 30- and 100-day mortality rates, respectively, decreased from 3.0% to 1.4% (p < 0.001) and from 5.1% to 3.0% (p < 0.011). Use of preoperative chemoradiotherapy increased from 6.5% in 1993 to 39.0% in 2010 (p < 0.001). Estimated local recurrence rate after major resection (R0/R1) decreased from 14.5% in 1993-1997 to 5.0% in 2007-2009 (p < 0.001), and distant recurrence rate decreased from 26.0% to 20.2% (p < 0.001). CONCLUSION: Long-term outcomes from a national population-based rectal cancer registry are presented. Improvements in rectal cancer treatment have led to decreased recurrence rates of 5% and increased survival on a national level.