BACKGROUND/AIM: Chest radiotherapy (RT) doubles late cardiac mortality. This study aimed to evaluate the evolution of cardiac changes in speckle tracking echocardiography during a three-year follow-up.
MATERIALS AND METHODS: This prospective study included 81 chemotherapy-naïve early-stage breast cancer patients who were evaluated at baseline, immediately after RT and three years after RT. Sixty-one patients had left-sided (LSBC) and 20 right-sided breast cancer (RSBC).
RESULTS: Global longitudinal strain (GLS) declined from baseline -18.0±3.3% to -17.0±3.0% (p=0.015) at the three-year follow-up examination. A decline over 15% (GLS15) was observed in 19 (27%) patients. GLS15 was independently associated with aromatase inhibitor use (β=-1.977, p=0.001). In regional analysis, patients with LSBC had apical strain decline by 3.2±5.5% (p<0.001) and patients with RSBC showed basal rotation decline by 1.8° (-0.2°, 3.8°) (p=0.030).
CONCLUSION: Even contemporary RT induced progressive global and regional decline in speckle tracking analysis. The regional changes complied with RT fields.

Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.

Colon cancer represents one of the most common cancers in the world. Despite improved treatment, mortality remains high. In order to improve the assessment of prognosis for colon cancer patients, identifying new prognostic markers remains necessary. We analyzed preoperative serum samples from 148 colon cancer patients surgically treated at Helsinki University Hospital from 1998 through 2002 using a multiplex proximity extension assay (Oncology II panel, Olink Bioscience, Uppsala, Sweden), a panel constituting 92 immunological and oncological markers. We performed univariate and multivariate analyses on these patients and calculated the disease-specific survival among patients using the log-rank test for Kaplan-Meier estimates. In the univariate survival analysis of 92 biomarkers, 26 resulted in p < 0.1. Among these, eight biomarkers emerged as statistically significant (p < 0.05). Patients with low levels of kallikrein 13 had a poor prognosis. Moreover, patients with high levels of amphiregulin, carcinoembryonic antigen-related adhesion molecule 5, interleukin 6, mucin 16, syndecan 1, transforming growth factor alpha, and vimentin also had a poor prognosis. In the multivariate analysis, kallikrein 13 and mucin 16 emerged as independent prognostic markers. The role of kallikrein 13, a member of the serine protease kallikrein biomarker family, in tumorigenesis remains unclear. Mucin 16 is also known as carbohydrate antigen 125, a well-known ovarian cancer biomarker. Patients with low levels of kallikrein 13 (hazard ratio: 0.36; 95% confidence interval: 0.14-0.92; p = 0.033) and high levels of mucin 16 (hazard ratio: 3.15; 95% confidence interval: 1.68-5.93; p < 0.005) had a poor prognosis. Mucin 16 and kallikrein 13 represent independent prognostic markers for colon cancer. Furthermore, the clinical utility of mucin 16 and kallikrein 13 serum tests warrants additional investigation.

BACKGROUND: An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC.
MATERIALS AND METHODS: A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS).
RESULTS: High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels.
CONCLUSION: Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.

AIMS: The aim of this study was to identify factors that determine outcomes of treatment for patients with chondroblastic osteosarcomas (COS) of the limbs and pelvis.
PATIENTS AND METHODS: The authors carried out a retrospective review of prospectively collected data from 256 patients diagnosed between 1979 and 2015. Of the 256 patients diagnosed with COS of the pelvis and the limbs, 147 patients (57%) were male and 109 patients (43%) were female. The mean age at presentation was 20 years (0 to 90).
RESULTS: In all, 82% of the patients had a poor response to chemotherapy, which was associated with the presence of a predominantly chondroblastic component (more than 50% of tumour volume). The incidence of local recurrence was 15%. Synchronous or metachronous metastasis was diagnosed in 60% of patients. Overall survival was 51% and 42% after five and ten years, respectively. Limb localization and wide surgical margins were associated with a lower risk of local recurrence after multivariable analysis, while the response to chemotherapy was not. Local recurrence, advanced patient age, pelvic tumours, and large volume negatively influenced survival. Resection of pulmonary metastases was associated with a survival benefit in the limited number of patients in whom this was undertaken.
CONCLUSION: COS demonstrates a poor response to chemotherapy and a high incidence of metastases. Wide resection is associated with improved local control and overall survival, while excision of pulmonary metastases is associated with improved survival in selected patients. Cite this article:

BACKGROUND: Epithelial ovarian cancer (EOC) typically spreads intra-abdominally, but preoperative evaluation with FDG PET/CT often reveals metabolically active supradiaphragmatic lymph nodes (sdLNs). Their clinical significance and behavior during treatment has not been established.
METHODS: EOC patients with PET positive sdLNs at diagnosis were prospectively followed with PET/CT after primary chemotherapy and at the first recurrence. In each patient, 2 most active LNs in 5 different supradiaphramatic regions were evaluated and the size and changes in FDG uptake (SUVmax) were recorded. The patients´ overall response to primary treatment was defined with RECIST criteria. The behavior of sdLNs during chemotherapy were compared in treatment responders and non-responders. Recurrence patterns were monitored.
RESULTS: Forty-one patients with 127 PET/CT scans were systematically evaluated. In pretreatment scan, 76% (31/41) of patients had FDG-avid sdLNs in multiple anatomical sites. Only a minority (22/136) of the sdLNs were enlarged in size, but their histopathologic confirmation by biopsy was not possible. Only 6/41 patients had FDG-avid sdLNs in a single surgically approachable site. The sdLNs became inactive during primary chemotherapy more often in the RECIST responders compared to the non-responders (HR 1.46 (95%CI: 1.09-1.96), p = 0.002). The size and SUVmax values did not predict treatment outcome. In 50% of the responders the same sdLNs reactivated when recurrence occurred. Persistent post-treatment metabolic activity did not predict earlier disease relapse (p = 0.59).
CONCLUSION: The behavior of metabolically active sdLNs during chemotherapy supports their metastatic nature. Due to their distribution to multiple regions, the benefit of removal of reachable sdLNS seems unlikely.
TRIAL REGISTRATION: NCT, NCT01276574 . Registered 1 September 2010.

The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

BACKGROUND: A single-institution experience of pulmonary metastasectomy in soft tissue sarcoma (STS) was retrospectively reviewed. Our specific aim was to examine, whether the resection of pulmonary metastases could be curative. We also compared overall survival (OS) of patients after complete or incomplete pulmonary resection and nonsurgical treatment.
METHODS: Between 1987 and 2016, 1580 patients were treated for STS with curative intent by Soft Tissue Sarcoma Group at Helsinki University Hospital, Finland. Three hundred forty-seven patients (22%) developed advanced disease and 130 STS patients (9%) developed pulmonary metastases as first systemic relapse. Seventy four patients (5%) were operated for lung metastases.
RESULTS: Fifty-five patients (42%) had a complete and 19 (15%) incomplete resection. Fifty-six (43%) were unoperated. Median OS after complete or incomplete metastasectomy, chemotherapy, or best supportive care was 22, 18, 8, and 5 months, respectively. Twelve patients (9%) developed no further metastases and are alive with no evidence of disease. Disease-free survival (DFS) for completely resected patients was 17% at 5 years. All long-term survivors had oligometastatic disease and they underwent one to three complete metastasectomies.
CONCLUSIONS: Complete pulmonary metastasectomy in STS results in 5 years DFS in nearly one-fifth of patients. Most of these patients are probably cured.

Toll-like receptors (TLRs) are involved in colorectal cancer (CRC) pathogenesis. However, the significance of serum TLR concentrations in CRC is unknown. We analyzed serum TLR2 and TLR4 concentrations with ELISA in preoperative samples from 118 patients with CRC and 88 matched controls. We also assessed tissue TLR expression with immunohistochemistry and by detecting serum determinants of systemic inflammation. Most participants (>70%) had undetectable serum TLR2. The mean serum TLR4 levels were lower in patients than in controls (1.1 vs 1.8 ng/mL; p = 0.015). Undetectable TLR4 was more common in stage I (39%) than in stages II-IV (11%, p < 0.001). TLR2 or TLR4 expression in tumor cells did not correlate with serum levels, but abundant TLR2 expression in normal colon epithelium was associated with detectable serum TLR2 (p = 0.034). Undetectable serum TLR2 was linked to high modified Glasgow prognostic scores (p = 0.010), high CRP levels (p = 0.013), blood vessel invasion (p = 0.013), and tended to be associated with worse 5-year survival (p = 0.052). In conclusion, serum TLR2 levels were inversely associated with systemic inflammation in patients with CRC. Moreover, serum TLR2 levels might depend more on normal colorectal mucosa contributions than on tumor tissue contributions. Further studies are required to assess the prognostic value of serum TLR2.

Type 1 collagen is an important part of the extracellular matrix and changes in its metabolism and distribution are essential in breast cancer induction and progression. Serum concentrations of type 1 collagen synthesis (aminoterminal propeptide (PINP)) and degradation markers (carboxyterminal telopeptide (ICTP)) have previously been studied in early and metastatic breast cancer, but no data are available on specific breast cancer subtypes. We assayed 662 preoperative serum samples for PINP and ICTP and 109 postoperative serum samples for ICTP. The results were linked to prospectively collected clinical data and the cases were divided into breast cancer subtypes for survival analyses. The concentrations of both pre- and postoperative ICTP serum levels increased linearly from ductal in situ carcinoma to stage I-II tumors, stage III tumors, and finally to those with concomitant primary metastases (preoperative ICTP, p = 0.009; postoperative ICTP, p = 0.016). High-preoperative ICTP levels were associated with better breast cancer-specific survival in connection with luminal-B-like (HER2-negative) tumors (p = 0.017), which was confirmed in Cox regression analysis (relative risk = 3.127; 95% confidence interval = 1.081-9.049, p = 0.035), when T-class (relative risk = 4.049; 95% confidence interval = 1.263-12.981; p = 0.019) and nodal status (relative risk = 3.896; 95% confidence interval = 1.088-13.959; p = 0.037) were included in the analysis. In patients with triple-negative breast cancer, a high-preoperative ICTP level was a significant predictor of local relapse-free survival in univariate (p = 0.0020) and multivariate analyses (relative risk = 13.04; 95% confidence interval = 1.354-125.5; p = 0.026; for T-class, relative risk = 2.128 and 95% confidence interval = 0.297-15.23; p = 0.452; for N-class, relative risk = 0.332 and 95% confidence interval = 0.033-3.307; p = 0.347). A preoperatively elevated serum ICTP level appears to be an important marker of better prognosis in triple-negative breast cancer and luminal-B-like (HER2-negative) subtypes.

PURPOSE: To review indications, patient characteristics, frequency, and safety for surgical tracheostomies performed by otolaryngologist-head and neck surgeons in a single tertiary care center.
METHODS: Surgical tracheostomies performed by otolaryngologist-head and neck surgeons at Helsinki University Hospital between January 2014 and February 2017 were retrospectively reviewed. Patient demographics, surgical data, and peri- and postoperative mortality information were collected from the hospital charts. Minimum follow-up was 18 months.
RESULTS: The total population was 255, with a majority (n = 181; 71%) of males. The majority of patients (n = 178; 70%) were classified as ASA 3 or 4. A total of 198 (78%) patients suffered from head and neck cancer. Multiple (14 altogether) indications for tracheostomy were identified, and simultaneous major head and neck tumor surgery was common (in 58%). Altogether, 163 (64%) patients were decannulated during follow-up with a median cannulation period of 9 days (range 1-425). The surgical mortality was 0.4%.
CONCLUSION: Simultaneously performed major tumor surgery was the most common indication for a tracheostomy. A notable number of patients had impaired physical status, but relatively insignificant comorbidities. Almost two-thirds of the patients were decannulated during follow-up, although some patients remained tracheostomy dependent for a prolonged period. Tracheostomy was found to be a safe procedure.
LEVEL OF EVIDENCE: 2b.

BACKGROUND/AIM: There is a growing need for information regarding the Health-Related Quality of Life (HRQoL) of cancer survivors. This study aimed to assess the HRQoL of patients treated for cutaneous malignant melanoma between 1980 and 2004 in the Helsinki and Uusimaa Hospital district and compare the results to the general population.
MATERIALS AND METHODS: HRQoL of 981 cutaneous melanoma patients (aged 13 to 97 years, 56.1% female) was assessed using the generic 15D instrument and compared to the general population. The association between demographic and clinical factors and HRQoL was analyzed using oneway ANOVA, student's t-test and multivariate regression.
RESULTS: The mean 15D score of melanoma patients was slightly lower (0.904) than that of the general population (0.911, p=0.027), but the difference was not statistically significant. HRQoL deteriorates with age and metastatic disease and improves with time.
CONCLUSION: No evidence was found that long-term HRQoL of melanoma survivors was worse than the general population.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

OBJECTIVES: To investigate whether semi-quantitative and pharmacokinetic perfusion dynamic contrast-enhanced (DCE) parameters are associated with traditional prognostic factors and can predict clinical outcome in ovarian cancer (OC).
METHODS: This prospective study, approved by local ethical committee, enrolled 38 patients with primary OC, 2011-2014. After preoperative DCE-MRI (3.0 T), two observers measured perfusion (K
RESULTS: Mean K
CONCLUSION: DCE-MRI parameters may represent imaging biomarkers for predicting tumor aggressiveness and prognosis in OC. Higher K

PURPOSE: Late-stage OTSCC is associated with poor overall survival (OS). Non-curative treatment approach aims to improve quality of life and prolong survival of patients deemed incurable. The purpose of this study was to investigate the used non-curative treatment modalities for OTSSC and patient survival.
METHODS: All patients diagnosed with OTSCC and treated with non-curative intent at the HUS Helsinki University Hospital (Helsinki, Finland) during the 12-year period of 2005-2016 were included. Survival analysis after the non-curative treatment decision was conducted using the Kaplan-Meier method in this population-based study.
RESULTS: Eighty-two patients were identified. A non-curative treatment decision was made at presentation without any previous treatment in 26 patients (7% of all patients diagnosed with OTSCC during the study period). Palliative radiotherapy was administered to 24% of all patients. The average survival time after the non-curative treatment decision was 3.7 months (median 2 and range 0-26).
CONCLUSIONS: Due to the short mean survival time after decision for treatment with non-curative intent, and the notable symptom burden in this patient population, a prompt initiation of all non-curative measures is warranted.

BACKGROUND/AIM: Appropriate decision-making in end-of-life (EOL) care is essential for both junior and senior physicians. The aim of this study was to compare the decision-making and attitudes of medical students with those of experienced general practitioners (GP) regarding EOL-care.
MATERIALS AND METHODS: A questionnaire presenting three cancer patient scenarios concerning decisions and ethical aspects of EOL-care was offered to 500 Finnish GPs and 639 graduating medical students in 2015-2016.
RESULTS: Responses were received from 222 (47%) GPs and 402 (63%) students. The GPs withdrew antibiotics (p<0.001) and nasogastric tubes (p=0.007) and withheld resuscitation (p<0.001), blood transfusions (p=0.002) and pleural drainage (p<0.001) more often than did the students. The students considered euthanasia and assisted suicide less reprehensible (p<0.001 in both) than did the GPs.
CONCLUSION: Medical students were more unwilling to withhold and withdraw therapies in EOL-care than were the GPs, but the students considered euthanasia less reprehensible. Medical education should include aspects of decision-making in EOL-care.

BACKGROUND/AIM: This is a report of the 5-year quality of life (QoL) findings of the BREX-study (n=444).
PATIENTS AND METHODS: A 12-month exercise intervention was arranged shortly after adjuvant treatments. Physical activity (PA) was assessed by PA diary, physical performance by a 2- km walking test, QoL by the EORTC QLQC30 and BR-23 questionnaires, fatigue by the FACIT-Fatigue scale and depression by the Beck's 13-item depression scale (BDI).
RESULTS: Participants who improved their PA from baseline to 5-year follow-up were more likely to improve their global health score (RRR=1.02, p=0.016), physical (RRR=1.02, p=0.009), social (RRR=1.03, p=0.013), role functioning (RRR=1.03, p=0.005), and fatigue (RRR=1.02, p=0.002). An improved 2-km walking test was associated to improved global health, physical and role functioning, body image, future perspectives, and fatigue (p=0.011, p<0.001, p=0.001, p=0.021, p=0.012 and p=0.003). No significant difference between the groups was found.
CONCLUSION: Improvement in PA or physical performance yields a positive change in QoL of breast cancer patients.

The pattern of clinical behaviour and response to treatment of recurrent and/or metastatic head and neck squamous cell carcinoma is heterogeneous. Treatment strategies that can be employed vary from potentially curative salvage surgery and re-irradiation to palliative systemic therapies and best supportive care. The advent of new therapeutic options, in terms of more sophisticated surgical approaches and techniques, highly conformal and precise radiation techniques and immunotherapy may offer improved control of disease and longer survival. Moreover, the epidemiological changes during the last decades, including the increase of human papilloma virus-related oropharyngeal primary tumors, are also reflected in the recurrent and metastatic setting. In this complex context the identification of predictive and prognostic factors is urgently needed to tailor treatment, to increase its efficacy, and to avoid unnecessary toxicities. A better knowledge of prognosis may also help the patients and caregivers in decision making on the optimal choice of care. The purpose of our review is to highlight the current evidence and shortcomings in this field.

OBJECTIVE: Head and neck cancer follow-up length, interval and content are controversial. Therefore, this study aimed to evaluate the efficacy of the follow-up protocol after curative treatment in head and neck cancer patients.
METHOD: Clinical data of 456 patients with new malignancy of the head and neck from a tertiary care centre district from 1999 to 2008 were analysed. Time from treatment, symptoms and second-line treatment outcomes of patients with recurrent disease were evaluated.
RESULTS: A total of 94 (22 per cent) patients relapsed during the 5-year follow-up period; 90 per cent of recurrences were found within 3 years. Fifty-six per cent of the patients had subjective symptoms indicating a recurrence of the tumour. All recurrent tumours found during routine follow-up visits without symptoms were found within 34 months after completion of treatment.
CONCLUSION: Routine follow up after three years is questionable; recurrent disease beyond this point was detected in only 2 per cent of patients. In this study, all late tumour recurrences had symptoms of the disease. Easy access to extra follow-up visits when symptoms occur could cover the need for late follow up.

It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0-1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1-1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0-1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9-1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1-1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9-1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8-1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

BACKGROUND: Locally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after first-line treatment has a poor prognosis. Recent randomized clinical trials (RCTs) have demonstrated survival benefits of alternative treatments to docetaxel. However, information is lacking on which patients benefit the most and what drug or regimen is optimal. We report a systematic review and network meta-analysis (NMA) of second-line treatments in all subgroup combinations determined by histology, programmed death ligand 1 (PD-L1) expression, and epidermal growth factor receptor (EGFR) mutation.
METHODS: MEDLINE, PubMed, EMBASE, Biosciences Information Service (using the Dialog Platform), Cochrane Library, and abstracts from scientific meetings were searched for RCTs published up to September 2015. Key outcomes were overall survival (OS) and progression-free survival (PFS). Bayesian hierarchical exchangeable NMAs were conducted to calculate mean survival times and relative differences for eight subgroups, using docetaxel as the reference comparator. For OS, the NMA was based on hazard ratios applied to a first-order fractional polynomial model fitted to the reference treatment. For PFS, a second-order fractional polynomial model was fitted to reconstructed patient-level data for the entire network of evidence.
RESULTS: The search identified 30 studies containing 17 different treatment regimens. Docetaxel plus ramucirumab was associated with a significant improvement in OS and PFS, relative to docetaxel, regardless of patient type. Docetaxel plus nintedanib showed similar efficacy to docetaxel plus ramucirumab in the nonsquamous populations. EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib showed superior levels of efficacy in EGFR mutation-positive populations and the one PD-1 immunotherapy (nivolumab) studied showed superior efficacy in the populations exhibiting high PD-L1 expression.
CONCLUSIONS: In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to synthesize evidence of the efficacy of each treatment. Benefits are optimized by targeting specific treatments to individual patients guided by histology, PD-L1 expression, and EGFR mutation status.
SYSTEMATIC REVIEW REGISTRATION: This review is registered in PROSPERO (registration number: CRD42014013780 available at www.crd.york.ac.uk/PROSPERO ).

BACKGROUND: While prophylactic human papillomavirus (HPV) vaccination exists, women are still developing cervical intraepithelial neoplasia (CIN) grade 2 or 3 for which an immunotherapeutic, non-surgical, approach may be effective. The primary aim was to assess the efficacy of tipapkinogen sovacivec (TS) vaccine in achieving histologic resolution of CIN2/3 associated with high risk (HR) HPV types.
METHODS: Women 18 years and older who had confirmed CIN2/3 were enrolled in a randomized, double blind, placebo-controlled phase II trial and assigned to drug in a 2:1 ratio (vaccine:placebo). The primary endpoint occurred at month 6 when the excisional therapy was performed; cytology and HR HPV typing were performed at months 3, 6 and every six months through month 30. The safety population included all patients who received at least one dose of study drug.
RESULTS: Of the 129 women randomized to vaccine and 63 to placebo, complete resolution was significantly higher in the vaccine group than placebo for CIN 2/3 regardless of the 13 HR HPV types assayed (24% vs. 10%, p < 0.05); as well as for only CIN 3 also regardless of HR HPV type (21% vs. 0%, p < 0.01). Irrespective of baseline HPV infection, viral DNA clearance was higher in the vaccine group compared to placebo (p < 0.01). The vaccine was well tolerated with the most common adverse events being injection site reactions.
CONCLUSIONS: The TS vaccine provides histologic clearance of CIN 2/3 irrespective of HR HPV type in one third of subjects and is generally safe through 30 months.

BACKGROUND: The prognostic value of vascular endothelial growth factor-A (VEGFA) and epithelial cadherin (E-cadherin) expression in patients with metastatic colorectal cancer (mCRC) is controversial.
MATERIALS AND METHODS: In this prospective study, patients diagnosed with mCRC between August 1, 1998, and August 30, 2003, at the Turku University Hospital, Finland were included. Expression of E-cadherin (membranous and cytoplasmic pattern) and VEGFA in tumour samples was assessed by immunohistochemistry. Tumours were classified as E-cadherin expressers if they demonstrated moderate or strong cytoplasmic or membranous staining, while those positive for VEGFA expression showed a moderate or strong cytoplasmic staining. Of particular interest was the association between membranous or cytoplasmic expression of E-cadherin and VEGFA. The value of strong VEGF-A staining and membranous or cytoplasmic expression of E-cadherin as a predictor of disease outcome over a 6-year period was another point of interest in this study.
RESULTS: Of the 67 patients with mCRC, 43 (64%) had tumours positive for cytoplasmic E-cadherin, while in 24 cases (36%), E-cadherin expression was membranous. Strong VEGFA staining was present in half of the cases (n=36, 54% of all 67 mCRC cases). VEGFA expression was significantly correlated with cytoplasmic E-cadherin expression in that 28/36 cases of VEGFA-positive tumours were also positive for cytoplasmic E-cadherin (p=0.012). In addition, among the patients with intense VEGFA expression (n=36), those who had positive cytoplasmic E-cadherin in their tumours had a lower response-rate to first-line therapy with irinotecan, fluorouracil and leucovorin regimen: 5 out of 36 (14%) were chemosensitive. This is in contrast to the patients with VEGFA-positive tumours and membranous E-cadherin (8/36, 22% chemosensitive (p=0.004). The former group also had more ominous prognosis (p<0.001).
CONCLUSION: Reduced membranous expression of E-cadherin and increased cytoplasmic E-cadherin expression predict poor survival in mCRC.

Secretory carcinoma (SC) of salivary glands is a newly described low-grade malignancy characterized by the presence of ETV6 rearrangement. Only a few cases and very small series with cytomorphology were reported so far. Six cases of fine-needle aspirations (FNAs) from afterward histologically, immunohistochemically and genetically confirmed SCs were retrieved from the archives of the authors. Ancillary immunocytochemistry (ICC) and translocation detection were performed on cell blocks (CBs). All aspirates were sufficiently cellular and cells were arranged in more or less cohesive groups with only mild nuclear polymorphism. The cytoplasm was eosinophilic, granulated and vacuolated, especially in CBs. Secretory material within the microcystic spaces was periodic acid-Schiff (PAS) positive. Triple positivity of immunomarkers S-100 protein, mammaglobin and vimentin was present. The proliferation index was low. Ancillary techniques suggested the possibility of SC in a few cytology cases; nevertheless, the final diagnosis was based on histomorphology, immunohistochemistry and genetics. The SC of salivary glands is detectable pre-operatively using ICC and genetics. The presence of the diagnostic ETV6 rearrangement increases the accuracy of FNA to the maximum. According to the Milan system, cases genetically not confirmed should be categorized as Suspicious for Malignancy or Salivary Gland Neoplasm of Uncertain Malignant Potential (SUMP), both requiring surgery.

BACKGROUND & AIMS: Bariatric surgery might reduce overall mortality from obesity. We investigated whether the survival times of patients who have had bariatric surgery are similar to those of the general population and are longer than of obese individuals who did not receive surgery.
METHODS: We performed a population-based cohort study of persons with a diagnosis of obesity listed in nationwide registries from Nordic countries from 1980 through 2012. Bariatric surgery was analyzed in relation to all-cause mortality and the obesity-related morbidities cardiovascular disease, diabetes, cancer, and suicide. Poisson models provided standardized mortality ratios (SMRs) with 95% confidence intervals (CIs). Multivariable Cox regression provided hazard ratios (HRs) for mortality in participants who did and did not have surgery.
RESULTS: Among 505,258 participants, 49,977 had bariatric surgery. Overall all-cause SMR was increased after surgery (1.94; 95% CI, 1.83-2.05) and increased with longer follow-up, to 2.28 (95% CI, 2.07-2.51) at ≥15 years after surgery. SMRs were increased for cardiovascular disease (2.39; 95% CI, 2.17-2.63), diabetes (3.67; 95% CI, 2.85-4.72), and suicide (2.39; 95% CI, 1.96-2.92) but not for cancer (1.05; 95% CI, 0.95-1.17); SMRs increased with time. In obese participants who did not have surgery, all-cause SMR was 2.15 (95% CI, 2.11-2.20), which remained stable during follow-up. Compared with obese participants who did not have surgery, patients who had bariatric surgery had decreased overall mortality from all causes (HR, 0.63; 95% CI, 0.60-0.66), cardiovascular disease (HR, 0.57; 95% CI, 0.52-0.63), and diabetes (HR, 0.38; 95% CI, 0.29-0.49) but increased mortality from suicide (HR, 1.68; 95% CI, 1.32-2.14). Cancer mortality was decreased overall (HR, 0.84; 95% CI, 0.76-0.93) but increased at ≥15 years of follow-up (HR, 1.20; 95% CI, 1.02-1.42).
CONCLUSIONS: In a study of persons with a diagnosis of obesity listed in nationwide registries of Nordic countries, we found that obese patients who have bariatric surgery have longer survival times than obese individuals who did not have bariatric surgery, but their mortality is higher than that of the general population and increases with time. Obesity-related morbidities could account for these findings.

Human papillomavirus is detected in over 50% of oropharyngeal squamous cell carcinomas. Human papillomavirus-positive oropharyngeal squamous cell carcinomas differ from human papillomavirus-negative tumors, and both expression patterns are classified as distinct entities. The Bmi-1 oncogene is a well-known member of the mammalian polycomb-group family. HESC5:3 and HES77 are newly developed monoclonal antibodies produced against undifferentiated embryonic stem cells. Our aim was to explore their roles in both human papillomavirus-positive and -negative oropharyngeal squamous cell carcinomas. Our cohort comprised 202 consecutive oropharyngeal squamous cell carcinoma patients diagnosed and treated with curative intent. We used tissue microarray tumor blocks to study the immunohistochemical expression of Bmi-1, HESC5:3, and HES77. We compared the expressions of these stem cell markers with p16 immunoexpression and human papillomavirus status, as well as with other characteristics of the tumor, and with patients' clinical data and follow-up data. Human papillomavirus- and p16-positive tumors expressed less Bmi-1 and more HESC5:3 than the negative tumors. HES77 expression was high in human papillomavirus-positive oropharyngeal squamous cell carcinoma, but it did not correlate with p16 positivity. In our multivariable model, Bmi-1 and HESC5:3 were still associated with human papillomavirus, but the association between human papillomavirus and HES77 remained absent. In conclusion, Bmi-1, HESC5:3, and HES77 may have a different role in human papillomavirus-positive and human papillomavirus-negative tumors. There was no correlation between Bmi-1, HESC5:3, and HES77 expression and survival.

Throughout the cancer continuum, patients are faced with the cancer- and treatment-related side effects that can have a negative impact on their overall quality of life. Cancer-related fatigue (CRF) and sleep deficiency are among the symptoms that patients and their caregivers most often experience. An increasing body of literature suggests that a strong correlation between CRF and sleep deficiency exists, indicating that they may be reciprocally related and that they may have similar underlying etiology. This paper aims at bringing together the opinions of leading cancer control (i.e., CRF and sleep) and oncology experts in order to increase the understanding of CRF and sleep deficiency's assessment, associated symptom clustering, symptom burden shared by caregivers, and CRF and sleep deficiency management in the cancer care context.

OBJECTIVES: The diagnostic performance of cytology in esophageal squamous cell carcinoma (ESCC) is meticulously described.
METHODS: Cytological and biopsy specimens were prospectively taken during esophagogastroduodenoscopy of 123 individuals in 2013 and 2014. Cytology samples were maintained in preservative fluid until processing and biopsies were formalin-fixed and paraffin-embedded.
RESULTS: Based on endoscopic biopsy results, 70 cases were positive for ESCC whilst 53 were negative for cancer. In addition, brush cytology showed high sensitivity and specificity (98.57 and 96.23%, respectively) in detecting the disease, and high accuracy (97.5%) comparable to that provided by histopathology which is the accepted gold standard.
CONCLUSION: Brush cytology specimens preserved in liquid medium may be a good alternative for ESCC diagnosis.