A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors.

BACKGROUND: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. PATIENTS AND METHODS: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. RESULTS: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). CONCLUSIONS: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan.

BACKGROUND: This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination. PATIENTS AND METHODS: Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination. RESULTS: The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease. CONCLUSION: The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.

Prospective trial for the treatment of malignant peritoneal mesothelioma.

Malignant peritoneal mesothelioma (MPM) is a rare and often rapidly fatal disease with median survival of 5 to 12 months for untreated cases and 16 months reported after multimodality treatment. We report a prospective clinical treatment study using cytoreductive surgery combined with intraoperative intraperitoneal heated chemotherapy (IPHC) perfusion using mitomycin C for MPM. Twelve patients (11 male with a mean age 51 years) were treated. Seven patients presented with bulky disease and seven with ascites. All underwent exploratory laparotomy with histologically confirmed diagnosis of MPM. Surgical debulking as feasible was performed. Complete gross tumor removal was possible in only one patient. Cytoreduction was followed by a 2-hour closed low-volume IPHC using mitomycin C. One patient died 50 days postoperatively from complications relating to small bowel perforation. Hematologic toxicity of the procedure was minimal. Ascites was controlled in all patients and permanently in 86 per cent of patients presenting with ascites. To date median survival is 34.2 months with median follow-up of 45.2 months. One patient was re-explored for ventral hernia 2 years post-IPHC, had negative peritoneal biopsies, and remains disease-free at 5 years. Given the dismal prognosis associated with MPM the results of treatment with cytoreductive surgery combined with IPHC perfusion are encouraging. The rarity of MPM makes appropriately powered prospective randomized trials unlikely. Therefore, we now offer this approach off protocol; however, further study of this combined modality therapy is warranted.

Gelatinous ascites: a cytohistologic study of pseudomyxoma peritonei in 67 patients.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare condition characterized by gelatinous ascites. Although the histologic attributes of PMP have been well studied, the cytologic features remain ill defined. METHODS: We reviewed the peritoneal washings (PW) in 67 patients with PMP to identify cytomorphologic features useful in classifying cases as either disseminated peritoneal adenomucinosis (DPAM) or peritoneal mucinous carcinomatosis (PMCA). Histologic specimens were correlated with the cytologic diagnoses. Correlation between cytologic diagnosis and patient outcome was investigated. RESULTS: Neoplastic epithelial cells were identified in 63 of 67 PW (94%). Concordance with the histologic diagnosis was obtained in 61 of 63 cases. Of these 36.5% were cytologically classified as DPAM with primary appendiceal neoplasms in 19 cases. Thirty-four of 63 cases (53.9%) were cytologically diagnosed as PMCA based on PW cytology. Most were of appendiceal or colonic origin. Four cases displayed cytologic features of both DPAM and PMCA. Two discordant cases each with a cytologic diagnosis of PMCA had an appendiceal adenoma. Acellular mucin alone was identified in the PW in four cases. Analysis of follow-up data revealed that cases diagnosed as DPAM had a better prognosis than those diagnosed as PMCA. CONCLUSIONS: Cytomorphologic features of epithelial cells in PW material can accurately categorize cases of PMP as either DPAM or PMCA. Furthermore, this categorization appears to have important prognostic implications.

Quality of life after intraperitoneal hyperthermic chemotherapy (IPHC) for peritoneal carcinomatosis.

AIMS: This study assessed the functional status and quality of life (QOL) of patients with disseminated peritoneal cancer (DPC) before and after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy (IPHC). METHODS: Patients with confirmed or suspected diagnosis of gastro-intestinal cancer including stomach, pancreas, hepatobiliary and colorectal cancer with peritoneal implants were enrolled in the study. Sixty-four patients completed the Functional Assessment of Cancer Therapy-Colon (FACT-C) scale and several other instruments at baseline. Forty-eight, 40, 39 and 31 patients were assessed at approximately 2 weeks post-surgery, and 3, 6 and 12 months respectively. RESULTS: There was a significant overall effect on the physical (P=0.0025), emotional (P<0.0001) and functional well-being (P=0.0044) subscales and the FACT-C (P=0.0076). Physical and functional well-being scores decreased at post-surgery follow-up and increased relative to baseline at 3, 6 and 12 months. Nineteen per cent, 46%, 59% and 74% of patients resumed greater than 50% of their normal activities post-operatively at 3, 6 and 12 months respectively. A percentage of patients reported depressive symptoms: baseline (28%), post-operatively (33%), 3 months (23%), 6 months (21%) and 12 months (29%). CONCLUSIONS: Cytoreductive surgery followed by IPHC was well tolerated. Most patients returned to baseline or better levels of functioning within 3 months post-treatment.

Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for disseminated peritoneal cancer of gastrointestinal origin.

No standard effective treatment exists for peritoneal carcinomatosis of gastrointestinal origin. The pharmacokinetic advantage of intraperitoneal chemotherapy and the synergy of heat and certain anticancer agents have prompted researchers to investigate intraperitoneal hyperthermic chemotherapy in treating disseminated peritoneal cancers. We have conducted a large Phase II trial to determine the safety and efficacy of aggressive cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC) in treating peritoneal carcinomatosis of gastrointestinal origin. Patients with disseminated peritoneal carcinomatosis of gastrointestinal origin with or without malignant ascites were eligible. After aggressive surgical debulking, patients were administered a 2-hour heated (40.5 degrees C) intraperitoneal perfusion with mitomycin C. The major response variable monitored was overall survival. Patients were assessed for toxicity after IPHC administration using the National Cancer Institute Common Toxicity Criteria. Eighty-four patients with peritoneal carcinomatosis of gastrointestinal origin were evaluated for survival and toxicity (colon, n = 38; appendix, n = 22; stomach, n = 19; other gastrointestinal, n = 5). Thirty-nine (46%) patients had malignant ascites at the time of therapy. The operative mortality (30-day) was 6 per cent. Hematologic toxicity was the most common toxicity but was of mild to moderate severity (7 and 4% of patients had grade 3/4 white blood cell or platelet toxicity, respectively). The overall median survival was 14.3 months. The median survival of patients with peritoneal carcinomatosis of appendiceal, colorectal, and gastric origins were 31.1+, 14.6, and 10.1 months, respectively. Significant differences in median survival were seen in patients without and with malignant ascites (27.7 vs 7.6 months; P = 0.0004) and R0/R1 (complete gross tumor resection) versus R2 (gross residual tumor) surgical resection status (28.5+ vs 10.8 months, P = 0.0002). These data suggest that aggressive cytoreductive surgery with IPHC using mitomycin C is safe and effective in treating peritoneal carcinomatosis of gastrointestinal origin. Additional studies and broader applications of this treatment are encouraged.

Administration and pharmacokinetics of high-dose cyclophosphamide with hemodialysis support for allogeneic bone marrow transplantation in acute leukemia and end-stage renal disease.

We report a patient with pre-existing end-stage renal disease (ESRD) who underwent successful matched related donor allogeneic bone marrow transplantation for AML in second complete remission (CR2) using conditioning with high-dose cyclophosphamide (CY, 60 mg/kg/day x 2) and TBI (165 cGy twice daily x 4 days). The timing of hemodialysis after high-dose CY was extrapolated from available data on the pharmacokinetics of high-dose CY and hemodialysis clearance of conventional dose CY and its metabolites. Pharmacokinetic analyses indicated that the elimination of high-dose CY and its alkylating metabolites is impaired in ESRD but is cleared with hemodialysis. The patient's early post-transplant course was uncomplicated, and WBC and platelet engraftment occurred by day +22. Bone marrow examination on day +25 showed trilineage engraftment with no AML; cytogenetics showed 100% donor karyotype. The patient remains in remission with 100% donor karyotype at 3 years post transplant. Clinical results indicate that the administration of high-dose CY is feasible with hemodialysis support for patients with ESRD.

Lifetime ultraviolet exposure estimates for selected population groups in south-east Queensland.

The lifetime erythemal UV exposures received by selected population groups in southeast Queensland from birth up to an age of 55 years have been quantitatively estimated. A representative sample of teachers and other school workers received (64 +/- 22) x 10(5) J m(-2) to the neck compared with (4.1 +/- 1.4) x 10(5) J m(-2) to the upper leg. A sample of indoor workers (bank officers, solicitors and psychologists) received approximately 2% less and a sample of outdoor workers (carpenters, tilers, electricians and labourers) received approximately 10% more to the neck than the school workers. These differences in erythemal UV exposures may influence the risk of non-melanoma skin cancer.

An overview of cyclophosphamide and ifosfamide pharmacology.

Cyclophosphamide and ifosfamide are alkylating agents administered to treat malignant disease. They are prodrugs and require activation by hepatic microsomal enzymes before being metabolized to their respective cytotoxic species, phosphoramide mustard and ifosfamide mustard. These species alkylate DNA, forming DNA-DNA cross-links that result in inhibition of DNA synthesis and cell death. Resistance to oxazaphosphorines is poorly understood, although increased aldehyde dehydrogenase activity may be a significant factor. Although both compounds share a common metabolic pathway, 4-hydroxylation of ifosfamide occurs at a slower rate and to a lesser extent than that of cyclophosphamide. This difference significantly alters the toxicity profile of ifosfamide. Leukopenia is the dose-limiting toxicity of cyclophosphamide, and neurotoxicity is the dose-limiting toxicity of ifosfamide when preventive measures are taken to reduce urotoxicity. With recent findings concerning their basic and clinical pharmacology, the therapeutic index of these compounds can be improved.

Thoracic complications in patients undergoing intraperitoneal heated chemotherapy with mitomycin following cytoreductive surgery.

BACKGROUND: The purpose of this study was to determine the incidence and severity of thoracic reactions in patients undergoing intraperitoneal heated chemotherapy (IPHC). METHODS: Forty-two patients who had intraperitoneal disseminated malignancies were treated with cytoreductive surgery (CS) and IPHC. The primary malignancies included carcinoma of the colon (n = 17), stomach (n = 6), appendix (n = 6), pseudomyxoma peritonei (n = 3), mesothelium (n = 2), ovaries (n = 2), jejunum (n = 2), gallbladder (n = 1), urachus (n = 1), and peritoneal carcinomatosis (n = 2). After CS, IPHC with mitomycin (MMC) was administered by perfusion at 40.5 degrees C. After IPHC, multiple radiographs of the chest were reviewed in comparison to the control group. RESULTS: Thoracic complications occurred in 36 patients (86%), including atelectasis in 32 patients (76%), pleural effusions in 27 (64%), pulmonary edema in 10 (24%), pneumonia in 2 (5%), and pneumothorax in 2 (5%). The incidence of thoracic complications in the IPHC group was significantly higher than that of patients in the control group (P < .05). Correlations between the prevalence of pleural effusion and the dose of MMC, duration of procedure, and presence of thrombocytopenia were not significant (P > .05). CONCLUSIONS: Bibasilar atelectasis and pleural effusions are common findings after IPHC with MMC, but most of them do not necessarily warrant intervention.

Peritoneal carcinomatosis with urachal signet-cell adenocarcinoma.

Urachal adenocarcinoma is an uncommon clinicopathologic entity associated with a dismal prognosis. We report a case of peritoneal carcinomatosis from urachal adenocarcinoma (signet cell type) treated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy (IPHC). Prior to treatment, disease had progressed with systemic chemotherapy. The patient remained free of symptomatic peritoneal disease or local recurrence but eventually died 23 months after IPHC and 31 months after diagnosis due to widespread bone metastases.

An estimate of the total UV-B exposure for outdoor workers during a south-east Queensland summer.

A numerical model was used to calculate the facial UV-B exposure received during summer (December-February) by typical outdoor farm workers in south-east Queensland (27.5 degrees S), a population among the groups at highest risk of skin cancer. The exposure was calculated using new, more detailed measurements of the probability of outdoor activity of farmers (FO-measured by the Fraction of time spent Outside), the distribution of incident solar radiation on the human face (ER-the Exposure Ratio, measured by the fraction of the ambient radiation which falls on each site) and the ambient UV-B levels (AE-the Ambient Exposure) for the region. Only the exposure of unprotected faces was considered. An analysis of the distribution of exposure over a typical working day and of the likely spread of exposures is also presented. The group average of exposures at three facial sites (the forehead, nose and cheek) were 8.7 J cm(-2), 14.0 J cm(-2), and 9.5 J cm(-2), respectively, which is substantially higher than estimates for summer made for populations in more temperate latitudes.

Treatment and prevention of malignant ascites associated with disseminated intraperitoneal malignancies by aggressive combined-modality therapy.

No satisfactory treatment exists to treat or prevent malignant ascites secondary to nonovarian intraperitoneal (IP) disseminated malignancies. A Phase I/II clinical trial combining radical cytoreductive surgery (CS) and IP hyperthermic chemotherapy (IPHC) with mitomycin C is presented. Between December 9, 1992 and July 31, 1995, 39 patients (pts) were explored for IP cancer. Five pts with known liver metastases were excluded, leaving 34 pts (15 female, 19 male) of median age 53 (range, 17-76). The majority of pts had disseminated IP cancers of gastrointestinal origin (80%). Prior therapy included the following: chemotherapy, 20 pts (59%); surgery, 29 pts (85%); and radiation, 2 pts (6%). Following CS, IPHC with mitomycin C was done. At surgery, 12 pts (35.3%) had frank ascites, and 12 pts (35.3%) had positive IP cytology without ascites. The median hospital stay was 9 days (range, 5-65) with no 30-day mortality. Complications for 36 treatments included: thrombocytopenia Eastern Cooperative Oncology Group grade 3 or 4, two cases (5.6%); neutropenia requiring granulocyte colony-stimulating factor, seven cases (19.4%); sepsis, four cases (11.1%); bowel leak, two cases (5.6%); and serous wound leak, two cases (5.6%). Ascites correlated with worse resection status (P = 0.025). Ascites was controlled in 9 of 12 (75.0%) pts, with failures at 1, 4, and 14 months (median follow-up, 7.5 months). No cytology-positive ascites-negative pts developed clinical ascites (median follow-up, 9.4 months). The median survival time in pts with ascites was 10.1 months versus 32.7 for patients without ascites (P = 0.013). For the entire study population, the 1- and 2-year survival rates were 74.6 and 48.5 per cent, respectively (median follow-up, 18.2 months). In this study, malignant ascites was controlled in 75 per cent of cases and prevented in all pts with positive IP cytology. CS plus IPHC appears to be relatively well tolerated and may be effective for the treatment and prevention of malignant ascites.

Cytologic assessment before and after intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis.

OBJECTIVE: A phase I/II clinical trial of surgical cytoreduction combined with intraperitoneal hyperthermic chemotherapy (IPHC) for patients with disseminated peritoneal carcinoma was begun in December 1991. The use of peritoneal cytology to assess this treatment modality was the objective of this study. STUDY DESIGN: Adult patients with primary intraabdominal cancer with peritoneal dissemination underwent surgical debulking and intraoperative, two-hour, heated abdominopelvic perfusion with mitomycin C (MMC). Peritoneal washings were sent before and after IPHC, and the use of peritoneal cytology in this setting was reviewed retrospectively. RESULTS: Twenty patients (9 female, 11 male) with adenocarcinoma (19) and one with epithelial mesothelioma, all with bulky peritoneal disease, were treated. Pre- and post-IPHC cytologic specimens were available for 18 cases. Cytology was tumor negative in three cases before and after IPHC. Conversion to negative post-IPHC cytology was seen in 6 of 15 cases and correlated with total or near-total tumor debulking (Fisher's exact test, P = .002). For 13 patients with follow-up > or = 6 months, 6 patients with both negative post-IPHC cytology and tumor < or = 1 g were alive at 6 months; of 7 patients with residual gross tumor or positive post-IPHC cytology, 5 had died within 6 months (P = .02). CONCLUSION: Some patients undergoing IPHC with tumor-positive peritoneal cytology will convert to negative cytology following IPHC. This correlates with total or near-total tumor debulking and is associated with improved survival.

Phase I study of N-(phosphonacetyl)-L-aspartate with fluorouracil and with or without dipyridamole in patients with advanced cancer.

We conducted a combined biochemical modulation trial of N-(phosphonacetyl)-L-aspartate (PALA), dipyridamole (DP), and fluorouracil (5-FU) in patients with cancer. Eighty-eight patients with advanced cancer were entered into this Phase I trial. During the first part of the study, four doses of PALA (125, 250, 500, and 1000 mg/m2, administered on day 1) were evaluated to determine the PALA dose with maximal suppression of aspartate transcarbamylase (ATCase) activity that was clinically tolerable. Patients were randomized to receive DP (or no DP), 50 mg/m2, p.o. every 6 h on days 1-6, and all patients received 5-FU, 400 mg/m2, by bolus administration on days 2-5. Prior to and during therapy, WBCs were collected and assayed for ATCase activity. After the maximally tolerated PALA dose with 400 mg/m2 5-FU +/- 50 mg/m2 DP was defined, the 5-FU dose was escalated using the same administration schedule of 5-FU, PALA, and DP. The dose of 5-FU was escalated by 25% in each of the DP cohorts until dose-limiting toxicity was reached. ATCase activity was inhibited in a dose-dependent manner with PALA doses of 125, 250, 500, and 1000 mg/m2, resulting in 0, 13, 17, and 49% inhibition of ATCase activity. Only at the higher PALA doses (i.e., 500 and 1000 mg/m2) was ATCase activity suppressed during days 2-5, but the activity returned to pretreatment levels by day 15. Based on the clinical tolerance and significant suppression of ATCase activity, a PALA dose of 500 mg/m2 was selected for the 5-FU dose escalation phase. At a 5-FU dose of 625 mg/m2, dose-limiting toxicity (leukopenia, stomatitis, and diarrhea) occurred in both DP cohorts. We recommend that for this monthly treatment schedule, 500 mg/m2 PALA and 500 mg/m2 5-FU, with or without 50 mg/m2 DP, be used in subsequent Phase II trials.

Annual reduction of solar UV exposure to the facial area of outdoor workers in Southeast Queensland by wearing a hat.

The total annual exposure to erythemally effective UVR was estimated for average work situations in a high exposure environment, viz, farm workers in Southeast Queensland (27.5 degrees S), and the effect of hat usage was examined. If no sun protection is used, the annual erythema exposures for this group of workers at three facial sites forehead, nose and cheek are 40, 57 and 34 J.cm-2 respectively. If a hat is worn throughout the year, the exposures are reduced to 6, 19 and 20 J.cm-2, respectively. The mean ratio of exposure without the hat to that with the hat (mean protection factor, MPF) was found to be 6 for the forehead, 3 for the nose and 2 for the cheek. The risk of non-melanoma skin cancers without the protection of the hat is estimated to increase by up to 100 times for basal cell carcinomas and 13 times for squamous cell carcinomas for a whole year of exposure.

The effects of body size and orientation on ultraviolet radiation exposure.

A method has been developed for determining the UV and erythemal exposures to the entire body. The difference between the ambient erythemal exposure and that to the body compared to the ambient exposure may be as high as 76%. The height, orientation, and overall height had a minimal effect on the exposure to the body with size, time of day and time of year having a significant effect. The diffuse component of UV to a side of the body ranged from 20% to 41% between different times of the year with different levels of cloud cover. The ratio of the body to the ambient erythemal exposures varied from 0.24 to 0.61, with the time of day and time of year with the smaller value for periods of high solar altitude.

Urinary elimination of cyclophosphamide alkylating metabolites and free thiols following two administration schedules of high-dose cyclophosphamide and mesna.

Twenty patients with a variety of neoplastic diseases were treated with preparative regimens containing high-dose cyclophosphamide (CY) administered as a 2-h infusion (60 mg/kg) for 2 days or by continuous infusion (1500 mg/m2/day) for 4 days. In patients receiving CY by 2-h infusion, the uroprotectant 2-mercaptoethane sulfonate (MESNA) was administered as an intermittent, bolus intravenous infusion (20% of CY dose) every 6 h. In patients receiving continuous infusion CY, MESNA was administrated concomitantly at an equivalent dose to CY by continuous infusion. During the first 24 h of CY administration, urine was collected at 2-h intervals and analyzed for free thiols and CY-alkylating metabolites. In patients receiving CY by short infusion and MESNA by intermittent bolus infusion, urinary concentrations of alkylating metabolites peaked at 4-8 h. During each dose of MESNA, urinary free thiols peaked at 2 h following administration but fell to pre-treatment levels at subsequent intervals. In patients receiving CY by continuous infusion, CY alkylating metabolites increased gradually over the 24-h study period while free thiols remained at a constant level during this period. With bolus administration of CY and intermittent bolus administration of MESNA every 6 h, there are periods where urinary CY-alkylating metabolites are elevated and free thiol concentrations are diminished. During continuous infusion of CY and MESNA, urinary CY alkylating metabolites reached peak concentrations at 18-22 h while the exposure of the bladder to free thiols remained constant. Recommendations are provided to increase the exposure of free thiols in the bladder when MESNA is administered by bolus or continuous infusion.

Complications of heated intraperitioneal chemotherapy and strategies for prevention.

Heated intraperitoneal chemotherapy is a potentially useful strategy for therapy of peritoneal carcinomatosis in adult patients, and we have found it to be associated with an acceptable complication rate. Careful perioperative management is critical, and we have presented our current experience guidelines for management and overview of complications.