Lung cancer registries in Denmark, Finland, Norway and Sweden: a comparison and proposal for harmonization.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in all Nordic countries which, though similar in demographics and healthcare systems, have noticeable differences in lung cancer survival. Historically, Denmark and Finland have had higher lung cancer incidences and lower survival than Norway and Sweden. All four countries have national cancer registries. Data in these registries are often compared, but their full potential as a source of learning across the Nordic countries is impeded by differences between the registries. In this paper, we describe and compare the Nordic registries on lung cancer-specific data and discuss how a more harmonized registration practice could increase their usefulness as a source for mutual learning and quality improvements. METHODS: We describe and compare the characteristics of data on lung cancer cases from registries in Denmark, Finland, Norway and Sweden. Moreover, we compare the results from the latest annual reports and specify how data may be acquired from the registries for research. RESULTS: Denmark has a separate clinical lung cancer registry with more detailed data than the other Nordic countries. Finland and Norway report lung cancer survival as relative survival, whereas Denmark and Sweden report overall survival. The Danish Lung Cancer Registry and the Swedish Cancer Registry do not receive data from the Cause of Death registries in contrast to the Finnish Cancer Registry and the Cancer Registry of Norway. CONCLUSION: The lung cancer registries in Denmark, Finland, Norway and Sweden have high level of completeness. However, several important differences between the registries may bias comparative analyses.

Impact of health care organization on surgical lung cancer care.

OBJECTIVES: Organization and governance of national healthcare might play an important role in decision-making and outcomes in patients with lung cancer. Both Denmark and the Netherlands have a high level of healthcare but a different financial coverage, governance and level of centralization. By using both national databases we analyzed the consequences of these differences on patterns of care and outcomes with a focus on morbidity, mortality and clinical staging. MATERIALS AND METHODS: General numbers on both healthcare systems were requested. All patients who had surgery for lung cancer from 2013 to 2016 were included. Mortality, morbidity and clinical staging were analyzed for patients with NSCLC without metastases, only one operation and no neo-adjuvant therapy. RESULTS: In 2016 annual budget as share of gross national product was 10.4% for both countries. In Denmark 4 hospitals performed lung surgery in 2016, compared to 43 hospitals in the Netherlands. We included 4030 Danish and 8286 Dutch patients. In the subgroup 30-day mortality was 1.5% in Denmark compared to 1.9% in the Netherlands. The percentage of patients with a complicated course was 24.4% and 34.8% respectively (p < 0.05). Accuracy between cTNM and pTNM was 53.0% in Denmark and 52.9% in the Netherlands. CONCLUSION: Surgery for lung cancer is at a high level in both countries, reflected by low mortality-rates. Centralization has been implemented successfully in Denmark, which might explain the lower rate of patients with a complicated post-operative course, although different definitions preclude firm conclusions. In both countries correct clinical staging of lung cancer remains a challenge.

Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.

Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods: Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information: NCT01506609.

History of Depression in Lung Cancer Patients: Impact of Delay.

AIMS: To examine the influence of a history of depression in the process of diagnostic evaluation and the choice of treatment in lung cancer. MATERIALS AND METHODS: The analysis was based on all patients with non-small cell lung cancer who were registered in 2008-2014; in total, 27 234 patients. To estimate the effect of depression on the diagnostic process and the choice of treatment in lung cancer we fitted a logistic regression model and a Cox regression model adjusting for age, gender, resection and stage. RESULTS: Depression in a patient's anamnesis had no significant effect on the delay in diagnostic evaluation (hazard ratio = 0.99 with 95% confidence interval 0.90; 1.09). Patients with a history of periodic depression had a 33% lower treatment rate (odds ratio = 0.66 with 95% confidence interval 0.51; 0.85) than patients without a history of depression. CONCLUSIONS: Our study shows that patients with a history of periodic depression need special attention when diagnosed with lung cancer.

Consequences of persistent pain after lung cancer surgery: a nationwide questionnaire study.

BACKGROUND: post-thoracotomy pain syndrome (PTPS) and its social consequences have been inconsistently investigated as most studies were either small sized, focused on a limited number of risk factors or included heterogeneous surgical procedures. The current objectives were to obtain detailed information on the consequences of PTPS after thoracotomy and video-assisted thoracic surgery (VATS) from homogenous unselected nationwide data, and to suggest mechanisms for the development of PTPS. METHODS: data from 1327 patients were collected using a prospective national database and combined with a detailed questionnaire. RESULTS: the response rate was 81.5%, resulting in 546 patients without prior thoracic surgery for the final analysis. Follow-up was 22 months (range 12-36). PTPS occurred in 33% thoracotomy patients and 25% VATS patients. Clinically relevant pain was present in 11-18% of the patients and severe pain in 4-12% depending on the level of physical activity. In PTPS patients, 64% also had pain from other locations on the body. Perceived sensory changes in the thoracic area were present in 63% of PTPS patients vs. 25% in pain-free patients (P<0.001). When comparing VATS with thoracotomy, no consistent differences in the prevalence, distribution of pain, sensory changes or effect of pain on daily activities were observed although clinically relevant and severe pain was reduced after VATS. CONCLUSIONS: this nationwide study corroborates that PTPS is a clinically relevant problem influencing daily activities a long time after thoracotomy and VATS. Nerve injury and increased pain responsiveness may explain the majority of symptoms, the prevalence and distribution of pain including perceived sensory sensations.

The prognostic importance of cyclooxygenase 2 and HER2 expression in epithelial ovarian cancer.

Both cyclooxygenase 2 (COX2) and human epidermal growth factor receptor 2 (HER2, also called c-erbB-2) overexpression have been related to a worse prognosis in epithelial ovarian cancer (EOC), but the data are conflicting and the percentage of tumors with overexpression varies widely in different studies. The aim of this study was to investigate the potential prognostic value of COX2 and HER2 expression in EOC. A further purpose was to investigate a possible coexpression of the two markers, and finally, to elucidate the agreement between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for evaluation of the HER2 status in EOC. Immunostaining was performed for COX2/HER2 together with FISH analysis for HER2 gene amplification in 160 patients with EOC, FIGO stages IIB-IV. Follow-up was more than 10 years. COX2 overexpression was found in 20.0% of the tumors. With HER2 staining, 64.4% were scored as 0, 24.4% as 1+, 6.9% as 2+, and 4.4% as 3+. Median survival time for COX2-negative tumors was 21.6 versus 36 months for COX2-positive tumors. The longer survival for COX2 positive was significant by both univariate analysis (P= 0.015) and multivariate analysis (P= 0.025). Positive immunostaining for HER2 was associated with poor overall survival (P= 0.03). Agreement between IHC and FISH was seen in all cases (P < 0.0000001). With long-term observation, patients with negative COX2 expression had significantly shorter survival compared to patients with COX2-positive tumors. Positive HER2 expression also notified a grave prognosis, but the low rate of overexpression reduces its potential clinical application.

Prognostic significance of p53, Her-2, and EGFR overexpression in borderline and epithelial ovarian cancer.

The objective of the study was to evaluate the prognostic effect of p53, Her-2, and EGFR in borderline and epithelial ovarian cancer. Tumor tissue from 85 patients with borderline and 783 patients with epithelial ovarian cancer stage I-IV were analyzed immunohistochemically for p53 positivity and over-expression of Her-2 and EGFR. In the ovarian cancer (OC) group 415 patients (53%) had p53-positive tumors, 272 (35%) had tumors with Her-2 over-expression, and 483 (62%) had over-expression of EGFR. In the OC group the classical prognostic factors (older age, higher FIGO stage, and poorer differentiated stage) had significant prognostic value in both uni- and multivariate analyses. Multivariate analyses in the OC group proved p53 positivity to increase mortality significantly depending on the grade of the tumor. Her-2 likewise increased the risk of mortality significantly in this group depending on the grade of the tumor. EGFR on the other hand did not have any additional prognostic effect in the OC group after adjustment for the classical prognostic and molecular factors was made. In the borderline group Her-2 and EGFR over-expression in combination, adjusted for age and p53, significantly improved the prognosis.

Combination chemotherapy containing mitoguazone, ifosfamide, methotrexate, etoposide (MIME) and G-CSF efficiently mobilize peripheral blood progenitor cells in heavily pre-treated relapsed lymphoma patients.

In this study we explored whether a standard chemotherapy regimen consisting of mitoguazone, ifosfamide, methotrexate and etoposide (MIME) combined with 5 micrograms/kg or 10 micrograms/kg G-CSF was capable of mobilizing peripheral blood progenitor cells (PBPC) in lymphoma patients. Thirty-three patients with Hodgkin's disease (HD) and 108 patients with non-Hodgkin's lymphoma (NHL) were mobilized with MIME/G-CSF. Most patients were heavily treated with different chemotherapy regimens receiving a median of 11 cycles (range 3-40) of chemotherapy prior to mobilization. Eight of 141 patients failed to mobilize PBPC and bone marrow was harvested. In addition, 10 patients obtained a harvest of < 2.0 x 10(6) CD34+ cells/kg. More than 2.0 x 10(6) CD34+ cells/kg were achieved in all HD patients and in 83% of the NHL patients. Fifty-eight per cent of the patients harvested > or = 5 x 10(6) CD34+ cells/kg. Eleven per cent of the patients developed neutropenic fever during the mobilization and 3% had nadir platelet values below 20 x 10(9)/L. An inverse correlation was observed in high-grade NHL (H-NHL) patients between the number of chemotherapy cycles given before mobilization and yield of CD34+ cells. Such an association was not seen among patients with HD, transformed and low-grade NHL. When G-CSF 10 micrograms/kg was used in combination with MIME, this correlation was no longer seen in patients with H-NHL. There was also association between CD34+ cell yield and prior radiotherapy in patients with HD or transformed NHL or low-grade NHL. These results demonstrate that an ordinary salvage chemotherapy regimen, such as MIME combined with G-CSF, can be successfully used to mobilize PBPC. Although no significant effect of increased dose of G-CSF was found, our data suggest that MIME/G-CSF 10 micrograms/kg should preferentially be used to mobilize PBPC in H-NHL patients pre-treated with > or = 12 cycles of chemotherapy, in irradiated HD patients and in all low-grade and transformed lymphomas.

Combination chemotherapy with mitoguazon, ifosfamide, MTX, etoposide (MIME) and G-CSF can efficiently mobilize PBPC in patients with Hodgkin's and non-Hodgkin's lymphoma.

Many centers use CY and G-CSF to mobilize PBPC. In this study we explored whether a standard chemotherapy regimen consisting of mitoguazon, ifosfamide, MTX and etoposide (MIME) combined with G-CSF was capable of mobilizing PBPC in lymphoma patients. Twelve patients with Hodgkin's disease (HD) and 38 patients with non-Hodgkin's lymphoma (NHL) were mobilized with MIME/G-CSF. Most patients were heavily treated with different chemotherapy regimens receiving a median of 11 cycles (range 3 to 20) of chemotherapy prior to mobilization. It was found that the optimal time of PBPC harvest was at days 12 and 13 after initiating the mobilization regimen. The median number of collected CD34+ cells per kg body weight was 7.1 x 10(6) (range 0.5-26.2). More than 2.0 x 10(6) CD34+ cells/kg were achieved in 69% of the patients after one apheresis. When additional cycles of apheresis were done, only 6% failed to harvest this number of CD34+ cells. There was a statistically significant inverse correlation between the number of prior chemotherapy cycles and CD34+ cell yield (P = 0.003). No such association was found between CD34+ cell yield and prior radiotherapy. When MIME/G-CSF was compared with Dexa-BEAM/G-CSF, it was found that MIME/G-CSF tended to be more efficient in mobilizing PBPC in spite of being less myelotoxic. All patients transplanted with MIME/G-CSF mobilized PBPC had fast and sustained engraftment. These results demonstrate that an ordinary salvage chemotherapy regimen, such as MIME combined with G-CSF can be successfully used to mobilize PBPC.

["Blue rubber bleb nevus syndrome"--or Bean's syndrome]. / "Blue rubber bleb naevus syndrome"--eller Beans syndrom.

We describe a case of the blue rubber bleb naevus syndrome, an uncommon systemic disorder characterized by multiple bluish haemangiomas of the skin and gastrointestinal tract. The syndrome is commonly associated with iron deficiency anaemia due to gastrointestinal bleeding. The syndrome is likely to be caused by a gene mapping to chromosome 9p and showing autosomal dominant inheritance. This is the first Danish report of this unusual disease. We hope that this case will heighten the awareness of this condition, because early recognition is essential for appropriate medical intervention and genetic counselling.

Suramin in non-small cell lung cancer and advanced breast cancer. Two parallel phase II studies.

Suramin inhibits the growth of non-small cell lung cancer (NSCLC) and breast cancer in vitro by blocking the action of most known growth factors. The clinical efficacy of suramin was evaluated in patients with unresectable or relapsed NSCLC (n = 16) and advanced breast cancer (ABC) resistant to conventional therapies (n = 12). A plasma level > or = 200 micrograms/ml was maintained by three times weekly administrations using adaptive control with feedback. Treatment was continued until documented progression of disease or unacceptable toxicity. No clinical responses were observed in any patient. Median overall survival was 4.5 months in NSCLC and 9 months in ABC patients. Mean treatment duration was 6.6 weeks in NSCLC patients and 15.9 weeks in ABC patients. Treatment was discontinued due to disease progression in 14 patients, unacceptable adverse effects in 11 patients, while three patients refused to continue therapy. We cannot recommend this drug for further clinical trials in NSCLC and ABC.

Immunomagnetic purging of lymphoma cells from autografts.

This report describes experiences at the Norwegian Radium Hospital in immunomagnetic purging of lymphoma from autologous stem cell grafts by negative and positive selection. Clinical data from 83 patients who received purged marrow grafts and 3 patients who received purged, mobilized leukapheresis products are presented. Early data indicate that immunomagnetic enrichment of CD34+ cells from leukapheresis products does not routinely achieve effective purging, as 1%-2% residual lymphoma cells could still be detected in the selected grafts.

[High-dose therapy with autologous stem cell support in malignant lymphoma and breast cancer. Experiences with hematopoietic stem cells isolate from blood]. / Høydosebehandling med autolog stamcellestøtte ved malignt lymfom og cancer mammae. Erfaring med hematopoetiske stamceller høstet fra blod.

Since 1994, 17 breast cancer patients and 16 lymphoma patients have been treated at the Norwegian Radium Hospital with high-dose therapy supported by autologous peripheral progenitor cells. All the patients were given granulocyte colony stimulating factor in the recovery phase after cytotoxic treatment in order to mobilize and harvest peripheral progenitor cells. Aphareses were successful in all patients and the mean number of CD34 cells reinfused per kilo body weight was 7.05 x 10(6) for the lymphoma patients and 11.1 x 10(6) for the breast cancer patients. The mean time to recover > or = 0.5 x 10(9)/l granulocytes and > or = 20 x 10(9)/l platelets after reinfusion of stem cells was 10 days and 11.7 days respectively for the lymphoma patients, while the breast cancer patients engrafted at day 8.6 and day 9.3. No severe treatment-related complications were observed.

[High-dose therapy of cancer with CD34 positive cells as stem cell support]. / Høydosebehandling av kreft ved bruk av CD34-positive celler som stamcellestøtte.

In this article we report our initial clinical experiences in connection with immunomagnetic isolated CD34-positive cells from peripheral blood progenitor cells. Six patients, five with breast cancer and one with non-Hodgkin's lymphoma, were mobilized by chemotherapy and G-CSF (5ug/kg). CD34-positive cells were isolated by means of immunomagnetic beads (Dynalbeads) and Isolex 300 Cell Separator (Baxter, USA). Mean purity of isolated CD34-positive cells was 97% (94.7-99.7) and mean yield was 54% (35-68). Three patients were treated with high dose therapy followed by reinfusion of CD34-positive cells as stem cell support. Recovery of neutrophils (> 0.5 x 10(9) leucocytes/liter) occurred at day 8, 11 and 13 and of platelets (> 20 x 10(9) platelets/litre) at day 9,14 and 32. It is concluded that immunomagnetic isolated CD34-positive cells give high purity and yield. Although use of CD34-positive cells reduces the content of contaminating tumour cells in the graft, breast cancer cells were still detectable in two out of five CD34-positive cell products.

Activation of coagulation and deep vein thrombosis after bone marrow harvesting and insertion of a Hickman-catheter in ABMT patients with malignant lymphoma.

Evidence of activation of coagulation was sought in serial plasma samples from 25 ABMT candidates with malignant lymphoma admitted for bone marrow harvesting: 10 females and 15 males, median age 41 years (range 27-58 years). Nineteen patients had non-Hodgkin's lymphoma (NHL) and six had Hodgkin's disease. Of those with NHL, 14 had high-grade and five low- grade disease. The plasma levels of markers of activation (prothrombin fragment 1 + 2, thrombin-antithrombin complexes, fibrinopeptide A and fibrinmonomers) increased significantly (P < 0.001) in association with harvesting. Except for fibrinopeptide A, the indicators of activation were still significantly elevated 24 h after marrow aspiration. Beta-thromboglobulin, a marker of the platelet release reaction, also increased significantly (P < 0.01). Four out of nine patients in whom a long-term central venous catheter was inserted just after marrow aspiration, developed catheter-related deep vein thrombosis, verified venographically, shortly after harvesting. These results suggest that patient with malignant lymphoma undergoing marrow harvesting develop a hypercoagulable state, and that insertion of a central intravenous catheter immediately after marrow harvesting should be avoided to prevent the development of symptomatic deep vein thrombosis.

[Chemotherapy-induced hemolytic uremic syndrome. A complication to mitomycin treatment of breast carcinoma]. / Kjemoterapiindusert hemolytisk uremisk syndrom. En komplikasjon til mitomycinbehandling ved carcinoma mammae.

Mitomycin is a cytotoxic antibiotic that was first introduced into clinical use in 1958. Not until twenty years later was it recognised that haemolytic uremic syndrome could develop after treatment with mitomycin. It can be asked whether this condition was undiagnosed in previous years, since its frequency is now reported to be 4-15%. The disease appears to be dose-related, since it rarely occurs in patients who have received mitomycin < 30 mg/m2. No effective therapy has been established. We describe two patients with breast cancer in remission after treatment with mitomycin in combination with 5-fluorouracil. Both developed haemolytic uremic syndrome with fatal outcome.

Prognosis after nephrectomy for renal cell carcinoma.

During the period 1977-1988 177 males and 81 females (age 28-87 years) had nephrectomy performed for renal cell carcinoma. The most frequent symptoms were flank pain (54%) and hematuria (53%). Few patients (6%) had the classical triad of symptoms. Overall survival at 2 and 5 years were 0.55 and 0.41. Renal cell carcinoma specific survival were 0.59 and 0.49. Univariate analyses showed that increasing T stage, positive N or M stage, increasing stage according to Robson, hypersedimentation, anaemia and perioperative blood transfusion had a significant detrimental influence on survival. Multivariate analysis showed that simple Robson stage gave a simpler and equally good description as did the TNM stage. In the Cox multiple regression analysis Robson stage and ESR were the only statistically significant variables.

Perioperative blood transfusion does not affect survival after operation for renal cell cancer.

We retrospectively studied the effect of perioperative blood transfusion in 208 transfused and 50 nontransfused patients operated on during a 12-year period for renal cell cancer. The 5-year renal cell cancer specific survival rate was 0.46 in the transfused patients versus 0.62 in the nontransfused patients. However, when differences in risk factors were accounted for by Cox regression analysis, perioperative blood transfusion was not a significant risk factor. The study does not support the hypothesis that blood transfusion promotes death after operation for renal cell cancer.