Twenty years experience in treating childhood medulloblastoma: Between the past and the present.

PURPOSE: Medulloblastoma is the most common primary malignant central nervous system tumour in children. These last decades, treatment modalities have largely evolved resulting in better survival rates. Nevertheless, long-term toxicity is a major concern in this setting. The purpose of this study was to analyse the clinical results and medical outcomes of a cohort of paediatric patients treated for medulloblastoma in Xhinhua Hospital in Shanghai. These results are compared with those from other centres reported in literature. PATIENTS AND METHODS: This was a retrospective study conducted at Xhinhua Hospital in Shanghai, China. It included 121 patients treated for medulloblastoma from 1993 to December 2013. RESULTS: Mean age at diagnosis was 6.7 years (range: 1-14.3 years). Total surgical resection was achieved in 60% of the cases. Classic medulloblastoma was found in 59% of the cases. Adjuvant radiotherapy was delivered in all cases and chemotherapy concerned 70.2% of the studied cohort. The median follow-up time of the study was 84 months (range: 24-120 months). Five- and 10 years progression-free survival rates were 83.2%, and 69.5% and 5 years and 10 years. Overall survival rates were 82.5%, and 72.5%. Patient's age significantly influenced survival: patients under 3 years old had the worse outcomes (P=0.01). T and M stages also significantly impacted survival rates: advanced stages were associated with lower rates (P=0.08 and 0.05 respectively). Finally, patients receiving temezolomide had bad outcomes when compared to the new standard protocol used in the department (P=0.03). The most commonly reported late toxicity was growth suppression in 35 patients (52.2%). Hypothyroidism requiring hormone replacement was recorded in 29% of the cases. Hearing loss, and problems including poor concentration, poor memory and learning difficulties were reported in 19% and 25% of the cases respectively. Second cancers were noted in three cases. CONCLUSION: Overall, our results are comparable to those reported in literature. Nevertheless, efforts should be made to ensure longer follow-ups and correctly assess treatment-related toxicity.

Analysis of National Institutes of Health Funding in Hand Surgery.

Background: Federal research dollars help investigators develop biomedical therapies for human diseases. Currently, the state of funding in hand surgery is poorly understood. This study defines the portfolio of National Institutes of Health (NIH) grants awarded in hand surgery. Methods: This was a cross-sectional study of hand surgeons in the US. Faculty members of accredited hand surgery fellowships and/or members of the American Society for Surgery of the Hand were queried in the NIH RePORT database for awards obtained during 2005-2015. Results: Of 2317 hand surgeons queried, only 18 obtained an NIH grant (0.8%). Thirty-eight unique grants were identified totaling $42 197 375. R01 awards comprised the majority of funding (78.0%) while K08 awards accounted for 1.1%. The K-to-R transition rate was zero. The National Institute of Arthritis and Musculoskeletal and Skin Disease supported the most funding (65.2%), followed by the National Institute of Neurological Disorders and Stroke (30.8%). There was no statistically significant difference in NIH funding totals with hand surgeon characteristics. Funding supported translational (46.0%), basic science (29.6%), clinical (21.0%), and education-based (3.4%) research. Peripheral nerve (33.3%) and bone and joint disease (30.1%) received the most research funding. Conclusions: Less than 1% of hand surgeons obtain NIH research grants. Of the 2 identified K08 awards, none led to a subsequent R award. Future research should identify barriers to grant procurement to design effective policies to increase NIH funding in hand surgery.

The Current State of Surgical Ergonomics Education in U.S. Surgical Training: A Survey Study.

OBJECTIVE: The aim of this study was to characterize the current state of surgical ergonomics education in the United States. BACKGROUND: The burden of work-related musculoskeletal disorders (MSDs) in surgeons is high and no overarching strategy for redress exists. Twelve distinct specialties describe an unmet need for surgical ergonomics education (SEE). This study aimed to define the current state of SEE in U.S. surgical training programs. METHODS: We performed a descriptive analysis of a 20-item questionnaire of ACGME-certified program directors from 14 surgical and interventional medical specialties. Formal SEE was defined as any organized education module that reviewed the occupation-specific burden of common work-related MSDs and described a framework for prevention via occupation-specific applied ergonomics. Program directors were queried regarding SEE provision, characteristics, and perceived trainee attitude toward the education. RESULTS: Questionnaires were received from 130 of 441 (29.5%) program directors. Two (1.5%) provided formal SEE and 33 (25.4%) provided informal SEE, which consisted of unstructured intraoperative directives and isolated lectures. Two programs previously provided SEE but discontinued the effort due to lack of an evidence-based framework and instructors. Trainees appeared to think that learning surgical ergonomics skills was a worthwhile time investment in 100% and 76.7% of current formal and informal SEE, respectively. CONCLUSION: SEE is rarely provided in any capacity (25.4%), let alone in a consistent or evaluable fashion (1.5%). Impediments to sustainable SEE include lack of an evidence-based framework for education and instructors. An evidence-based, reproducible, and accreditation council-compliant SEE module would be a valuable resource for the surgical and interventional medical communities.

Does Hormone Therapy Use Increase Perioperative Complications in Abdominally Based Microsurgical Breast Reconstruction?

BACKGROUND: The use of hormone therapy (tamoxifen and aromatase inhibitors) has been shown to increase venous thromboembolism. As breast cancer patients undergoing microsurgical breast reconstruction are often receiving hormone therapy, it is unclear whether this increased thrombotic risk is associated with increased flap loss. METHODS: A retrospective review was performed on patients undergoing abdominally based microsurgical breast reconstruction at an academic institution from 2004 to 2015. Patients were divided by use of hormone therapy at the time of surgery. Complication rates, including complete or partial flap loss and overall complications, were compared and analyzed using univariate and logistic regression models. RESULTS: Among a total of 853 patients (1253 flaps), 193 patients (269 flaps) were receiving hormone therapy and 660 patients (984 flaps) were not. Patients on hormone therapy had higher rates of previous breast surgery, advanced cancer stage, chemoradiation before reconstruction, and delayed and unilateral reconstruction. There were no statistically significant differences between hormone therapy patients and nontherapy patients in complete flap loss (1.0 percent versus 1.1 percent) and partial flap loss (2.2 percent versus 1.5 percent). Hypertension and previous breast surgery were the only independent risk factors for minor complications (adjusted OR, 2.1; 95 percent CI, 1.3 to 3.6; p = 0.005; and adjusted OR, 1.8; 95 percent CI, 1.2 to 2.7; p = 0.009, respectively) and overall complications (adjusted OR, 2.2; 95 percent CI, 1.3 to 3.7; p = 0.004; and adjusted OR, 1.9; 95 percent CI, 1.3 to 3.0; p = 0.003, respectively). CONCLUSIONS: Hormone therapy was not associated with a higher incidence of complete or partial flap loss or overall complications. The authors propose an individualized approach to the preoperative cessation of tamoxifen or aromatase inhibitors. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Comparing Head and Facial Computed Tomographic Imaging in Identifying Operative Facial Fractures.

BACKGROUND: Patients who present for a trauma workup often have a head computed tomography (CT) performed to identify intracranial pathology. Facial fractures are routinely identified in these patients, and further imaging is the norm with dedicated facial CT scans. Additional imaging increases radiation doses; however, it is unclear if additional operative fractures are identified. The aim of this study was to examine differences between these 2 CT imaging modalities. METHODS: A retrospective review of all operative facial trauma patients receiving both head and facial scans at a single institution was performed (1999-2012). Identified fracture patterns were compared between the head and facial CT scans of each patient to determine if the results correlated. Demographic information and injury mechanism were compared. RESULTS: A total of 307 patients receiving both types of CT scan underwent facial fracture repair. In the 106 patients (35%) with differences identified fractures between the scans, 151 additional operative fractures were found through dedicated facial imaging: nasal fractures (58 vs 15; P < 0.001), midface fractures (69 vs 34; P < 0.001), zygoma fractures (51 vs 21; P < 0.001), and orbital fractures (90 vs 51; P < 0.001). No differences in demographics or mechanisms of injury were observed between groups. CONCLUSIONS: Standard head CT scans alone failed to identify a significant number of operative facial fractures compared with facial CT in 35% of patients. Dedicated facial CT scans should be considered for patients with known or suspected facial fractures, even if a head scan has been performed previously.

Prevalence of Work-Related Musculoskeletal Disorders Among Surgeons and Interventionalists: A Systematic Review and Meta-analysis.

Importance: Physicians in procedural specialties are at high risk for work-related musculoskeletal disorders (MSDs). This has been called "an impending epidemic" in the context of the looming workforce shortage; however, prevalence estimates vary by study. Objectives: To estimate the prevalence of work-related MSDs among at-risk physicians and to evaluate the scope of preventive efforts. Data Sources and Study Selection: Systematic search in MEDLINE (Ovid), Embase (Elsevier), Web of Science, PubMed (National Center for Biotechnology Information), and 2 clinical trial registries, without language restriction, for studies reporting on the prevalence and prevention of work-related MSDs among at-risk physicians published until December 2016. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for meta-analyses and systematic reviews of observational studies were used. At-risk physicians were defined as surgeons and medical interventionalists. Studies reporting on specific disorders or pain assessed with validated instruments were included. Data Extraction and Synthesis: Study characteristics; disease prevalence for the neck, shoulder, back, and upper extremity; and measures of resulting disability were recorded. Study estimates were pooled using random-effects meta-analytic models. Main Outcomes and Measures: Career prevalence of injuries and 12-month prevalence of pain. Results: Among 21 articles (5828 physicians [mean age, 46.0 years; 78.5% male; 12.8 years in practice; 14.4 hours performing procedures per week]) included in this systematic review and meta-analysis, pooled crude prevalence estimates of the most common work-related MSDs were degenerative cervical spine disease in 17% (457 of 2406 physicians) (95% CI, 12%-25%), rotator cuff pathology in 18% (300 of 1513 physicians) (95% CI, 13%-25%), degenerative lumbar spine disease in 19% (544 of 2449 physicians) (95% CI, 5%-16%), and carpal tunnel syndrome in 9% (256 of 2449 physicians) (95% CI, 5%-16%). From 1997 to 2015, the prevalence of degenerative cervical spine disease and degenerative lumbar spine disease increased by 18.3% and 27%, respectively. Pooled prevalence estimates for pain ranged from 35% to 60% and differed by assessment instrument. Of those with a work-related MSD, 12% (277 of 2319 physicians) (95% CI, 7%-18%) required a leave of absence, practice restriction or modification, or early retirement. Heterogeneity was considerable for all crude analyses (mean I2 = 93.5%) but was lower for sensitivity analyses (mean I2 = 72.3%). Interventions focused on products and behaviors. Twelve at-risk specialties described a gross lack of awareness and an unmet need for ergonomics education. Conclusions and Relevance: Prevalence estimates of work-related MSDs among at-risk physicians appear to be high. Further research is needed to develop and validate an evidence-based applied ergonomics program aimed at preventing these disorders in this population.

Work-Related Musculoskeletal Disorders among Plastic Surgeons: A Systematic Review.

BACKGROUND: To date, no review has been conducted on the growing body of literature describing various work-related musculoskeletal disorders (MSDs), ergonomic hazards, and potential interventions relevant to plastic surgeons. This systematic review sought to (1) define the scope of coverage of this important issue in the peer-reviewed literature; (2) critically assess the evidence; and (3) provide recommendations for future directions. METHODS: We conducted a literature search of MEDLINE, Embase, Web of Science, and PubMed from the inception of each database until 2016. All articles reporting on work-related MSDs or ergonomics among plastic surgeons were reviewed, summarized, and assessed for trends. RESULTS: Sixteen articles met our inclusion criteria including five expert opinions, four cross-sectional studies and case reports/series, one review, and six experimental studies. Four articles presented evidence on disease burden. The most commonly described work-related MSD was cervical spine disease, for which one study reported a career prevalence of 24.7% (point prevalence in the general population: 0.1-0.4%); three studies reported 64 cases of surgeon work-related MSD resulting in surgical intervention, decreased productivity, or involuntary early retirement. Eight studies described interventions, most of which aimed to improve the ergonomics of microsurgery. CONCLUSION: This review found low-level evidence of plastic surgeons' vulnerability to a work-related MSD at times severe enough to end careers. Further investigation is needed to clearly define this important problem in plastic surgery. Specifically, future directions should include more methodologically rigorous epidemiologic studies evaluating disease burden.

A novel pilot animal model for the surgical prevention of lymphedema: the power of optical imaging.

BACKGROUND: Breast cancer-related lymphedema affects more than 400,000 survivors in the United States. In 2009, lymphatic microsurgical preventive healing approach (LYMPHA) was first described as a surgical technique to prevent lymphedema by bypassing divided arm lymphatics into adjacent veins at the time of an axillary lymph node dissection. We describe the first animal model of LYMPHA. METHODS: In Yorkshire pigs, each distal hind limb lymphatic system was cannulated and injected with a different fluorophore (human serum albumin-conjugated indocyanine green or Evans Blue). Fluorescence-assisted resection and exploration imaging system was used to map the respective lymphangiosomes to the groin. Baseline lymphatic clearance of each hind limb lymphangiosome was obtained by measuring the fluorescence of each dye from centrally obtained blood samples. A lymphadenectomy versus lymphadenectomy with LYMPHA was then performed. The injections were then repeated to obtain clearance rates that were compared against baseline values. RESULTS: Human serum albumin-conjugated indocyanine green and Evans Blue allowed for precise lymphatic mapping of each respective hind limb using fluorescence-assisted resection and exploration imaging. Lymphatic clearance from the distal hind limb dropped 68% when comparing baseline clearance versus after a groin lymphadenectomy. In comparison, lymphatic clearance dropped only 21% when comparing baseline clearance versus a lymphadenectomy with LYMPHA. CONCLUSIONS: We describe the first animal model for LYMPHA, which will enable future studies to further evaluate the efficacy and potential limitations of this technique. Of equal importance, we demonstrate the power of optical imaging to provide real-time lymphatic clearance rates for each hind limb.

Literacy analysis of National Comprehensive Cancer Network patient guidelines for the most common malignancies in the United States.

BACKGROUND: Cancer information is of critical interest to the public. The National Comprehensive Cancer Network (NCCN) offers a series of comprehensive patient guidelines on the management of the most common cancer diagnoses. This study was aimed at assessing the health literacy demands of NCCN patient guidelines for the most common malignancies in the United States. METHODS: The American Cancer Society's most common malignancies by annual incidence in the United States and their corresponding NCCN patient guidelines were identified. Four validated tools were used to evaluate literacy levels: 1) the Simple Measure of Gobbledygook, 2) the Peter Mosenthal and Irwin Kirsch readability formula (PMOSE/IKIRSCH), 3) the Patient Education Materials Assessment Tool (PEMAT), and 4) the Clear Communication Index from the Centers for Disease Control and Prevention (CDC). RESULTS: The average reading grade level was 10.3, which was higher than the recommended 6th-grade level. The average PMOSE/IKIRSCH score was 11; this corresponded to moderate complexity and required some college-level education for interpretation. Only 1 tool, the PEMAT, yielded scores above the benchmarks for high-quality materials. The PEMAT's understandability, actionability, and overall scores were 94%, 83%, and 91%, respectively. The average CDC index was 85%, which was below the recommended 90% for an appropriate health literacy demand. CONCLUSIONS: Overall, the assessment indicates high demand scores for the readability and complexity of the NCCN patient guidelines and thus that the materials are not quite suitable for the general US adult population. Further input from patient focus groups to address appropriateness and usefulness is critical. Cancer 2018;124:769-74. © 2017 American Cancer Society.

Primary spinal glioma in children: Results from a referral pediatric institution in Shanghai.

PURPOSE: Primary spinal cord glioma is a rare entity especially in children; accounting for less than 10% of all central nervous system tumors. Low grade is the most reported subtype. Treatment modalities have largely evolved; large improvements have been made in the surgical field but also in both of radiotherapy and chemotherapy. Nevertheless, the optimal treatment is yet to be defined. MATERIAL AND METHODS: A chart review of 11 pediatric patients with a diagnosis of low grade spinal cord glioma at Xhinhua hospital in Shanghai was conducted. A statistical package for Social Sciences Package (SPSS) was used for analysis. Means and standard deviations were calculated. The Kaplan-Meier method was used to analyze overall survival and progression-free survival. RESULTS: The mean age was 6.7 years (range: 6 months-14.3 years). Revealing symptoms were variable and slowly progressive. The mean duration of symptoms prior to diagnosis was of 7±3.2 months. Astrocytoma was the most commonly reported histological type (seven cases, 63.6%), ependymomas were reported in three cases (27.3%). Surgery was performed in all patients. Subtotal resection concerned the majority of patients (nine patients, 81.8%). Adjuvant radiotherapy was indicated in all cases. A total dose of 39.6Gy was delivered to the whole group. Three patients received adjuvant chemotherapy, of whom two patients had grade III glioma and one patient had a tumor recurrence. Temozolomide-based regimen was the main protocol used for all our patients. The 3 years overall survival rate was 100%, whereas the progression free survival rate was 87.5%. One case relapsed during the next year following completion of treatment. CONCLUSION: Our preliminary results are consistent with that of other similar published reports, however longer follow up is needed. So are specific recommendations that are still lacking in this setting.

Protective effect of ischemia preconditioning on ischemia-reperfusion injury in rat liver transplantation.

We explored the protective effect of ischemia preconditioning (IP) on ischemia-reperfusion injury in rat liver transplantation. An orthotopic liver transplantation model was utilized in the study. A total of 54 Sprague-Dawley rats were divided into a control group (group A, no liver transplantation), liver transplantation group (group B, heparin Ringer's lactate solution was perfused via the portal vein before donor liver collection), and liver transplantation with IP group (group C, IP was performed for different time periods before donor liver collection). Liver function, B-cell lymphoma 2 expression in hepatic cells, cell apoptosis, and cellular ultrastructure changes were detected after surgery. After surgery, serum alanine aminotransferase activity was significantly higher in group B than in group A, while it was not clearly enhanced in group C and decreased progressively with increasing cycles of IP as bile capacity gradually increased. Compared with group B, group C showed alleviated injury of hepatic cells, increased B-cell lymphoma 2 expression, and a lower apoptosis index. IP had a protective effect on ischemia-reperfusion injury in rat liver transplantation, and the mechanism correlated with increased B-cell lymphoma 2 expression in hepatic cells and inhibition of cell apoptosis.

Small cell neuroendocrine carcinoma of the cervix: analysis of the prognosis and role of radiation therapy for 43 cases.

OBJECTIVE: To explore the outcomes and pattern of recurrence in patients with small cell neuroendocrine carcinoma of the cervix (SCNEC), and to determine the effects of adjuvant radiation therapy on survival in patients with early-stage disease. METHODS: A retrospective analysis of 43 patients with SCNEC was carried out at Zhejiang Provincial Tumor Hospital between January 1985 and August 2007. All pathological specimens were examined and definitively diagnosed by two independent pathologists. The radiotherapeutic efficacy and prognosis of SCNEC were explored. Patient survival status was analyzed with the Kaplan-Meier method and survival rate was compared with the log-rank test; p < 0.05 was considered statistically significant. RESULTS: Of 43 patients, 32 were early-stage and 11 were advance-stage. The median age was 45 years (range 25-85 years). There were 21 cases of metastasis or progression occurring in the lungs, retroperitoneal lymph node and brain within two years. In early-stage patients, distant metastasis or progression occurred in 13 cases within two years. The estimated 5-year survival rate for the entire group was 29%. Median overall survival for patients with early-stage disease was 89.6 months and 34.4 months for patients with advance-stage disease (p = 0.001). The 3-year survival for early-stage patients who received postoperative adjuvant chemotherapy was 57.1% compared with 56.4% for those who underwent adjuvant chemoradiotherapy, and their median survival periods were 84.7 and 89.1 months, respectively (p = 0.671). CONCLUSION: We confirmed the unfavorable prognosis related to early nodal and hematogenous metastasis in SCNEC, resulting in a relatively poor prognosis; clinical staging was an important prognostic factor. Chemoradiotherapy may be provided for advance-stage patients. For early-stage patients, the efficacy and site of postoperative adjuvant radiotherapy need further evaluation.

The roles of centrosome in cancer development.

The accumulation of a series of genetic alterations involving the activation of proto-oncogenes and inactivation of tumor suppressor genes has long been regarded as a major driving force in carcinogenesis. Therefore, cancer is currently considered a genetic disease induced by DNA damage. However, the molecular etiology remains enigmatic. In recent years, the centrosome, together with the embedded centrioles and connecting filaments (or microtubules), has come to be regarded as the "brain" of a cell, being a key in maintaining genetic stability and in coordinating other cellular activities. Abnormalities in the centrosome and/or microtubules may result in unequal chromosome segregation leading to genetic alterations. Therefore, cancer is appropriately interpreted primarily as a "brain illness" of a cell rather than a genetic disease. We provide a brief overview of the latest advances in the understanding of the roles of the centrosome in cancer development, and then we discuss the mechanisms causing centrosome abnormalities and the implications for future research.

[Treatment of hemangioma in oral and maxillofacial region with intralesional injection of pingyangmycin].

OBJECTIVE: To investigate the indication and long term treatment results of intralesional injection of Pingyangmycin for hemangiomas in oral and maxillofacial regions. METHODS: Between June 1986 and June 2000, 1040 patients with maxillofacial hemangiomas were treated by intralesional injection of Pingyangmycin PYM . There were 312 males and 712 females. The types of hemangiomas included capillary 436, cavernous 238, mixed 260, arterial venous malformation 8 and port wine stain 9 . The injection was performed in stages and multi sites, repeated after 14 to 21 days for 2 to 3 times as one course. RESULTS: All the patients were followed up for 1 to 14 years. The cure rates of capillary, mixed and cavernous hemangioma were 96.40%, 92.20% and 67.20%, respectively. No effect was found for arterial venous malformations. The best dose effect was attained in 1mg/cm(2). The best concentration of Pingyangmycin was 1mg/ml for capillary hemangioma and the concentration may be higher for cavernous hemangiomas. Fever occurred in 6.54% of the cases. Serious complications associated with Pingyangmycin injection, such as pulmonary fibrosis were not found. CONCLUSION: Intralesional injection of Pingyangmycin can be used as the therapy of choice for capillary, mixed and cavernous hemangiomas in oral and maxillofacial region. The advantages included a high cure rate, safety, short course, manipulation with ease and fewer side effects.

Influence of adhesion molecule expression by human brain microvessel endothelium on cancer cell adhesion.

Cultures of endothelial (En) cells derived from human brain microvessels were established in order to characterize adhesion molecule expression and to assay the adhesion properties of neoplastic cell lines to monolayers of En cells. Low constitutive expression of beta1 integrin (CD29), and ICAM-2 (CD102) was detected on human brain microvessel En cells. The beta1 chain of the VLA integrin family, ICAM-1, E-selectin (CD62E) and VCAM-1 (CD106) but not ICAM-2 and PECAM-1 (CD31) expression was upregulated by IL1-alpha, and TNF-alpha proinflammatory cytokines. High expression of PECAM-1 was found on non-activated human brain EN cells. In order to study the potential role of adhesion molecules in neoplastic cell adhesion two tumor cell lines were chosen. Adhesion of a cell line (DU145) derived from a cerebral metastasis of prostate carcinoma to human brain microvessel En cell monolayers was less pronounced compared to adhesion of a primary prostate carcinoma cell line (ND1). Adhesion of cerebral metastatic neoplastic cell line (DU145) was not significantly influenced by incubation of endothelial cells with different proinflammatory cytokines. The adhesion capability of primary prostate carcinoma line (NDI) was significantly upregulated by TNF-alpha proinflammatory cytokine. Furthermore, the adhesion of ND1 was partly inhibited using anti-E-selectin and VCAM-1 monoclonal antibodies. There was no significant effect of anti-adhesion antibodies on the adhesion characteristics of the cerebral metastatic (DU145) cell line. Our data demonstrate that different mechanisms are involved in the adhesion of neoplastic cells to cerebral En cells and turn our attention to the importance of adhesion molecule expression in the formation of metastases.

The catalytic domain of human immunodeficiency virus integrase: ordered active site in the F185H mutant.

We solved the structure and traced the complete active site of the catalytic domain of the human immunodeficiency virus type 1 integrase (HIV-1 IN) with the F185H mutation. The only previously available crystal structure, the F185K mutant of this domain, lacks one of the catalytically important residues, E152, located in a stretch of 12 disordered residues [Dyda et al. (1994) Science 266, 1981-1986]. It is clear, however, that the active site of HIV-1 IN observed in either structure cannot correspond to that of the functional enzyme, since the cluster of three conserved carboxylic acids does not create a proper metal-binding site. The conformation of the loop was compared with two different conformations found in the catalytic domain of the related avian sarcoma virus integrase [Bujacz et al. (1995) J. Mol. Biol. 253, 333-346]. Flexibility of the active site region of integrases may be required in order for the enzyme to assume a functional conformation in the presence of substrate and/or cofactors.