Stress urinary incontinence after hysterectomy: a 10-year national follow-up study.

PURPOSE: Hysterectomy has been associated with increased risk for developing stress urinary incontinence (SUI) and having a SUI operation. We examined the long-term rate of SUI operations after hysterectomy and associated risk factors. METHODS: We followed up 5000 women without prior urinary incontinence (UI) who had a hysterectomy in a prospective FINHYST 2006 cohort study until the end of 2016 through a national health register. The main outcome was SUI operations, and secondary outcomes were outpatient visits for UI, and their association of preoperative patient and operation factors. RESULTS: During the median follow-up time of 10.6 years (IQR 10.3-10.8), 111 (2.2%) women had a SUI operation and 241 (4.8%) had an outpatient visit for UI. The SUI operation rate was higher after vaginal hysterectomy and laparoscopic hysterectomy (n = 71 and 28, 3.3% and 1.8%, respectively) compared to abdominal hysterectomy (n = 11, 0.8%). In a multivariate risk analysis by Cox regression, the association with vaginal hysterectomy and SUI operation remained significant when adjusted for vaginal deliveries, preceding pelvic organ prolapse (POP), uterus size, age and BMI (HR 2.4, 95% CI 1.1-5.3). Preceding POP, three or more deliveries and laparoscopic hysterectomy were significantly associated with UI visits but not with SUI operations. CONCLUSION: After hysterectomy, 2.2% of women underwent operative treatment for SUI. The number of SUI operations was more than double after vaginal hysterectomy compared to abdominal hysterectomy, but preceding POP explained this added risk partially. Preceding POP and three or more vaginal deliveries were independently associated with UI visits after hysterectomy.

A randomized phase II study of stem cell mobilization with cyclophosphamide+G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma.

The most common means of mobilizing autologous stem cells is G-CSF alone or combined with cyclophosphamide (CY) to obtain sufficient CD34+ cells for one to two transplants. There are few prospective, randomized studies investigating mobilization regimens in multiple myeloma (MM), especially after lenalidomide-based induction. We designed this prospective, randomized study to compare low-dose CY 2 g/m2 +G-CSF (arm A) and G-CSF alone (arm B) after lenalidomide-based up-front induction in MM. Of the 80 initially randomized patients, 69 patients were evaluable, 34 and 35 patients in arms A and B, respectively. The primary end point was the proportion of patients achieving a yield of ⩾3 × 10(6)/kg CD34+ cells with 1-2 aphereses, which was achieved in 94% and 77% in arms A and B, respectively (P=0.084). The median number of aphereses needed to reach the yield of ⩾3 × 10(6)/kg was lower in arm A than in arm B (1 vs. 2, P=0.035). Two patients needed plerixafor in arm A and five patients in arm B (P=0.428). Although CY-based mobilization was more effective, G-CSF alone was successful in a great majority of patients to reach the defined collection target after three cycles of lenalidomide-based induction.

Assessment of myocardial perfusion with MRI using a modified dual bolus method.

Quantification of regional myocardial blood flow (rMBF) with first-pass magnetic resonance imaging (FP-MRI) requires two contrast agent injections (dual bolus technique), inducing error in the determined rMBF if the injections differ. We hypothesize that using input and residue curves of the same injection would be more reliable. We aim to introduce and evaluate a novel method to correct the high concentration arterial input function (AIF) for determination of rMBF. Sixteen patients with non-Hodgkin's lymphoma were examined before and after chemotherapy. The input function was solved by correcting initial high concentration AIF using the ratio of low and high contrast AIF areas, normalized by corresponding heart rates (modified dual bolus method). For comparison, the scaled low contrast AIF was used as an input function (dual bolus method). Unidirectional transfer coefficient K(trans) was calculated using both methods. K(trans)-values determined with the dual bolus (0.81 ± 0.32 ml g(-1) min(-1)) and modified dual bolus (0.77 ± 0.42 ml g(-1) min(-1)) methods were in agreement (p = 0.21). Mean K(trans)-values increased from 0.76 ± 0.43 to 0.89 ± 0.55 ml g(-1) min(-1) after chemotherapy (p = 0.17). The modified dual bolus technique agrees with the dual bolus technique (R2 = 0.899) when the low and high contrast injections are similar. However, when this is not the case, the modified dual bolus technique may be more reliable.

Pre-emptive plerixafor injection increases blood neutrophil, lymphocyte and monocyte counts in addition to CD34+ counts in patients with non-Hodgkin lymphoma mobilizing poorly with chemotherapy plus G-CSF: potential implications for apheresis and graft composition.

BACKGROUND: CXCR4 receptor antagonist plerixafor is used to mobilize hematopoietic stem cells. No detailed data regarding the effects of plerixafor on other blood cell components have been published but may be of importance in regard to graft composition collected after plerixafor injection. PATIENTS AND METHODS: The study included thirty-nine patients with non-Hodgkin lymphoma (NHL) mobilized with chemotherapy plus G-CSF. Plerixafor was given pre-emptively in twenty patients due to poor mobilization or low collection yield. Nineteen NHL patients served as controls. We evaluated CD34(+) counts and WBC counts and differential from the morning of the first plerixafor injection and 8h after the plerixafor injection. From the control patients the corresponding values were evaluated on the morning of the first apheresis and 24h before it. RESULTS: The first plerixafor dose increased CD34(+) counts and number of leukocytes, neutrophils, lymphocytes, eosinophils and monocytes. Leukocyte, neutrophil, lymphocyte, monocyte and eosinophil counts were higher after plerixafor injection compared to the control group at the time of the first apheresis. Minimal graft (⩾2×10(6)/kg CD34(+) cells) was collected in 85% of plerixafor treated patients, with a single apheresis in 45% of the patients. DISCUSSION: Plerixafor significantly increases B-CD34(+) cell counts on the next morning making effective blood stem cell collection possible in the majority of the patients mobilizing poorly. It also influences other blood cell components but impact of this observation in regard to graft content and post-transplant course needs to be assessed in further studies.

Kinetics of blood CD34(+) cells after chemotherapy plus G-CSF in poor mobilizers: implications for pre-emptive plerixafor use.

Mobilization and collection of stem cells is difficult in a proportion of patients intended for autologous stem cell transplantation (ASCT). We have evaluated mobilization kinetics of blood CD34(+) cells (B-CD34(+)) to form basis for algorithm to facilitate rational pre-emptive plerixafor use. Altogether 390 chemomobilized patients were included.Forty-three patients (11%) did not reach BCD34+count ≥10×10(6)/l. Mobilization kinetics differed according to the mobilization capacity observed. Among those who were very poor or inadequate mobilizers (peak BCD34(+)count ≤5×10(6)/l and 6­10×10(6)/l, respectively), BCD34+counts rarely rose after white blood cells (WBC) >5­10×10(9)/l, whereas in many standard mobilizers a later rise in CD34(+) counts could be observed. Four algorithms based on WBC and CD34(+) counts were constructed. According to this patient series, algorithm II (WBC >5×109/l and BCD34+≤10×10(6)/l) and algorithm IV (WBC >10×10(9)/l andB-CD34(+) ≤10×10(9)/l) were the most applicable. For algorithm II the sensitivity was 0.97 and specificity 1.00, respectively, to identify patients for plerixafor use provided that all patients with B-CD34+ maximum ≤10×10(6)/l would have needed plerixafor.This simple model needs a prospective validation.

Severe sepsis in autologous stem cell transplant recipients: microbiological aetiology, risk factors and outcome.

Infectious complications are the main reason for early treatment-related mortality after autologous stem cell transplantation (ASCT). We evaluated retrospectively microbiological aetiology, risk factors and clinical consequences of severe sepsis in this patient cohort. From 1996 to 2006 a total of 319 patients underwent ASCT at our institution. Antibacterial prophylaxis was not used. Neutropenic fever occurred in 83% (n=265) and was complicated by severe sepsis in 5% (n=17) of patients. Severe sepsis tended to be more common in patients with non-Hodgkin's lymphoma (NHL) than in other patients (9% vs 3%, p=0.009). Bacteraemia was observed more commonly in patients with severe sepsis (76% vs 22%, p<0.001); Pseudomonas sp. was found in 30% (n=5) of these patients. Kinetics of C-reactive protein (CRP) more commonly coincided with, rather than predicted, the development of severe sepsis. All other observed risk factors for severe sepsis (length of neutropenia, fever and blood culture findings) were late indicators. Severe sepsis was fatal in 9 patients (53%), and all had NHL (p=0.003 compared to other patients). Severe sepsis is an important cause of early mortality after ASCT, especially in NHL patients. Ways to prevent development of severe sepsis or predict its development might reduce early mortality among ASCT recipients.

Blood stem cell mobilization and collection in patients with chronic lymphocytic leukaemia: a nationwide analysis.

Some reports suggest that blood stem cell mobilization is difficult in a proportion of patients with CLL. We evaluated this issue in a large cohort of CLL patients. One hundred and twenty-eight patients with CLL underwent blood stem cell mobilization during 1995-2005 in Finland. Ninety-five percent of the patients had received fludarabine. The most common mobilization regimen was intermediate-dose CY plus G-CSF (90 patients, 70%). At least 2 x 10(6)/kg CD34+ cells were collected after the first mobilization attempt in 83 patients (65%), whereas 45 patients (35%) failed to reach this collection target. No differences were observed between these patient groups with regard to age, time from the diagnosis to mobilization, number of previous treatment lines, number of fludarabine courses, time from the last fludarabine-containing chemotherapy to mobilization, disease status or degree of marrow infiltration. Patients who failed collection had platelets <100 x 10(9)/l more commonly at the time of mobilization (30 vs 4%, P<0.001). A significant proportion of patients with CLL were difficult to mobilize. Adequate marrow function including platelet counts >100 x 10(9)/l seem to be important factors in terms of successful blood stem cell collection.

Cardiac effects within 3 months of BEAC high-dose therapy in non-Hodgkin's lymphoma patients undergoing autologous stem cell transplantation.

OBJECTIVES: Limited data are available on the cardiac effects of high-dose cyclophosphamide (CY) in patients with non-Hodgkin's lymphoma (NHL). We prospectively assessed the cardiac effects of high-dose CY in 30 adult NHL patients receiving CY 6 g/m(2) as part of BEAC high-dose therapy (HDT). METHODS: Radionuclide ventriculography (RVG) and plasma natriuretic peptide (NT-proANP, NT-proBNP) measurements were performed simultaneously prior to BEAC at baseline (d - 7), 12 days (d + 12) and 3 months (m + 3) after stem cell infusion (D0). In addition to these time points, natriuretic peptides were measured 2 days before (d - 2) and 1 week (d + 7) after stem cell infusion. RESULTS: Left ventricular ejection fraction (LVEF) decreased from d - 7 (53% +/- 2%) to d + 12 (49% +/- 2%, P = 0.009). However, no significant change in cardiac diastolic function was observed. The LVEF returned towards baseline by m + 3. Plasma NT-proANP and NT-proBNP increased significantly from baseline (445 +/- 65 pmol/L and 129 +/- 33 pmol/L) to d - 2 (1,127 +/- 142 pmol/L, P < 0.001 and 624 +/- 148 pmol/L, P < 0.001, respectively). Thereafter, they started to decrease, but on d + 7 NT-proANP (404 +/- 157 pmol/L, P = 0.048) and NT-proBNP (648 +/- 125 pmol/L, P = 0.015) were still significantly higher than at baseline. On d + 12 and m + 3 they no longer differed from baseline. CONCLUSIONS: Our findings suggest that high-dose CY results in acute, subclinical systolic dysfunction in NHL patients previously treated with anthracyclines. Natriuretic peptides seem to be more sensitive than LVEF to reflect this transient cardiac effect. Serial measurements of natriuretic peptides might be a useful tool to assess cardiac effects of high-dose CY.

High-dose melphalan (200 mg/m2) supported by autologous stem cell transplantation is safe and effective in elderly (>or=65 years) myeloma patients: comparison with younger patients treated on the same protocol.

Limited information is available on the feasibility and efficacy of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients >65 years of age. In 1995-2005, 22 myeloma patients >or=65 years (median 68, eight >or=70) and 79 patients <65 years (median 57) were included in an identical treatment protocol. The first progenitor cell mobilization with cyclophosphamide plus granulocyte-colony stimulating factor (G-CSF) was successful in 95 and 96% of the patients, respectively. To date, 92 patients have received MEL (melphalan) 200 mg/m2 supported by ASCT. No early treatment-related deaths were observed among 22 elderly patients, whereas one younger patient died early. Engraftment and the need for supportive care were comparable between groups. The elderly patients tended to have more WHO grade 3-4 oral or gastrointestinal toxicity when compared to the younger patients (45 vs 23%, P=0.06). After ASCT, a complete response was observed in 44% of the elderly patients and 36% of the younger patients, respectively. No difference was observed between these age groups in progression-free survival (23 vs 21 months) or overall survival (57 vs 66 months) after ASCT. We conclude that MEL200 is a safe and efficacious treatment in selected elderly myeloma patients.

Very acute cardiac toxicity during BEAC chemotherapy in non-Hodgkin's lymphoma patients undergoing autologous stem cell transplantation.

Cardiotoxicity is potentially the most threatening nonhaematological side effect of high-dose CY. We prospectively evaluated the very acute cardiac effects of high-dose CY in 17 adult non-Hodgkin's lymphoma (NHL) patients receiving CY 1500 mg/m2/day as a part of BEAC high-dose therapy (HDT). Magnetic resonance imaging (MRI) and plasma natriuretic peptide (NT-proBNP, NT-proANP) measurements were performed prior to HDT (d-7) and just after completing HDT (d-2). After the high-dose CY left atrial end-systolic area increased from 15.2+/-1.2 to 18.5+/-1.4 cm2 (P=0.001), left ventricular end-diastolic volume from 136.1+/-12.3 to 156.6+/-11.1 cm3 (P=0.04) and left ventricular end-systolic volume from 67.4+/-7.8 to 75.3+/-7.1 cm3 (P=0.018). However, no significant change in left ventricular ejection fraction (LVEF) was observed. At the same time, plasma levels of NT-proBNP increased from 134.9+/-53.3 to 547.1+/-168.4 pmol/l (P=0.003) and NT-proANP from 481.1+/-105.5 to 1056.6+/-193.1 pmol/l (P=0.001), respectively. To conclude, high-dose CY results in very acute cardiac toxicity characterised by enlargement of the heart chambers in NHL patients previously treated with anthracyclines. This toxicity can be detected with increased concentrations of circulating natriuretic peptides but not with LVEF measurement.

Outcome of progressive disease after autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a nation-wide survey.

OBJECTIVES: To analyse outcome and prognostic factors in non-Hodgkin's lymphoma (NHL) patients who progress after autologous stem cell transplantation (ASCT). PATIENTS: Altogether 115 consecutive NHL patients transplanted in 1991-2000 were studied. Histology included diffuse large B cell (n = 52), follicular (n = 26), mantle cell (n = 15), T cell (n = 16) and other subtypes (n = 6). The median time from ASCT to the progression was 7 months. Ninety-six patients (83%) received salvage treatment. RESULTS: Twenty-four patients (25%) achieved complete remission and 30 (31%) partial remission. The median overall survival was 8 months (range 0-98+) and the projected 4-year survival 21%. In multivariate analysis factors predicting treatment response after the progression included the use of rituximab (P = 0.036), histology other than diffuse large B cell (P = 0.001) and International Prognostic Index < or =2 at progression (P < 0.001). Normal lactate dehydrogenase (LDH) at progression (P = 0.002), response to salvage treatment (P < 0.001) and time from ASCT to progression > or =7 months (P = 0.022) were predictors for overall survival. CONCLUSIONS: Although the prognosis of patients who progress after ASCT is generally poor, many patients will respond to current therapies, and some may experience prolonged survival. Normal LDH at time of disease progression and longer time to progression after ASCT were the most powerful predictors for a promising outcome.

Prediction of mobilisation failure in patients with non-Hodgkin's lymphoma.

Factors affecting progenitor cell mobilisation in patients with non-Hodgkin's lymphoma (NHL) are incompletely understood. We have analysed factors predicting mobilisation failure in 97 consecutive patients with NHL (59 males, 38 females; median age 49 years) who received mobilisation with intermediate-dose CY (4 g/m(2)) followed by G-CSF. The histology included large cell B (N=50), mantle cell (N=16), follicular (N=16) and other NHL (N=15). The disease status was 1CR/PR/primary refractory in 66 patients and >1 CR/PR in 31 patients. The minimum criterion for successful mobilisation was the collection of >or=1.5 x 10(6)/kg CD34(+) cells. In all, 18 patients (19%) failed to reach this threshold. In univariate analysis, premobilisation factors associated with mobilisation failure included BM involvement at the time of diagnosis (P=0.001) or prior to mobilisation (P=0.001) and low platelet count just prior to mobilisation (P=0.001). In multivariate analysis, only BM involvement at diagnosis (P=0.004) and platelet count just prior to mobilisation (P=0.01) were associated with mobilisation failure. A mathematical model based on these two factors and presented in the form of a receiver operating characteristics curve showed a sensitivity of 0.71 and a specificity of 0.77 in the prediction of mobilisation failure. Patients at a high risk of mobilisation failure may benefit from novel approaches.

Is chemotherapy scoring useful to predict progenitor cell mobilisation in patients with non-Hodgkin's lymphoma?

About 10-30% of patients with non-Hodgkin's lymphoma (NHL) intended to receive high-dose therapy are difficult to mobilise. Damage to the stem cell pool caused by previous chemotherapy may be an important factor in predicting progenitor cell mobilisation. We have analysed associations between chemotherapy score and efficiency of progenitor cell mobilisation in 120 consecutive NHL patients mobilised with intermediate-dose cyclophosphamide (4 g/m(2)) plus G-CSF. The original chemotherapy scoring system proposed by Drake et al was applicable in only 27% of our patients and was not predictive for mobilisation outcome. Therefore we made an improved scoring system for previous chemotherapy by adding new drugs. Altogether, 111 patients (93%) could be scored. Our chemotherapy score showed an inverse correlation with the peak blood CD34(+) count measured after the mobilisation (r=-0.214, P=0.024) and with the number of CD34(+) cells collected (r=-0.234, P=0.02). However, in the receiver operating characteristics curve, no threshold value could be detected for chemotherapy score predicting mobilisation failure. Thus, both the original scoring system as well as our more widely applicable scoring system seem to be of limited value in predicting progenitor cell mobilisation in patients with NHL.

BEAC or BEAM for high-dose therapy in patients with non-Hodgkin's lymphoma? A single centre analysis on toxicity and efficacy.

High-dose chemotherapy supported by autologous stem cell transplantation is widely used in patients with non-Hodgkin's lymphoma (NHL). Limited data is available on the comparative toxicity and efficacy of various high-dose regimens applied in NHL. We therefore analysed regimen-related toxicity and outcome in 71 consecutive NHL patients who received either BEAC (N = 36) or BEAM (N = 35) supported by peripheral blood progenitor cell infusion plus granulocyte colony-stimulating factor. The patients who received BEAM had significantly more often WHO grade > 2 mucositis (63 vs. 28%, P = 0.009) and diarrhoea grade >2 (29 vs. 8%, P = 0.062). Septicaemia also tended to be more frequent and the peak CRP value was higher in the BEAM group (140 vs. 113 mg/l, P = 0.034). Transplant-related mortality (< 100 d) was 3 and 9% in the BEAC and BEAM groups, respectively. No significant differences were observed in overall survival or progression free survival between these two groups. While BEAC and BEAM appears to have equal antitumour efficacy in patients with NHL, BEAM seems to be more toxic to the gastrointestinal tract. However, randomised studies are needed for more definitive conclusions on the relative merits of various high-dose regimens in patients with NHL.

A pilot study on feasibility and efficacy of amifostine preceding high-dose melphalan with autologous stem cell support in myeloma patients.

To evaluate feasibility and potential efficacy of amifostine (AMI) in the prevention of toxicities associated with high-dose melphalan (MEL), ten myeloma patients received AMI 910 mg/m2 in 15 min infusion preceding MEL 200 mg/m2 followed by stem cell infusion (AMI group). Hematologic and extra-hematologic toxicities as well as the need for supportive care observed in the AMI group were compared with ten myeloma patients treated in an identical protocol but without AMI. Hypotension was the most important adverse event of AMI infusion. No differences were observed in the time of engraftment between the AMI group and the control group neither was there any difference in the need for supportive care. Oral mucositis grade >2 was observed in 30% of the patients in both groups. Diarrhea grade >2 occurred only in two AMI patients but in five control patients. AMI preceding high-dose MEL is feasible, although adverse events are observed in some patients. Whether AMI could reduce the gastrointestinal toxicity associated with high-dose MEL can be reliably assessed only in prospective randomized trials.

Physical map of a 1.5 mb region on 12p11.2 harbouring a synpolydactyly associated chromosomal breakpoint.

Synpolydactyly (SPD) is a rare malformation of the distal limbs known to be caused by mutations in HOXD13. We have previously described a complex form of SPD associated with synostoses in three members of a Belgian family, which co-segregates with a t(12;22)(p11.2;q13.3) chromosomal translocation. The chromosome 12 breakpoint of this translocation maps to 12p11.2 between markers D12S1034 and D12S1596. Here we show that a mutation in the HOXD13 gene is not responsible for the phenotype, and present a physical map of the region around the 12p11.2 breakpoint. Starting from D12S1034 and D12S1596, we have established a contig approximately 1.5 Mb in length, containing 13 YAC clones, 16 BAC clones, and 11 cosmid clones. FISH analysis shows that cosmid LL12NCO1-149H4 maps across the breakpoint, and Southern blot experiments using fragments of this cosmid as probes identify a rearranged BamHI fragment in the patients carrying the translocation. A search for expressed sequences within the contig have so far revealed one CpG island, seven anonymous ESTs and three previously characterised genes, DAD-R, KRAG and HT21, all of which were found not to be directly disrupted by the translocation. The gene represented by EST R72964 was found to be disrupted by the translocation. These findings lay the groundwork for further efforts to characterise a gene critical for normal distal limb development that is perturbed by this translocation.

A novel human processed gene, DAD-R, maps to 12p12 and is expressed in several organs.

A cDNA of a processed gene of human DAD-1 (defender against apoptotic cell death) was cloned from the human neuroblastoma cell line SH-SY5Y. The genomic sequence of this novel processed gene, DAD-R, lacked introns and was flanked by 8 bp terminal repeats. RT-PCR showed that the transcript is expressed predominantly in testis, ovaries, pancreas, lung and skeletal muscle. DAD-R has several possible initiation codons, one of them producing an open reading frame comprising 75% of the DAD-1 gene. We determined the chromosomal localization of DAD-R as 12p11.2-12p12.1, an area linked to familial synpolydactyly and frequently amplified in a variety of cancers, including those of testis, ovaries, pancreas and lungs.