Jari Sjöberg

MED12, the Mediator Complex Subunit 12 Gene, Is Mutated at High Frequency in Uterine Leiomyomas

Uterine fibroids frequently harbor mutations in a specific gene that has been implicated in transcriptional regulation. Uterine leiomyomas, or fibroids, are benign tumors that affect millions of women worldwide and that can cause considerable morbidity. To study the genetic basis of this tumor type, we examined 18 uterine leiomyomas derived from 17 different patients by exome sequencing and identified tumor-specific mutations in the mediator complex subunit 12 (MED12) gene in 10. Through analysis of 207 additional tumors, we determined that MED12 is altered in 70% (159 of 225) of tumors from a total of 80 patients. The Mediator complex is a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. All mutations resided in exon 2, suggesting that aberrant function of this region of MED12 contributes to tumorigenesis.

Urinary tract injuries after hysterectomy

Objective To evaluate the nationwide incidence and characteristics of urinary tract injuries after laparoscopic hysterectomy, total abdominal hysterectomy, supracervical abdominal hysterectomy, and vaginal hysterectomy. Methods We analyzed retrospectively 142 urinary tract injuries after hysterectomy, reported to the National Patient Insurance Association in Finland from 1990 through 1995. The Finnish Hospital Discharge Register collects data on procedures from all hospitals, and 62,379 hysterectomies were carried out during the study period. Results The total incidence of ureteral injury after all hysterectomies was 1.0 of 1000 procedures: 13.9 of 1000 after laparoscopic, 0.4 of 1000 after total abdominal, 0.3 of 1000 after supracervical abdominal, and 0.2 of 1000 after vaginal hysterectomy. Difficulties during an operation with a ureteral injury were encountered in 51%, 76%, 100%, and 100%; the failure rates of primary repair of a ureteral injury were 5%, 12%, 0%, and 0%; and the convalescence times after a ureteral injury were 86 days, 94 days, 71 days, and 47 days after laparoscopic, abdominal, supracervical abdominal, and vaginal hysterectomies, respectively. The incidence of bladder injury was 1.3 of 1000 procedures. Sixty-five percent of reported bladder injuries were fistulas, giving an incidence of vesicovaginal fistula of 0.8 of 1000 procedures after all hysterectomies: 2.2 of 1000 after laparoscopic, 1.0 of 1000 after total abdominal, 0 of 1000 after supracervical abdominal, and 0.2 of 1000 after vaginal hysterectomy. Difficulties during an operation with a bladder injury were encountered in 53%, 37%, 100%, and 0%; the failure rates of primary repair of a simple bladder injury were 5%, 18%, 0%, and 0%; the failure rates of primary repair of a vesicovaginal fistula were 17%, 20%, 0%, and 0%; and the convalescence times after a bladder injury were 51 days, 118 days, 71 days, and 99 days after laparoscopic, abdominal, supracervical abdominal, and vaginal hysterectomy, respectively. Conclusion The risk of ureteral injury is higher after laparoscopic hysterectomy compared with traditional hysterectomies.

Major complications of laparoscopy: a follow-up Finnish study.

Abstract Objective: To examine recent figures on major laparoscopic complications in Finland. Methods: This was a nationwide record-linkage study from January 1995 through December 1996 including all Finnish hospitals performing gynecologic laparoscopies. Data files of the National Patient Insurance Association and the Finnish Hospital Discharge Register were used. Data were compared with previous results from 1990 to 1994. Results: Among 32,205 gynecologic laparoscopies, 130 major complications were noted. The total complication rate was 4.0 per 1000 procedures: 0.6 per 1000 in diagnostic laparoscopies, 0.5 per 1000 in sterilization, and 12.6 per 1000 in operative laparoscopies. Intestinal injuries were reported in 0.7 per 1000, incisional hernias in 0.3 per 1000, urinary tract injuries in 2.5 per 1000, major vascular injuries in 0.1 per 1000, and other injuries in 0.5 per 1000 gynecologic laparoscopic procedures. Seventy-five percent (88 of 118) of the major complications in operative laparoscopies occurred during hysterectomies. The total major complication rate decreased from 4.9% in 1993 to 2.3% in 1996 (χ 2 = 8.55, P = .003), but the incidence of ureteral injuries remained stable, at about 1% of laparoscopic hysterectomies. Ureteral injuries were most common in local hospitals (2.6%), followed by central (1.1%) and university hospitals (0.9%). From 1990 through 1996, the relative risk for ureteral injury in laparoscopic hysterectomies, compared with other operative laparoscopies was 29.0 (95% confidence interval [CI] 13.3, 63.0), for bladder injury 13.0 (95% CI 6.0, 28.2), for intestinal injury 1.3 (95% CI 0.6, 2.5), and for major vascular injury 0.4 (95% CI 0.1, 3.6). Compared with the figures for 1990–1994, all major complications in operative laparoscopies increased, from 0 per 1000 in 1990 to 14.0 per 1000 in 1996 (χ 2 = 20.28, P Conclusion: Laparoscopic hysterectomies are still associated with a stable 1% risk of ureteral injury, whereas other major complications were decreasing until 1996. Complications in other laparoscopic procedures generally are rare.

Characterization of Uterine Leiomyomas by Whole-Genome Sequencing

BACKGROUND Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions. METHODS We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women. RESULTS Identical variants observed in some separate tumor nodules suggested that these nodules have a common origin. Complex chromosomal rearrangements resembling chromothripsis were a common feature of leiomyomas. These rearrangements are best explained by a single event of multiple chromosomal breaks and random reassembly. The rearrangements created tissue-specific changes consistent with a role in the initiation of leiomyoma, such as translocations of the HMGA2 and RAD51B loci and aberrations at the COL4A5-COL4A6 locus, and occurred in the presence of normal TP53 alleles. In some cases, separate events had occurred more than once in single tumor-cell lineages. CONCLUSIONS Chromosome shattering and reassembly resembling chromothripsis (a single genomic event that results in focal losses and rearrangements in multiple genomic regions) is a major cause of chromosomal abnormalities in uterine leiomyomas; we propose that tumorigenesis occurs when tissue-specific tumor-promoting changes are formed through these events. Chromothripsis has previously been associated with aggressive cancer; its common occurrence in leiomyomas suggests that it also has a role in the genesis and progression of benign tumors. We observed that multiple separate tumors could be seeded from a single lineage of uterine leiomyoma cells. (Funded by the Academy of Finland Center of Excellence program and others.).

FINHYST, a prospective study of 5279 hysterectomies: complications and their risk factors

BACKGROUND Hysterectomy guidelines highlight an increase in urinary tract injuries with laparoscopic hysterectomy (LH). This national survey analyses complications of LH, abdominal hysterectomy (AH) and vaginal hysterectomy (VH). METHODS A prospective cohort undergoing hysterectomy for benign indications during 2006 was drawn from 53 hospitals in Finland; all communal hospitals participated. Detailed questionnaires covered surgical data and intra- and post-operative major and minor complications, for which risk factors were analysed by a multivariate logistic regression model adjusted for surgical data and patient characteristics. RESULTS Major complications rates in AH (n= 1255, 24%), LH (1679, 32%) and VH (2345, 44%) were 4.0, 4.3 and 2.6%, and total complications rates were 19.2, 15.4 and 11.7%, respectively. Logistic regression showed no statistically significant differences between approaches for any organ injuries or other major complications. Most bladder and bowel injuries (88 and 83%), but not ureter injuries (10%), were recognized intra-operatively. The ureter injury rate was low after LH (0.3%), as it was after other types of hysterectomy. Compared with LH, AH increased the odds of wound infection, and was an independent risk factor for urinary infections and febrile events. Compared with AH, LH and VH both presented a higher risk for pelvic infection; surgically treated equally often regardless of the type of hysterectomy. No differences in complications emerged between LH and VH. Obesity was a risk factor for many infections. Surgical adhesiolysis [odds ratio (OR) 2.41, 95% confidence interval (CI) 1.38-4.21] was the strongest single risk factor for major complications as a whole. Bladder injury was associated with a history of caesarean section (OR 4.01, 95% CI 2.06-7.83) and with a large uterus ≥500 g (OR 2.88, 95% CI 1.05-7.90), while bowel injury was associated with adhesiolysis (OR 29.07, 95% CI 7.17-117.88). CONCLUSIONS FINHYST is a large prospective hysterectomy study illustrating actual complications. Whenever possible, hysterectomy should be minimally invasive.

Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors

Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.

Finnish national register of laparoscopic hysterectomies: A review and complications of 1165 operations

OBJECTIVE We evaluated the advantages and disadvantages of laparoscopic hysterectomy over a 2-year period when this new technique was introduced to several hospitals in Finland. STUDY DESIGN A nationwide register was founded and a prospective multicenter survey of 1165 laparoscopic hysterectomies was carried out from January 1993 to December 1994. The operations were performed because of uterine fibroids (54%), menorrhagia (27%), dysmenorrhea (8%), endometriosis (2%), and other reasons (9%) by 68 gynecologists at 30 hospitals. RESULTS The mean operation time was 132 minutes. The patients stayed in hospital for an average of 3.3 days, and the mean convalescence period was 17.9 days, half that after abdominal hysterectomy. Complications occurred in 10.2% of the procedures: infections in 5.6%, vascular complications in 1.2%, urinary tract complications in 2.7%, and bowel complications in 0.4%. CONCLUSIONS Laparoscopic hysterectomy offers a short hospital stay and convalescence time to the patient, but effective teaching is imperative to minimize, in particular, the risk of urinary tract injuries.

Evaluation and the learning curve of the first one hundred laparoscopic hysterectomies

Background. We analyzed the first one hundred laparoscopic hysterectomies done by one senior gynecologist to study the learning curve and complications of this technique.

Clinical outcome and tissue trauma after laparoscopic and abdominal hysterectomy: a randomized controlled study

BACKGROUND To evaluate clinical outcome and tissue trauma after laparoscopic and abdominal hysterectomy. METHODS Fifty women scheduled for abdominal hysterectomy were randomized to undergo either laparoscopic (n = 25) or abdominal (n = 25) hysterectomy. Surgical characteristics, hospital stay, convalescence and complications were analyzed. Blood samples for assay of markers of tissue trauma (interleukin-6, C-reactive protein, tumor-associated trypsin inhibitor and tumor-associated antigen CA 125) were taken preoperatively, on the first, second and seventh postoperative day and at the follow-up visit four weeks after surgery. RESULTS In uncomplicated hysterectomies (n = 18) the operating time (85.3 min versus 57.5 min, p < 0.00001) was longer for laparoscopic group but the hospital stay (2.1 days versus 3.4 days, p < 0.00001) and sick leave (21.4 days versus 38.5 days, p < 0.00001) were shorter in the laparoscopic group. Postoperative increases in all markers were significant in both groups. The interleukin-6 concentration was highest on the first postoperative day in both groups, that of C-reactive protein on the second postoperative day in both groups, tumor-associated trypsin inhibitor on the seventh postoperative day in the laparoscopic group and on the second postoperative day in the abdominal group and tumor-associated antigen CA 125 on the seventh postoperative day in both groups. Both interleukin-6 and C-reactive protein levels were lower in the laparoscopic group on the first (p = 0.01 and p = 0.03, respectively) and on the second postoperative day (p = 0.02 and p < 0.001, respectively) compared with the abdominal group. No differences were seen in tumor-associated trypsin inhibitor and tumor-associated antigen CA 125 levels between the groups. CONCLUSION Laparoscopic hysterectomy should replace abdominal hysterectomy whenever possible because of a more favorable clinical outcome and less tissue trauma.

FINHYST 2006—national prospective 1-year survey of 5 279 hysterectomies

BACKGROUND In Finland, the number of hysterectomies during one decade has decreased by 34%. The national prospective FINHYST study in 1996 showed abdominal hysterectomy (AH) as being most common: 58%. In Finland since 2002, vaginal hysterectomy (VH) has been most preferred, with laparoscopic hysterectomy (LH) surpassing AH in 2005. METHODS FINHYST 2006 is a national prospective hysterectomy study in which all hospitals collaborated from 1 January to 31 December 2006. Questionnaires, completed by gynaecologists, covered their experience, patient characteristics and surgical data. RESULTS The 5279 hysterectomies distributed by approaches were 44% VHs, 32% LHs and 24% AHs. Less than 2% were subtotal. The main indications for hysterectomy were myomas (33%), uterine prolapse (28%) and menorrhagia (21%). The main indication for VH was not related to uterine prolapse in 39%. Bilateral salpingo-ooforectomy was performed in 36% of AHs, 32% of LHs and 2% of VHs. Antibiotic prophylaxis was used in 97%, and thrombosis prophylaxis in 65%. Haemorrhage was least and operation time shortest with VH, and hospital stay and sick leave were shortest after LH. CONCLUSIONS In Finland, less invasive approaches comprise 76% of hysterectomies. This trend has resulted nationally in shortening of hospital stay and of convalescence time.