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PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) health-related quality of life questionnaire for anal cancer (QLQ-ANL27) supplements the EORTC cancer generic measure (QLQ-C30) to measure concerns specific to people with anal cancer treated with chemoradiotherapy. This study tested the psychometric properties and acceptability of the QLQ-ANL27.METHODS AND MATERIALS: People with anal cancer were recruited from 15 countries to complete the QLQ-C30 and QLQ-ANL27 and provide feedback on the QLQ-ANL27. Item responses, scale structure (multitrait scaling, factor analysis), reliability (internal consistency and reproducibility) and sensitivity (known group comparisons and responsiveness to change) of the QLQ-ANL27 were evaluated.RESULTS: Data from 382 people were included in the analyses. The EORTC QLQ-ANL27 was acceptable, comprehensive, and easy to complete, taking an average 8 minutes to complete. Psychometric analyses supported the EORTC QLQ-ANL27 items and reliability (Cronbach's α ranging from 0.71-0.93 and test-retest coefficients above 0.7) and validity of the scales (particularly nonstoma bowel symptoms and pain/discomfort). Most scales distinguished people according to treatment phase and performance status. Bowel (nonstoma), pain/discomfort, and vaginal symptoms were sensitive to deteriorations over time. The stoma-related scales remained untested because of low numbers of people with a stoma. Revisions to the scoring and question ordering of the sexual items were proposed.CONCLUSIONS: The QLQ-ANL27 has good psychometric properties and is available in 16 languages for people treated with chemoradiotherapy for anal cancer. It is used in clinical trials and has a potential role in clinical practice.

Anal cancer is a rare disease, albeit with an increasing incidence [1,2]. Standard treatment consists of radiotherapy with concurrent chemotherapy. The treatment outcome is affected by a number of ...

Squamous cell cancer of the anus is an uncommon malignancy, usually caused by human papilloma virus (HPV). Chemoradiotherapy (CRT) is the recommended treatment in localized disease with cure rates of 60-80%. Local failures should be considered for salvage surgery. With the purpose of improving and equalizing the anal cancer care in Sweden, a number of actions were taken between 2015 and 2017. The aim of this study was to describe the implementation of guidelines and organizational changes and to present early results from the first 5 years of the Swedish anal cancer registry (SACR).The following were implemented: (1) the first national care program with treatment guidelines, (2) standardized care process, (3) centralization of CRT to four centers and salvage surgery to two centers, (4) weekly national multidisciplinary team meetings where all new cases are discussed, (5) the Swedish anal cancer registry (SACR) was started in 2015.The SACR included 912 patients with a diagnosis of anal cancer from 2015 to 2019, reaching a national coverage of 95%. We could show that guidelines issued in 2017 regarding staging procedures and radiotherapy dose modifications were rapidly implemented. At baseline 52% of patients had lymph node metastases and 9% had distant metastases. Out of all patients in the SACR 89% were treated with curative intent, most of them with CRT, after which 92% achieved a local complete remission and the estimated overall 3-year survival was 85%.This is the first report from the SACR, demonstrating rapid nation-wide implementation of guidelines and apparently good treatment outcome in patients with anal cancer in Sweden. The SACR will hopefully be a valuable source for future research.

Squamous-cell carcinoma of the anus (ASCC) is a rare disease. Barriers have been encountered to conduct clinical and translational research in this setting. Despite this, ASCC has been a prime example of collaboration amongst researchers. We performed a bibliometric analysis of ASCC-related literature of the last 20 years, exploring common patterns in research, tracking collaboration and identifying gaps. The electronic Scopus database was searched using the keywords “anal cancer”, to include manuscripts published in English, between 2000 and 2020. Data analysis was performed using R-Studio 0.98.1091 software. A machine-learning bibliometric method was applied. The bibliometrix R package was used. A total of 2322 scientific documents was found. The average annual growth rate in publication was around 40% during 2000–2020. The five most productive countries were United States of America (USA), United Kingdom (UK), France, Italy and Australia. The USA and UK had the greatest link strength of international collaboration (22.6% and 19.0%). Two main clusters of keywords for published research were identified: (a) prevention and screening and (b) overall management. Emerging topics included imaging, biomarkers and patient-reported outcomes. Further efforts are required to increase collaboration and funding to sustain future research in the setting of ASCC.

The COVID-19 pandemic is unprecedented. The pandemic not only induced a public health crisis, but has led to severe economic, social, and educational crises. Across economies and societies, the distributional consequences of the pandemic have been uneven. Among groups living in vulnerable conditions, the pandemic substantially magnified the inequality gaps, with possible negative implications for these individuals' long-term physical, socioeconomic, and mental wellbeing. This Viewpoint proposes priority, programmatic, and policy recommendations that governments, resource partners, and relevant stakeholders should consider in formulating medium-term to long-term strategies for preventing the spread of COVID-19, addressing the virus's impacts, and decreasing health inequalities. The world is at a never more crucial moment, requiring collaboration and cooperation from all sectors to mitigate the inequality gaps and improve people's health and wellbeing with universal health coverage and social protection, in addition to implementation of the health in all policies approach.

Anal cancer is a relatively rare, mostly HPV-related cancer. The curative treatment consists of concurrent chemoradiation delivered with modern radiotherapy techniques. The prognosis for most patients with early localized disease is very favourable; however patients with locally advanced disease and/or HPV negative tumours are at higher risk of locoregional and distant treatment failure. Tailored approaches are presently being investigated to determine the most suitable regimen in terms of radiotherapy dose prescription, target volume selection, normal tissue avoidance, and combination therapy. Metastatic anal cancer is treated with chemotherapy aiming at prolonged survival. The role of immune therapy in the clinical setting is being investigated. There is little knowledge on the biology of anal cancer, and an urgent need for more clinical and translational research dedicated to this disease. In this article, the evidence-base for the current treatment is briefly reviewed, and perspectives on future research needs are high-lighted.

Aminolevulinic acid and hexyl-aminolevulinate serve as biological precursors to produce photosensitive porphyrins in cells via the heme biosynthetic pathway. This pathway is integral to porphyrin-based photodynamic diagnosis and therapy. By adding exogenous hexyl-aminolevulinate to rat bladder cancer cells (AY27, in vitro) and an animal bladder cancer model (in vivo), fluorescent endogenous porphyrin production was stimulated. Lipophilic protoporphyrin IX was identified as the dominant species by reverse high-pressure liquid chromatography. Subcellular porphyrin localization in the AY27 cells was evaluated by confocal laser scanning microscopy and showed almost quantitative bleaching after 20 s. From this study, we ascertained that the protocol described herein is suitable for hexyl-aminolevulinate-mediated photodynamic therapy and diagnosis when protoporphyrin IX is the active agent.

Background Treatment-related white blood cell (WBC) toxicity has been associated with an inferior prognosis in different malignancies, including anal cancer. The aim of the present study was to investigate predictors of WBC grade ≥ 3 (G3+) toxicity during chemoradiotherapy (CRT) of anal cancer. Methods Consecutive patients with locally advanced (T2 ≥ 4 cm—T4 or N+) anal cancer scheduled for two cycles of concomitant 5-fluorouracil and mitomycin C chemotherapy were selected from an institutional database (n = 106). All received intensity modulated radiotherapy (IMRT; mean dose primary tumor 59.5 Gy; mean dose elective lymph nodes 45.1 Gy). Clinical data were extracted from medical records. The highest-grade WBC toxicity was recorded according to CTCAE version 5.0. Pelvic bone marrow (PBM) was retrospectively contoured and dose-volume histograms were generated. The planning CT was used to measure sarcopenia. Dosimetric, anthropometric, and clinical variables were tested for associations with WBC G3+ toxicity using the Mann–Whitney test and logistic regression. Cox proportional hazard regression was used to assess predictors for overall survival (OS) and anal cancer specific survival (ACSS). Results WBC G3+ was seen in 50.9% of the patients, and 38.7% were sarcopenic. None of the dosimetric parameters showed an association with WBC G3+ toxicity. The most significant predictor of WBC G3+ toxicity was sarcopenia (adjusted OR 4.0; P = 0.002). Sarcopenia was also associated with an inferior OS (adjusted HR 3.9; P = 0.01), but not ACSS (P = 0.07). Sensitivity analysis did not suggest that the inferior prognosis for sarcopenic patients was a consequence of reduced doses of chemotherapy or a prolonged radiation treatment time. Patients who experienced WBC G3+ toxicity had an inferior OS and ACSS, even after adjustment for sarcopenia. Conclusions Sarcopenia was associated with increased risks of both WBC G3+ toxicity and death following CRT for locally advanced anal cancer. In this study, radiation dose to PBM was not associated with WBC G3+ toxicity. However, PBM was not used as an organ at risk for radiotherapy planning purposes and doses to PBM were high, which may have obscured any dose–response relationships.

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.

Background Anal cancer is a rare disease, which might be the reason for the “one size fits all” approach still used for radiotherapy target contouring. To refine and individualize future guidelines, detailed and contemporary pattern of recurrence studies are needed. Methods Consecutive anal cancer patients, all treated with curative intent intensity-modulated radiotherapy (IMRT), were retrospectively studied (n = 170). Data was extracted from medical records and radiological images. Radiotherapy planning CT’s and treatment plans were reviewed, and recurrences were mapped and categorized according to radiation dose. Results The mean dose to the primary tumor was 59.0 Gy. With a median follow-up of 50 months (range 14–117 months), 5-year anal cancer specific survival was 86.1%. Only 1 of 20 local recurrences was located outside the high dose (CTVT) volume. More patients experienced a distant recurrence (n = 34; 20.0%) than a locoregional recurrence (n = 24; 14.1%). Seven patients (4.2%) had a common iliac and/or para-aortic (CI/PA) recurrence. External iliac lymph node involvement (P = 0.04), and metastases in ≥3 inguinal or pelvic lymph node regions (P = 0.02) were associated with a 15–18% risk of CI/PA recurrence. Following chemoradiotherapy, 6 patients with recurrent or primary metastatic CI/PA lymph nodes were free of recurrence at last follow-up. The overall rate of ano-inguinal lymphatic drainage (AILD) recurrence was 2 of 170 (1.2%), and among patients with inguinal metastases at initial diagnosis it was 2 of 65 (3.1%). Conclusions We conclude that other measures than increased margins around the primary tumor are needed to improve local control. Furthermore, metastatic CI/PA lymph nodes, either at initial diagnosis or in the recurrent setting, should be considered potentially curable. Patients with certain patterns of metastatic pelvic lymph nodes might be at an increased risk of harboring tumor cells also in the CI/PA lymph nodes.

Background and purpose: Anal squamous cell carcinoma is primarily treated with radiotherapy (RT), but the optimal RT dose for anal tumours of different sizes is not known. The purpose of this study was to identify determinants for local tumour control probability (LTCP). Material and methods: From a large Nordic database 901 patients who received RT for anal cancer between 2000 and 2007 were selected. LTCP was analysed in a series of uni- and multivariable regression analyses. Results: Higher RT dose, female gender and addition of chemotherapy were associated with higher LTCP whereas increasing tumour size, tumour invasiveness (stage T4) and lymph node metastases (N+) were associated with lower LTCP. Male patients needed approximately 10 Gy higher RT dose than female patients for similar LTCP. The addition of chemotherapy corresponded to 5–10 Gy RT dose. Conclusions: Our results basically support current guidelines recommending: (1) lower RT dose in small tumours (

Standard treatment of localized squamous cell carcinoma of the anus (SCCA) is radiotherapy (RT) combined with chemotherapy, that is, chemoradiation (CRT). Primary surgery has a limited role, but is a recommended treatment for small well differentiated SCCA localized in the anal margin, with re-excision or postoperative RT/CRT in case of involved surgical margins. The evidence supporting these strategies is limited.To study the recurrence patterns and survival outcomes in patients treated with surgery alone compared with surgery followed by postoperative RT/CRT.From a large Nordic database we identified 93 patients with stage TxT1-2N0M0 SCCA treated with surgery alone (n = 59) or surgery followed by RT/CRT (n = 34). Surgery consisted of local excision in 86 patients and abdominoperineal resection in seven patients, all of them in the surgery alone group. In 38 (41%) of the patients, the tumor was localized merely in the anal margin and in all remaining cases the anal canal was involved. Median RT dose to the tumor bed was 54 (range 46-66) Gy. Adjuvant RT to lymph nodes was given in 75% of the patients. Half of the patients received concomitant chemotherapy, usually 5-fluorouracil and mitomycin C.The locoregional recurrence (LRR) rate was significantly higher after surgery alone compared to surgery followed by adjuvant RT/CRT (36% vs. 9%, p = .006). The 3-year recurrence free survival (RFS) and overall survival (OS) were significantly better in patients who received postoperative RT/CRT than in patients who did not (3-year RFS 84.2% vs. 52.7%, p .001 and 3-year OS 87.2% vs. 70%, p = .026).Surgery alone of SCCA was associated with a high LRR rate and poor survival. The addition of postoperative RT/CRT lead to significantly improved locoregional control and survival.

Knock can be measured using in-cylinder pressure measurement. In series production, however, pressure sensors are rarely used due to cost and life time issues. Alternatives to the pressure sensor are vibration and ion sensors. However, robust knock detection using these sensors is a challenge and limits the overall engine performance and protection. By combining multiple knock indications, the performance of the overall knock detection can be improved. A classification approach is described that significantly improves the performance and robustness of knock detection. Also, the calibration is simplified, and the calibration effort reduced. A practical application on a HD natural gas fueled engine shows that the correct detection of knock given a fixed probability of false alarm is significantly improved.

Composite films were sprayed from mixtures of water soluble hydroxypropyl methylcellulose (HPMC) and either nanofibrillated cellulose (NFC) or cellulose nanocrystals (CNC). Fiber diameter was similar for both nanocelluloses but fiber length was several μm for NFC and about 200 nm for CNC. Films were characterized for morphology, swelling, mass loss and transport properties. NFC-HPMC films swelled less than CNC-HPMC films; with a HPMC content of 20 wt% NFC-HPMC and CNC-HPMC films presented swelling of 7 and 75 g/g, respectively. The swelling strongly influenced water transport across the films, with slower transport for CNC-based materials compared to NFC-based materials. The properties of NFC-based films were comparable to previous results using microfibrillated cellulose (MFC) with heterogeneous structural content and fiber lengths of ~10 μm. The findings have implications for using nanocellulose to modulate material properties in wet-state applications, with effects being in strong contrast when using as a hardening filler in dry materials. Keywords: Cellulose nanocrystals, Composite films, Controlled release, Microfibrillated cellulose, Nanofibrillated cellulose, Structure

Hypertension is a common early adverse event of anti-angiogenic treatment of cancer and may associate with treatment response. However, blood pressure measurement as a surrogate response biomarker has methodological limitations, and predictive biomarkers of angiogenesis inhibitors are lacking. In disease associated with hypertension, vasoactive peptides have been linked to cardiovascular pressure load. Here, we have explored potential associations between circulating levels of vasoactive peptides and tumor response during bevacizumab-containing treatment of colorectal cancer.Metastatic colorectal cancer (mCRC) patients with available best objective response (ORR) and time to tumor progression (TTP) data were included from a randomized clinical trial investigating maintenance therapy after first line chemotherapy plus bevacizumab. Midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic-peptide (MR-proANP), and C-terminal-prepro-vasopressin (Copeptin) vasoactive peptide concentrations were measured in plasma at baseline and after 6 weeks of chemotherapy and bevacizumab treatment (n = 97). We determined associations among clinical outcome (ORR and TTP), peptide levels, and hypertension (NCI-CTCAE 4.0 criteria), using Spearman's test, multiple linear regression, and Mann-Whitney's test.Increasing levels of vasoactive peptides from baseline and after six weeks of treatment were associated with improved treatment outcome (MR-proADM: ORR, p = .0003; TTP, p = .05; MR-proANP: ORR, p = .05; TTP, p = .03; Copeptin: ORR, p = .10; TTP, p = .02). Patients with increasing levels of all three peptides (n = 28) versus increasing levels of one or two peptides (n = 59) showed a median TTP of 284 and 225 d, respectively (p = .02).Our results suggest that increasing systemic levels of vasoactive peptides associate with improved tumor response and TTP in mCRC patients treated with a bevacizumab-containing regimen. These findings support the proposed link between the tumor vasculature and the cardiovascular system of the host. This should motivate further studies that investigate the potential role of vasoactive peptides as a novel class of dynamic biomarkers in the treatment of cancer.

Background: The majority of patients with incurable esophageal adenocarcinoma suffer from dysphagia. We assessed a novel treatment strategy with initial short-course radiotherapy followed by chemotherapy with the primary aim to achieve long-term relief of dysphagia. Methods: This phase II trial included treatment-naive patients with dysphagia due to esophageal adenocarcinoma not eligible for curative treatment. External beam radiotherapy with 20 Gy in five fractions to the primary tumor was followed by four cycles of chemotherapy (FOLFOX regimen). Dysphagia was assessed using a five-grade scale. Results: From October 2014 to May 2018 a total of 29 patients were enrolled. The rate of dysphagia improvement was 79%, median duration of improvement 6.7 months (12.2 months for responders) and median overall survival 9.9 months. In the pre-specified per protocol analysis (23 patients) the rate of dysphagia improvement was 91%, median duration of improvement 12.2 months (14.0 months for responders) and median overall survival 16.0 months. The most common grade 3–4 adverse events were neutropenia (29%), infection (25%), anorexia (11%), esophagitis (11%) and fatigue (11%). Conclusion: Initial palliative short-course radiotherapy followed by chemotherapy is a promising treatment strategy that can provide long-lasting relief of dysphagia in patients with esophageal adenocarcinoma.

Background Neoadjuvant chemotherapy in resectable gastric and esophageal adenocarcinoma is often hampered by toxicities and fragile patients resulting in dose reductions and/or treatment delays. The aim of this study was to assess how these treatment modifications affect outcome. Methods A series of 63 consecutive patients treated 2008-2014 with neoadjuvant EOX (epirubicin, oxaliplatin and capecitabine) and surgical resection, with or without adjuvant treatment, were reviewed. Chemotherapy dose index (DI), i.e. the ratio of actual to planned cumulative dose, and time index (TI), i.e. the ratio of planned to actual total duration, were calculated. Associations of neoadjuvant EOX DI and TI with histopathologic response were analysed with binary logistic regression. Time to recurrence (TTR) and overall survival (OS) were estimated using Kaplan-Meier analyses. Results Statistically significant associations were found between neoadjuvant EOX TI >= 0.95 and a major histopathologic response (0-10% residual cancer cells) and between neoadjuvant EOX DI >= 0.95 and a response with 0-50% residual cancer cells. Significantly improved TTR and OS were seen in patients with a major histopathologic response. Conclusions Our results suggest that treatment delays of neoadjuvant chemotherapy in gastric or esophageal adenocarcinoma should be avoided in order to achieve a major response.

Finding rock reinforcement solutions for poor rock conditions has attracted increased attention in recent years. While modern face drilling, long hole drilling, truck and loader technologies are able to improve productivity, rock reinforcement has become the bottleneck point in the drill and blast process. As a result, the overall productivity of underground hard rock mining has essentially stalled, especially as mines go deeper and deeper in the pursuit of orebodies. Commonly used bolt designs are not necessarily designed for ease of mechanised installation, resulting in long installation times and uncertain installation quality. The industry needs a step change in order to move forward. As part of the ground control work package of the Sustainable and Intelligent Mining Systems (SIMS) initiative, Luossavaara-Kiirunavaara AB (LKAB) and Epiroc Rock Drills AB partnered in a project to develop a rock bolting system solution to improve the productivity, flexibility, quality and safety of mechanised rock reinforcement. This paper illustrates the project background, development stages, implementation and results from new technologies that have provided significant improvements in rock bolt and mesh installation at LKAB’s Malmberget underground operation.

BACKGROUND: Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap).PATIENTS AND METHODS: Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed.RESULTS: We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C).CONCLUSIONS: Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results.CLINICALTRIALSGOV: NCT01229813.

5-fluorouracil (5FU) and mitomycin C (MMC)-based chemoradiotherapy (CRT) is standard treatment for anal squamous cell carcinoma. In this phase I study cetuximab was added and the primary aim was to determine the maximum tolerated dose (MTD) of 5FU and MMC in this combination.Patients with locally advanced anal cancer, T2 (≥4 cm)-4N0-3M0, received weekly standard doses of cetuximab starting 1 week before CRT. Intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) was given to 57.5/54.0/48.6 Gy in 27 fractions to primary tumour/lymph node metastases/adjuvant lymph node regions. 5FU/MMC was given concomitantly on RT weeks 1 and 5 according to a predefined dose escalation schedule.Thirteen patients were enrolled. Two patients discontinued cetuximab due to hypersensitivity reaction. The median age was 65 years (range 46-70), nine were females, and 85% had stage IIIB disease. Dose-limiting toxicity events (diarrheoa, febrile neutropenia and thrombocytopenia) occurred in 3 of 11 patients. The most common grade 3-4 side-effects were radiation dermatitis (63%), haematologic toxicity (54%), and diarrheoa (36%). No treatment-related deaths occurred. Three months following completion of treatment, ten patients (91%) had a local complete remission (CR), but two patients had developed liver metastases, yielding a total CR rate of 73%.The MTDs were determined as 5FU 800 mg/m(2) on RT days 1-4 and 29-32 and MMC 8 mg/m(2) on days 1 and 29 when combined with IMRT/VMAT with SIB and cetuximab in locally advanced anal cancer.

Item does not contain fulltext BACKGROUND: Both perioperative chemotherapy and postoperative chemoradiotherapy improve survival in patients with resectable gastric cancer from Europe and North America. To our knowledge, these treatment strategies have not been investigated in a head to head comparison. We aimed to compare perioperative chemotherapy with preoperative chemotherapy and postoperative chemoradiotherapy in patients with resectable gastric adenocarcinoma. METHODS: In this investigator-initiated, open-label, randomised phase 3 trial, we enrolled patients aged 18 years or older who had stage IB- IVA resectable gastric or gastro-oesophageal adenocarcinoma (as defined by the American Joint Committee on Cancer, sixth edition), with a WHO performance status of 0 or 1, and adequate cardiac, bone marrow, liver, and kidney function. Patients were enrolled from 56 hospitals in the Netherlands, Sweden, and Denmark, and were randomly assigned (1:1) with a computerised minimisation programme with a random element to either perioperative chemotherapy (chemotherapy group) or preoperative chemotherapy with postoperative chemoradiotherapy (chemoradiotherapy group). Randomisation was done before patients were given any preoperative chemotherapy treatment and was stratified by histological subtype, tumour localisation, and hospital. Patients and investigators were not masked to treatment allocation. Surgery consisted of a radical resection of the primary tumour and at least a D1+ lymph node dissection. Postoperative treatment started within 4-12 weeks after surgery. Chemotherapy consisted of three preoperative 21-day cycles and three postoperative cycles of intravenous epirubicin (50 mg/m(2) on day 1), cisplatin (60 mg/m(2) on day 1) or oxaliplatin (130 mg/m(2) on day 1), and capecitabine (1000 mg/m(2) orally as tablets twice daily for 14 days in combination with epirubicin and cisplatin, or 625 mg/m(2) orally as tablets twice daily for 21 days in combination with epirubicin and oxaliplatin), received once every three weeks. Chemoradiotherapy consisted of 45 Gy in 25 fractions of 1.8 Gy, for 5 weeks, five daily fractions per week, combined with capecitabine (575 mg/m(2) orally twice daily on radiotherapy days) and cisplatin (20 mg/m(2) intravenously on day 1 of each 5 weeks of radiation treatment). The primary endpoint was overall survival, analysed by intention-to-treat. The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02. FINDINGS: Between Jan 11, 2007, and April 17, 2015, 788 patients were enrolled and randomly assigned to chemotherapy (n=393) or chemoradiotherapy (n=395). After preoperative chemotherapy, 372 (95%) of 393 patients in the chemotherapy group and 369 (93%) of 395 patients in the chemoradiotherapy group proceeded to surgery, with a potentially curative resection done in 310 (79%) of 393 patients in the chemotherapy group and 326 (83%) of 395 in the chemoradiotherapy group. Postoperatively, 233 (59%) of 393 patients started chemotherapy and 245 (62%) of 395 started chemoradiotherapy. At a median follow-up of 61.4 months (IQR 43.3-82.8), median overall survival was 43 months (95% CI 31-57) in the chemotherapy group and 37 months (30-48) in the chemoradiotherapy group (hazard ratio from stratified analysis 1.01 (95% CI 0.84-1.22; p=0.90). After preoperative chemotherapy, in the total safety population of 781 patients (assessed together), there were 368 (47%) grade 3 adverse events; 130 (17%) grade 4 adverse events, and 13 (2%) deaths. Causes of death during preoperative treatment were diarrhoea (n=2), dihydropyrimidine deficiency (n=1), sudden death (n=1), cardiovascular events (n=8), and functional bowel obstruction (n=1). During postoperative treatment, grade 3 and 4 adverse events occurred in 113 (48%) and 22 (9%) of 233 patients in the chemotherapy group, respectively, and in 101 (41%) and ten (4%) of 245 patients in the chemoradiotherapy group, respectively. Non-febrile neutropenia occurred more frequently during postoperative chemotherapy (79 [34%] of 233) than during postoperative chemoradiotherapy (11 [4%] of 245). No deaths were observed during postoperative treatment. INTERPRETATION: Postoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery. In view of the poor postoperative patient compliance in both treatment groups, future studies should focus on optimising preoperative treatment strategies. FUNDING: Dutch Cancer Society, Dutch Colorectal Cancer Group, and Hoffmann-La Roche.

INTRODUCTION:Physical activity (PA) leads to improved survival in women following the diagnosis of breast cancer, but it is less clear whether PA has equally positive effects regardless of age at diagnosis. The purpose of our study was to evaluate the association between post-diagnosis PA and survival in women aged below or over 55 years at diagnosis.METHODS:From a prospective population-based cohort of Swedish women, we included 847 women, aged 34-84 years, who were diagnosed with breast cancer from 1992 to 2012. A PA score was calculated based on three different questions regarding self-reported PA. Cox proportional hazard model was used to estimate the association between PA and mortality.RESULTS:A significant association between PA score and all-cause mortality was observed, in a dose-response manner (ptrend = 0.01). The mortality was clearly lower in the most active compared to the least active group (hazard ratio 0.29, 95% confidence intervals 0.09-0.90). A subgroup analysis showed that the improved survival was only seen in women over 55 years of age at diagnosis.CONCLUSION:Physical activity, which is a modifiable lifestyle factor, should be encouraged after breast cancer diagnosis, especially in women with post-menopausal breast cancer.

The possibility of using photochemical internalization (PCI) to enhance the effects of the cytotoxic drug bleomycin is investigated, together with photophysical determination and outlines of a possible treatment for intravesical therapy of bladder cancer. In vitro experiments indicated that the employment of PCI technology using the novel photosensitizer TPCS2a® can enhance the cytotoxic effect of bleomycin in bladder cancer cells. Furthermore, experiments in an orthotopic in vivo bladder cancer model show an effective reduction in both the necrotic area and the bladder weight after TPCS2a based photodynamic therapy (PDT). The tumor selectivity and PDT effects may be sufficient to destroy tumors without damaging the detrusor muscle layer. Our results present a possible new treatment strategy for non-muscle invasive bladder cancer, with the intravesical instillation of the photosensitizer and bleomycin followed by illumination through an optic fiber by using a catheter.

Background Patients with esophageal cancer commonly suffer from dysphagia, leading to nutritional problems and impaired quality of life. Self-expanding metallic stents (SEMS) is frequently used in the palliative setting providing a rapid but short-term relief. In this phase II study we assessed a novel first-line treatment schedule with short-course radiotherapy followed by chemotherapy with the primary aim to achieve a long-term improvement of dysphagia. Methods Patients with dysphagia due to adenocarcinoma of the esophagus or esophagogastric junction, not eligible for curative treatment, were recruited. Treatment consisted of radiotherapy (5 x 4 Gy) followed by 4 cycles of chemotherapy (FOLFOX regimen). Dysphagia was assessed using a 5-grade scale and a response was defined as an improvement from baseline with at least one step in dysphagia score during the study treatment period or within 4 weeks after end of study treatment. Response of the primary tumour was assessed using endoscopy and PET imaging. Results From October 2014 to May 2018 a total of 29 patients were enrolled. Median age was 68 years. WHO PS (0/1/2); 10/12/7, female/male; 6/23, stage III/IV; 3/26, dysphagia score (0/1/2/3/4); 0/15/6/7/1. In the per-protocol (PP) population of 23 patients (treated with at least 4 fractions of radiotherapy and 2 cycles of chemotherapy) the rate of dysphagia improvement was 91%, the median time to improvement was 2.0 months (95% CI: 1.5, 2.5) and the median duration of improvement was 12.2 months (95% CI: 6.2, 18.2). 5 patients received SEMS during follow-up. In the PP population the endoscopic response rate was 78% with 22% complete responders, the metabolic response rate of the primary tumor was 61% with 30% complete responders. Median overall survival was 16.0 months (95% CI: 9.6, 22.5). In the safety population (28 patients who started treatment) the most frequent grade 3-4 adverse events were neutropenia (32%), infection (25%), pain (14%), esophagitis (11%) and anorexia (11%). Conclusions Palliative short-course radiotherapy followed by chemotherapy is a promising treatment strategy that can provide long-lasting relief of dysphagia in patients with esophageal adenocarcinoma. Clinical trial identification 2014-002362-74. Legal entity responsible for the study Skane University Hospital, Department of Oncology. Funding Lund University Faculty of Medicine and Skane University Hospital Funds and Donations. Disclosure All authors have declared no conflicts of interest.

Objectives To describe changes in physical activity levels related to health-enhancing physical activity guidelines during and after adjuvant chemotherapy in a cohort of Swedish patients with breast cancer. Design Exploratory clinical prospective longitudinal study with 6 and 12 months of follow-up. Participants Forty women treated for breast cancer with adjuvant chemotherapy were included, and 33 women completed the study. Main outcome measures The primary outcome was the proportion of participants meeting the health-enhancing physical activity guidelines, both in relative terms (perceived exertion using Borg’s rate of perceived exertion scale) and absolute terms (metabolic equivalent). Results The proportion of participants meeting the guidelines when leisure-time physical activity was measured in terms of absolute intensity was 81 (25/31) to 94% (31/33) during chemotherapy, 93% (29/31) at 6-month follow-up and 87% (26/30) at 12-month follow-up. Women who had been physically active before their cancer diagnosis and women who had received information about physical activity were more physically active during chemotherapy. Conclusions Swedish patients with breast cancer are generally more physically active during adjuvant chemotherapy than has been reported previously in international studies. Physical activity habits prior to cancer diagnosis and information about the benefits of physical activity appear to be important factors for higher levels of physical activity during and after chemotherapy.

Epidemiological studies have indicated that physical activity reduces the risk of developing breast cancer. More recently, sedentary behavior has been suggested as a risk factor independent of physical activity level. The purpose of the present study was to investigate occupational sedentariness and breast cancer risk in pre- and postmenopausal women.In a population-based prospective cohort study (n = 29 524), working history was assessed by a questionnaire between 1990 and 1992. Participants were classified as having: (1) sedentary occupations only; (2) mixed occupations or (3) non-sedentary occupations only. The association between occupational sedentariness and breast cancer incidence was analyzed by Cox regression, adjusted for known risk factors and participation in competitive sports.Women with a working history of occupational sedentariness had a significantly increased risk of breast cancer (adjusted HR 1.20; 95% CI 1.05, 1.37) compared with those with mixed or non-sedentary occupations. The association was stronger among women younger than 55 years (adjusted HR 1.54; 95% CI 1.20, 1.96), whereas no association was seen in women 55 years or older. Adjustment for participation in competitive sports did not change the association.We found that occupational sedentariness was associated with increased breast cancer risk, especially in women younger than 55 years. This may be a modifiable risk factor by planning breaks during the working day. Whether this reduces the risk of breast cancer needs to be further studied.

Background Podocalyxin-like protein (PODXL) is a cell surface transmembrane glycoprotein, the expression of which has been associated with poor prognosis in a range of malignancies. The aim of this study was to investigate the impact of PODXL expression on survival in esophageal and gastric adenocarcinoma. Methods The study cohort consists of a consecutive series of 174 patients with esophageal (including the gastroesophageal junction) or gastric adenocarcinoma, surgically treated between 2006 and 2010 and not subjected to neoadjuvant treatment. Immunohistochemical expression of PODXL was assessed in tissue microarrays with cores from primary tumors, lymph node metastases, intestinal metaplasia and adjacent normal epithelium. Survival analyses were performed on patients with no distant metastases and no macroscopic residual tumor. Results In the majority of cases, expression of PODXL was significantly higher in cancer cells compared to normal epithelial cells and was significantly associated with lymph node metastases and high grade tumors. In esophageal adenocarcinoma, Kaplan-Meier analyses revealed that patients with PODXL negative tumors had a superior time to recurrence (TTR) and overall survival (OS) compared to patients with PODXL positive tumors. In gastric adenocarcinoma, patients with PODXL negative tumors had a superior TTR and a trend towards an improved OS. In esophageal and gastric adenocarcinoma combined, the prognostic significance of PODXL expression on TTR was confirmed in unadjusted Cox regression analysis (HR = 5.36, 95 % CI 1.68-17.06, p = 0.005) and remained significant in the adjusted model (HR = 3.39, 95 % CI 1.01-11.35, p = 0.048). Moreover, the impact of PODXL expression on OS was also confirmed in unadjusted analysis (HR = 2.52, 95 % CI 1.31-4.85, p = 0.006) and remained significant in the adjusted model (HR = 2.03, 95 % CI 1.04-3.98, p = 0.039). Conclusions In esophageal and gastric adenocarcinoma, PODXL expression is an independent prognostic biomarker for reduced time to recurrence and poor overall survival. This is the first report on the prognostic role of PODXL in esophageal adenocarcinoma and validates recent findings in gastric cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12907-016-0034-8) contains supplementary material, which is available to authorized users.

Background There is an increasing amount of reports on IFITM1 (interferon-inducible transmembrane protein 1) in various malignancies. The aim of this study was to examine the expression of IFITM1 and its prognostic significance in gastroesophageal adenocarcinoma. Methods Tissue samples were obtained from a consecutive cohort of 174 patients surgically treated between 2006 and 2010 for gastroesophageal (gastric, gastroesophageal junction and esophageal) adenocarcinoma, not subjected to neoadjuvant therapy. Expression of IFITM1 was examined using immunohistochemistry on tissue microarrays of primary tumors and paired samples of adjacent normal epithelium, intestinal metaplasia and lymph node metastases. Results Expression of IFITM1 was significantly elevated in primary tumors and lymph node metastases compared to adjacent normal epithelium and intestinal metaplasia, regardless of tumor location. Overexpression of IFITM1 was associated with M0-disease (no distant metastases). In gastric cancer IFITM1 expression was significantly associated with improved TTR (time to recurrence) in Kaplan-Meier analysis and Cox regression, both in the unadjusted analysis (HR 0.33, 95 % CI 0.12-0.88) and in the adjusted analysis (HR 0.32, 95 % CI 0.12-0.87) but there was no significant impact on OS (overall survival). In esophageal adenocarcinoma expression of IFITM1 had no impact on TTR or OS in Kaplan-Meier-analyses, but in the adjusted Cox regression IFITM1 expression had a negative impact on both TTR (HR 3.05, 95 % CI 1.09-8.53) and OS (HR 2.71, 95 % CI 1.11-6.67). Conclusions IFITM1 was overexpressed in gastroesophageal adenocarcinoma and associated with M0-disease. In gastric cancer IFITM1 expression had a positive impact on TTR but in esophageal cancer it seemed to have an adverse impact on survival. The reason for the diverging prognostic impact of IFITM1 in esophageal and gastric cancer is unclear and warrants further studies. Electronic supplementary material The online version of this article (doi:10.1186/s40364-016-0064-5) contains supplementary material, which is available to authorized users.

Introduction: Regional and hospital decision-makers increasingly require analyses assessing the cost-benefit profile of new cancer drugs. This analysis evaluates the cost-benefit profile of nano albumin-bound paclitaxel (nab-paclitaxel) in pancreatic cancer, versus other drugs indicated in high-unmet need solid tumour indications in Nordic countries (Sweden, Denmark, Finland, Norway and Sweden). Methods: For a selected number of cancer dugs, approved for metastatic cancer or non-curable treatment intention patients by the European Medicine Agency (EMA) after 2000, and indicated in high-unmet need solid tumours (defined as OS in first line for trial comparator ≤12 months), a regression analysis was conducted. Overall treatment costs of cancer drugs, divided by OS and PFS months, were related to the clinical improvement offered versus trial comparator. Results: Eleven of 42 drugs (26.2%) with at least one indication in solid tumours met inclusion criteria. On average, a good (R 2 = 0.5359) fit between costs per OS month and OS relative benefit versus trial comparator was observed. Nab-paclitaxel offered an OS improvement of +27% versus trial comparator (average improvement: +31%), at a cost per OS month of €1,684 (average cost: €2,247). Correlation between costs per PFS month and relative PFS benefit versus trial comparator was still observed, but the goodness of fit was lower (R 2 = 0.1853) than for the OS analysis. Conclusion: Treatment costs of new cancer therapies should reflect their clinical value, consistently among different indications with comparable characteristics. Nab-paclitaxel, recently approved in pancreatic cancer, showed a similar cost per OS or PFS month ratio compared to other drugs for high-unmet need solid tumours.

Purpose The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. Patients and Methods Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. Results Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. Conclusion Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

Predictive strategies for the treatment efficacy of cetuximab are currently not available for head and neck cancer. We investigated the correlation between the expression of epidermal growth factor receptor (EGFR) ligands and EGFR expression, and the growth inhibitory activity of cetuximab in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines.The growth inhibiting effect of cetuximab was measured for eight HNSCC cell lines and correlated with the autocrine production of five EGFR ligands as measured by ELISA, and the mRNA expression of two ligands, as measured by quantitative RT-PCR. EGFR expression was assessed by western blot analysis.There was a good correlation between the expression of four of the EGFR ligands (TGF-α, amphiregulin, epiregulin and epigen) and the growth inhibiting effect of cetuximab. TGF-α had the highest predictive potential but had to be combined with epigen for full prediction. EGFR expression also correlated with cetuximab sensitivity but less clearly.The results indicate that the expression of several EGFR ligands has to be used to predict sensitivity to cetuximab in HNSCC. This has to be further evaluated in clinical samples.

Photodynamic therapy (PDT) is of increasing interest as a relevant treatment for human urinary bladder cancer. In the present experiments, the rat bladder transitional carcinoma cell line AY-27 was used as a model to study cell destruction mechanisms induced by PDT. Red LED light (630 nm) PDT with hexylaminolevulinate (HAL) as precursor for the photosensitizer protoporphyrin IX (PpIX) was used in treatment of the cells. Flow cytometry with fluorescent markers annexin V, propidium iodide and YO-PRO-1, as well as MTT assay and confocal microscopy, were used to map cell inactivation after PDT. Dark toxicity of HAL alone was low in these procedures and LD(50) (24 h, MTT assay) was approximately 1.6 J cm(-2) for standard red light (LED) irradiation (36 mW cm(-2)). Measurements done 1 h after HAL-PDT showed a maximum apoptotic level of about 10% at 6 J cm(-2), however the dominating mode of cell death was necrosis. Forward light scattering indicated an increase in cell size at low doses, possibly due to necrosis. Survival curves had a dual-slope shape, a fit to single hit, multi-target approximation gave a parameter estimate of n = 10 and D(0) about 2.6 J cm(-2). Replacing continuous light with fractionated light delivery (45 s light/60 s darkness) did not affect the treatment outcome.

Background and Purpose: In this multicentre phase I-II trial we evaluated the feasibility and efficacy of capecitabine and oxaliplatin followed by the combination of these two drugs with radiotherapy in patients with locally advanced pancreatic or biliary tract cancer. Material and methods: Thirty-nine patients with inextirpable adenocarcinoma of the pancreas, gallbladder or extrahepatic bile ducts were included. Two cycles of XELOX (capecitabine 1000 mg/m(2) bid d1-14 + oxaliplatin 130 mg/m(2) d1, q3w) were followed by XELOX-RT (radiotherapy (50.4 Gy), combined with capecitabine 750-675 mg/m(2) bid every radiotherapy day and oxaliplatin 40-30 mg/m(2) once weekly). Primary end-points were tolerance (phase I) and objective response (phase II). Results: The maximum tolerated doses of oxaliplatin and capecitabine to combine with irradiation were 30 mg/m(2) and 675 mg/m(2), respectively. Twenty-one percent (95% CI: 9-38%) of evaluable patients achieved partial response. Five patients went through surgery (three R0 resections). Two-year survival was 28%, and estimated local tumour control rate at 2 years was 72%. The most common grade 3-4 toxicity was nausea and vomiting. Conclusions: XELOX-RT (30 mg/m(2) oxaliplatin/675 mg/m(2) capecitabine in combination with 50.4 Gy/28 fractions) was well tolerated and effective for locally advanced pancreatic and biliary tract cancer. (C) 2010 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 95 (2010) 292-297 (Less)

AIMS: This study assessed radiotherapy combined with capecitabine and oxaliplatin in patients with primary, inextirpable colorectal adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients entered the trial. Two cycles of XELOX (capecitabine 1000mg/m(2) bid d1-14+oxaliplatin 130mg/m(2) d1, q3w) were followed by radiotherapy (50.4Gy), combined with capecitabine 825mg/m(2) bid every radiotherapy day and oxaliplatin 60mg/m(2) once weekly. The primary end-point was objective response. RESULTS: Forty-seven patients were evaluable. Twenty-nine (62% [95% CI: 46-75%]) achieved complete or partial response. Thirty-eight (81%) went through surgery of whom 37 (97%) had an R0 resection and five (13%) had a pathological complete response. Seventy-eight percent were alive and estimated local progression rate was 11% at 2 years. The most common grade 3+ toxicity during chemoradiotherapy was diarrhoea (24%). CONCLUSIONS: XELOX-RT was feasible and showed promising efficacy when treating patients with primary inextirpable colorectal cancer, establishing high local control rate.

The precise description of the gravitropic curvature response of plants is often difficult due to the presence of gravity when the response is recorded. Therefore, unambiguous results on the gravitropic reactions in differents segments of coleoptiles, the participation of auxin transport in the curvature development and the reactions to hypogravity stimulations can only be achieved in weightlessness. To answer these questions, curvatures of Avena coleoptiles at different distances from the apex were studied after transverse, hypogravity stimulations. The experiments were conducted in Spacelab on the Shuttle in earth orbit. Test plants were cultivated on 1.0 g-centrifuges in Spacelab. The stimulation accelerations, were between 0.1 and 1.0 g, and duration varied between 2 and 130 min. All plant responses were recorded in weightlessness by a video cassette recorder for analysis. The gravitropic curvature started almost simultaneously in apical segments, and occurred later in the basal ones. After maximum response, the curvature in the top segments showed a clear autotropic reaction, that was not seen in the basal segments. Initial wrong-way curvatures were recorded in the basal part of the coleoptiles at several g-levels. The further down along the coleoptile, the later the occurrence of the maximum gravitropic curvature of each segment. For example, after a stimulus of 25 g min the maxima appeared to travel down the coleoptile with a speed of about 50 mm h−1 in the upper and 20 mm h−1 in the lower part of the coleoptiles. It is concluded that the basipetal auxin transport can contribute only marginally to the gravitropic curvature pattern due to its much lower transport rate. Local reactions control the curvature pattern in each segment (even if the basipetal auxin transport must add to the reactions). Extrapolations from stimulus response data curves allowed some determinations of threshold stimulation times for different segments along the coleoptiles. Data for the individual segments along the coleoptiles were not at variance with the reciprocity law.

Background - A large proportion of the population in Norway has experienced headache in connection with mobile phone use, but several double-blind provocation studies with radiofrequency (RF) and sham exposures have shown no relation between headache and mobile phone RF fields. Aims - To investigate the type and location of headache experienced by participants in one provocation study in order to gain insight into possible causes and mechanisms of the headaches. Method - Questionnaire about headache, indication on figure of location of headache after exposure, interview with neurologist about headache features to make headache diagnoses. Results - The 17 participants went through 130 trials (sham or RF exposure). No significant difference existed in headache type, laterality or location between the headaches experienced with the two exposures types. In most participants, the headache was compatible with tension-type headache. Discussion - As participants experienced their typical 'mobile phone headache' both with and without RF exposure, and since the experiment did not involve the stress or the arm/head position of mobile phone use, the most likely explanation is that the headache in this situation is caused by negative expectations (nocebo). Conclusion - This and other similar studies indicate that headache occurring in connection with mobile phone use is not related to RF fields, and that a nocebo effect is important for this and possibly other headache triggers.

Epidemiological studies have indicated a connection between extremely low frequency magnetic flux densities above 0.4 microT (time weighted average) and childhood leukemia risks. This conclusion is based mainly on indoor exposure measurements. We therefore regarded it important to map outdoor magnetic flux densities in public areas in Trondheim, Norway. Because of seasonal power consumption variations, the fields were measured during both summer and winter. Magnetic flux density was mapped 1.0 m above the ground along 17 km of pavements in downtown Trondheim. The spectrum was measured at some spots and the magnetic flux density emanated mainly from the power frequency of 50 Hz. In summer less than 4% of the streets showed values exceeding 0.4 microT, increasing to 29% and 34% on cold and on snowy winter days, respectively. The average levels were 0.13 microT (summer), 0.85 microT (winter, cold), and 0.90 microT (winter, snow), with the highest recorded value of 37 microT. High spot measurements were usually encountered above underground transformer substations. In winter electric heating of pavements also gave rise to relatively high flux densities. There was no indication that the ICNIRP basic restriction was exceeded. It would be of interest to map the flux density situation in other cities and towns with a cold climate.

Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations. Funding Agencies|Swedish Research Council; Swedish Cancer Society; Medical Research Council of Southeast Sweden; Novartis