Prophylactic negative-pressure wound therapy after ileostomy reversal for the prevention of wound healing complications in colorectal cancer patients: a randomized controlled trial.

BACKGROUND: The aim of this study was to assess the usefulness of protective negative-pressure wound therapy (NPWT) in the reduction of wound healing complications (WHC) and surgical site infections (SSI) after diverting ileostomy closure in patients who underwent surgery for colorectal cancer. METHODS: In this prospective randomized clinical trial in a tertiary academic surgical center, patients who had colorectal cancer surgery with protective loop ileostomy and were scheduled to undergo ileostomy closure with primary wound closure from January 2016 to December 2018 were randomized to be treated with or without NPWT. The primary endpoint was the incidence of WHC. Secondary endpoints were incidence of SSI, length of postoperative hospital stay (LOS), and length of complete wound healing (CWH) time. RESULTS: We enrolled 35 patients NPWT (24 males [68.6%]; mean age 61.6 ± 11.3 years), with NPWT and 36 patients (20 males [55.6%]; mean age 62.4 ± 11.3 years) with only primary wound closure (control group). WHC was observed in 11 patients (30.6%) in the control group and 3 (8.57%) in the NPWT group (p = 0.020). Patients in the NPWT group had a significantly lower incidence of SSI (2 [5.71%] vs. 8 [22.2%] in the control group; p = 0.046) as well as significantly shorter median CWH (7 [7-7] days vs. 7 [7-15.5] days, p = 0.030). There was no difference in median LOS between groups (3 [2.5-5] days in the control group vs. 4 [2-4] days in the NPWT group; p = 0.072). CONCLUSIONS: Prophylactic postoperative NPWT after diverting ileostomy closure in colorectal cancer patients reduces the incidence of WRC and SSI. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT04088162).

Arterial structure and function and its short- and long-term changes after bariatric surgery.

Subclinical arterial damage connected with endothelial dysfunction is a common denominator of cardiovascular complications in a variety of metabolic diseases, including obesity. The aims of the study was to assess functional vascular changes measured by flow-mediated dilatation (FMD) and nitroglycerin-mediated dilation (NMD) of brachial artery, and to measure vascular structural alterations estimated by carotid intima-media complex thickness (IMT) in short- (10 days) and medium-term (6 months) time after bariatric surgery in patients with extreme obesity. Anthropometric, blood pressure (BP), FMD, NMD, IMT measurements, and laboratory assessment were performed on patients who met the eligibility criteria for bariatric surgery (age 18 - 60 years old, BMI ≥ 40.0 kg/m2 or with BMI 35.0 - 39.9 kg/m2 and co-morbidities), at baseline and during follow-up. The study population consisted of 71 patients: mean SD aged 45.6 (± 10.9) years; BMI = 47.7 (± 6.1) kg/m2; 45% of them were men). A significant reduction of systolic BP, glucose, HDL cholesterol, leptin, insulin and HOMA-IR were observed 10 days post intervention. A significant increase of FMD values was observed in the entire group 6 months after surgery (median (IQR) 6.2 (2.9 - 10.3) versus 8.5 (6.1 - 16.6), P < 0.05). Changes of NMD were insignificant. Carotid IMT diminished significantly after 6 months (median (IQR) 0.6 (0.5 - 0.7) versus 0.6 (0.5 - 0.6) mm, P < 0.05). A subgroup analysis revealed that FMD parameters had improved significantly after 6 months, mainly in men, hypertensives, and in the Roux-en Y bypass (RYGB) subgroup. In conclusion, endothelial function and subclinical atherosclerosis improved after bariatric surgery in patients with extreme obesity. A lack of changes of the dilatation independent of endothelial function may indicate the persistence of residual changes in the vascular bed.

There is no difference in outcome between laparoscopic and open surgery for rectal cancer: a systematic review and meta-analysis on short- and long-term oncologic outcomes.

BACKGROUND: Until recently there has been little data available about long-term outcomes of laparoscopic rectal cancer surgery. But new randomized controlled trials regarding laparoscopic colorectal surgery have been published. The aim of this study was to compare the short- and long-term oncologic outcomes of laparoscopy and open surgery for rectal cancer through a systematic review of the literature and a meta-analysis of relevant RCTs. METHODS: A systematic review of Medline, Embase and the Cochrane library from January 1966 to October 2016 with a subsequent meta-analysis was performed. Only randomized controlled trials with data on circumferential resection margins were included. The primary outcome was the status of circumferential resection margins. Secondary outcomes included lymph node yield, distal resection margins, disease-free and overall survival rates for 3 and 5 years and local recurrence rates. RESULTS: Eleven studies were evaluated, involving a total of 2018 patients in the laparoscopic group and 1526 patients in the open group. The presence of involved circumferential margins was reported in all studies. There were no statistically significant differences in the number of positive circumferential margins between the laparoscopic group and open group, RR 1.16, 95% CI 0.89-1.50 and no significant differences in involvement of distal margins (RR 1.13 95% CI 0.35-3.66), completeness of mesorectal excision (RR 1.22, 95% CI 0.82-1.82) or number of harvested lymph nodes (mean difference = -0.01, 95% CI -0.89 to 0.87). Disease-free survival rates at 3 and 5 years were not different (p = 0.26 and p = 0.71 respectively), and neither were overall survival rates (p = 0.19 and p = 0.64 respectively), nor local recurrence rates (RR 0.88, 95% CI 0.63-1.23). CONCLUSIONS: Laparoscopic surgery for rectal cancer is associated with similar short-term and long-term oncologic outcomes compared to open surgery. The oncologic quality of extracted specimens seems comparable regardless of the approach used.

Laparoscopic colorectal cancer surgery combined with enhanced recovery after surgery protocol (ERAS) reduces the negative impact of sarcopenia on short-term outcomes.

INTRODUCTION: Progressive skeletal muscle loss (sarcopenia) is a negative prognostic factor in patients treated for colorectal cancer. Nevertheless, the clinical impact of those changes in body composition has been analyzed only in patients undergoing open resections. The aim of the study was to assess whether laparoscopy may eliminate the deleterious prognostic impact of sarcopenia and whether the combination with enhanced recovery after surgery (ERAS) protocol may improve postoperative recovery also in sarcopenic patients. METHODS: The study included 124 (73M/51F, mean age 65.9 years) patients undergoing elective laparoscopic colorectal resection for cancer. In all of them 16-item ERAS protocol was applied. The L3 skeletal muscle area identified on a preoperative CT scan was used to calculate skeletal muscle index and assess for sarcopenia and myosteatosis. The entire study group was divided into groups regarding the presence of sarcopenia or myosteatosis. The outcome measures were: length of hospital stay, complication rate and functional recovery parameters. RESULTS: The prevalence of sarcopenia and myosteatosis was 27.4% and 38.7%, respectively. There was no association between the presence of sarcopenia or myosteatosis and postoperative complications. There were also no differences in the length of stay or readmission rates. Functional recovery (time to first flatus, oral diet tolerance and mobilization) was similar regardless of the presence of muscle depletion. CONCLUSIONS: In contrary to traditional surgical approach, laparoscopy can reduce the negative impact of sarcopenia and myosteatosis on treatment results. ERAS protocol does not affect negatively the surgical outcomes in sarcopenic patients, compared to patients without changes in body skeletal mass.

The knowledge of Polish medical students about surgical treatment of obesity.

BACKGROUND: Surgical treatment of morbid obesity is becoming an increasingly important approach for the treatment of this condition. However, knowledge about the possibility of surgical procedures among general practitioners is far from satisfactory. The source of the problem might be due to a lack of information about bariatric surgery in university curriculum. METHODS: We assessed the knowledge of students from four Polish medical universities. The survey was conducted among 468 students, in their sixth (final) year of study. The survey included two parts-the first nine questions assessed of the level of the students' knowledge about the methods of surgical treatment of obesity, and the following three questions allowed for an evaluation of the amount of information on metabolic surgery provided to students during surgery courses. RESULTS: The results demonstrate a low level of knowledge on the possibility of applying metabolic surgery to treat morbid obesity. The students themselves expressed a need to improve their knowledge and favorably assessed the proposition of expanding the curriculum to include more information on the subject of metabolic surgery. CONCLUSION: The awareness of surgical treatment for morbid obesity among medical students should be improved. The development of an interesting curriculum that is based on current guidelines should be undertaken.

Guidelines on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal surface malignancy arising from colorectal or appendiceal neoplasms.

To meet the needs of patients, Canadian surgical and medical oncology leaders in the treatment of peritoneal surface malignancies (psms), together with patient representatives, formed the Canadian HIPEC Collaborative Group (chicg). The group is dedicated to standardizing and improving the treatment of psm in Canada so that access to treatment and, ultimately, the prognosis of Canadian patients with psm are improved. Patients with resectable psm arising from colorectal or appendiceal neoplasms should be reviewed by a multidisciplinary team including surgeons and medical oncologists with experience in treating patients with psm. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be offered to appropriately selected patients and performed at experienced centres. The aim of this publication is to present guidelines that we recommend be applied across the country for the treatment of psm.

Assessing the reliability of MRI-CBCT image registration to visualize temporomandibular joints.

OBJECTIVES: To evaluate image quality of two methods of registering MRI and CBCT images of the temporomandibular joint (TMJ), particularly regarding TMJ articular disc-condyle relationship and osseous abnormality. METHODS: MR and CBCT images for 10 patients (20 TMJs) were obtained and co-registered using two methods (non-guided and marker guided) using Mirada XD software (Mirada Medical Ltd, Oxford, UK). Three radiologists independently and blindly evaluated three types of images (MRI, CBCT and registered MRI-CBCT) at two times (T1 and T2) on two criteria: (1) quality of MRI-CBCT registrations (excellent, fair or poor) and (2) TMJ disc-condylar position and articular osseous abnormalities (osteophytes, erosions and subcortical cyst, surface flattening, sclerosis). RESULTS: 75% of the non-guided registered images showed excellent quality, and 95% of the marker-guided registered images showed poor quality. Significant difference was found between the non-guided and marker-guided registration (χ(2) = 108.5; p < 0.01). The interexaminer variability of the disc position in MRI [intraclass correlation coefficient (ICC) = 0.50 at T1, 0.56 at T2] was lower than that in MRI-CBCT registered images [ICC = 0.80 (0.52-0.92) at T1, 0.84 (0.62-0.93) at T2]. Erosions and subcortical cysts were noticed less frequently in the MRI-CBCT images than in CBCT images. CONCLUSIONS: Non-guided registration proved superior to marker-guided registration. Although MRI-CBCT fused images were slightly more limited than CBCT alone to detect osseous abnormalities, use of the fused images improved the consistency among examiners in detecting disc position in relation to the condyle.

BMI1 attenuates etoposide-induced G2/M checkpoints via reducing ATM activation.

The BMI1 protein contributes to stem cell pluripotency and oncogenesis via multiple functions, including its newly identified role in DNA damage response (DDR). Although evidence clearly demonstrates that BMI1 facilitates the repair of double-stranded breaks via homologous recombination (HR), it remains unclear how BMI1 regulates checkpoint activation during DDR. We report here that BMI1 has a role in G2/M checkpoint activation in response to etoposide (ETOP) treatment. Ectopic expression of BMI1 in MCF7 breast cancer and DU145 prostate cancer cells significantly reduced ETOP-induced G2/M arrest. Conversely, knockdown of BMI1 in both lines enhanced the arrest. Consistent with ETOP-induced activation of the G2/M checkpoints via the ATM pathway, overexpression and knockdown of BMI1, respectively, reduced and enhanced ETOP-induced phosphorylation of ATM at serine 1981 (ATM pS1981). Furthermore, the phosphorylation of ATM targets, including γH2AX, threonine 68 (T68) on CHK2 (CHK2 pT68) and serine 15 (S15) on p53 were decreased in overexpression and increased in knockdown BMI1 cells in response to ETOP. In line with the requirement of NBS1 in ATM activation, we were able to show that BMI1 associates with NBS1 and that this interaction altered the binding of NBS1 with ATM. BMI1 consists of a ring finger (RF), helix-turn-helix-turn-helix-turn (HT), proline/serine (PS) domain and two nuclear localization signals (NLS). Although deletion of either RF or HT did not affect the association of BMI1 with NBS1, the individual deletions of PS and one NLS (KRMK) robustly reduced the interaction. Stable expression of these BMI1 mutants decreased ETOP-induced ATM pS1981 and CHK2 pT68, but not ETOP-elicited γH2AX in MCF7 cells. Furthermore, ectopic expression of BMI1 in non-transformed breast epithelial MCF10A cells also compromised ETOP-initiated ATM pS1981 and γH2AX. Taken together, we provide compelling evidence that BMI1 decreases ETOP-induced G2/M checkpoint activation via reducing NBS1-mediated ATM activation.

Laparoscopic Surgery In The Treatment of Gastrointestinal Stromal Tumors.

BACKGROUND AND AIMS: Gastrointestinal stromal tumors are rare neoplasms of the gastrointestinal tract. These lesions are characterized by different levels of malignancy. Only radical surgery offers a chance of curing the disease. The aim of this study is to present the results of gastrointestinal stromal tumor treatment with minimally invasive surgery. MATERIAL AND METHODS: The study group included 27 patients operated laparoscopically on for gastrointestinal stromal tumor with laparoscopic surgery between September 2009 and December 2013. The most common location of the tumor was the stomach (21 patients, 77.8%) and the small intestine (4 patients, 14.8%). We analyzed early surgery results, the number and character of complications, lengths of hospital stays, histological types of the removed tumors, and long-term results of treatment. RESULTS: There was no need for conversion to open surgery in any patient from the study group. Post-surgery complications occurred in 2 patients (7.4%). The median duration of the hospital stay was 4.5 days; none of the patients had to be readmitted to the hospital in the first 30 days after the procedure. In 26 out of 27 patients, microscopic examination confirmed the radicality of the surgical procedure (R0 resection). The mean size of the removed lesions was 4.1 cm. Using the Joensuu malignancy classification model, it was established that in 6 (22.2%) patients gastrointestinal stromal tumor was characterized by a very low level of malignancy, in 11 patients (40.7%) a low level, in 4 (14.9%) a medium level, and in 6 (22.2%) a high level. The average duration of follow-up was 13 months. During the observation period, there was no recurrence of the disease. CONCLUSION: Minimally invasive surgery in the treatment of gastrointestinal stromal tumors is possible and allows for satisfactory results both in terms of the postoperative course and the oncological quality of the procedure.

Mechanical Bowel Obstruction--Changes in Aetiology over the Past 145 Years: A Single Centre Retrospective Cohort Study.

INTRODUCTION: Mechanical bowel obstruction (MBO) remains one of the most common abdominal surgical emergencies. The aetiology of MBO depends on the population demographics and period of time in which a given population was studied. We are presenting the results of an analysis covering 145 years of observations based on patients operated in our department. METHODS: The single centre retrospective analysis included 1825 patients with MBO. They were divided into 4 groups depending on the years in which they were treated : group 1 (1868-1898), group 2 (1956-1970), group 3 (1987-1999), group 4 (2000-2013). The analysis covered the sex distribution, the mean age of patients versus the life expectancy and changes in MBO aetiology in every period. RESULTS: We noticed an increase in the mean age and the growing divergence between life expectancy. Additionally, an increasing percentage of women were observed. There were also significant changes in the aetiology. An increase in MBO caused by cancer was observed. The rate of strangulated hernias doubled in the second period of time, and then it gradually decreased. Intestinal volvulus was common in the first period and became one of the rarest causes of MBO in the subsequent periods. MBO due to adhesions remained at the same level. It became, however, the most common cause in the last period. CONCLUSIONS: Within nearly 150 years significant changes occurred in the demographics and aetiology of MBO. Currently, the most common cause is peritoneal adhesions after previous surgeries. Although our results represent a single centre experience, they may reflect changing patterns in MBO in the Polish population over time.

Short hospital stays after laparoscopic gastric surgery under an Enhanced Recovery After Surgery (ERAS) pathway: experience at a single center.

INTRODUCTION: Recently, first reports on benefits from Enhanced Recovery After Surgery (ERAS) pathway in patients undergoing gastric surgery have appeared. It seems that maximal reduction of unfavorable surgery-induced trauma in patients with gastric malignancy via ERAS protocol combined with minimally invasive techniques can improve outcomes. OBJECTIVE: The aim of this study was to determine the influence of laparoscopic surgery and ERAS protocol in oncological gastric surgery on early outcomes. MATERIALS AND METHODS: Prospective analysis involved 28 patients (18 female and 10 male) with gastric malignancy who underwent laparoscopic gastric resection between 2009 and 2013. Gastric tumors (gastrointestinal stromal tumors or adenocarcinoma) were the indication for the surgery. A total of 17 patients underwent laparoscopic local excision, and 11 patients with adenocarcinoma or multiple neuroendocrine tumors underwent laparoscopic D2 total gastrectomy. Perioperative care was based on ERAS principles. Length of hospital stay, postoperative course, perioperative complications, and readmission rates were analyzed. RESULTS: There was one conversion in the gastrectomy group. All patients were mobilized on the day of surgery. Oral fluids were introduced on day 0 and were well tolerated. Full hospital diet was started on day 2 in all patients, but was well tolerated in only 18 of them. One postoperative complication requiring reoperation was noted. The length of stay after gastrectomy and gastric wedge resection was 4.6 (2-6) and 3.3 (2-6) days, respectively. No readmissions were noted in the entire group. CONCLUSIONS: The implementation of ERAS protocol to clinical practice in combination with laparoscopy in patients with gastric tumors can result in improved postoperative care quality, shortening of hospital stay, and quicker return to normal activity.

Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy.

BACKGROUND: The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies. METHODS: Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m(-2) loading dose then 250 mg m(-2) weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses. RESULTS: Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months. CONCLUSIONS: The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex.

OBJECTIVE: The purpose of this study was to assess the prevalence of and to identify epidemiologic, genetic, electrophysiologic, and neuroanatomic risk factors for autism spectrum disorders (ASD) in a cohort of patients with tuberous sclerosis complex (TSC). METHODS: A total of 103 patients with TSC were evaluated for ASD. A retrospective review of patients' records was performed, including mutational analysis. EEG reports were analyzed for the presence of ictal and interictal epileptiform features. Brain MRI scans were evaluated for TSC neuropathology, including tuber burden. RESULTS: Of the 103 patients with TSC, 40%were diagnosed with an ASD. On univariate analysis, patients with ASD were less likely to have mutations in the TSC1 gene. Patients with ASD also had an earlier age at seizure onset and more frequent seizures. On EEG, those with ASD had a significantly greater amount of interictal epileptiform features in the left temporal lobe only. On MRI, there were no differences in the regional distribution of tuber burden, although those with TSC2 and ASD had a higher prevalence of cyst-like tubers. CONCLUSIONS: The development of ASD in TSC is not well understood. Given our findings, ASD may be associated with persistent seizure activity early in development in particular brain regions, such as those responsible for social perception and communication in the left temporal lobe. The presence of cyst-like tubers on MRI could provide a structural basis or marker for ASD pathology in TSC, although studies assessing their effect on cortical function are needed.

Surface analysis of etched molar enamel by gas adsorption.

Much research has been devoted to the study of etched enamel, since it is critical to bonding. Currently, there are no precise data regarding the etched-enamel specific surface area. The aim of this study was to characterize, by two different methods, the surface of human dental enamel in vitro after being etched. It was hypothesized that differences would be observed between specimens in terms of specific surface area and grade of etching. Sixteen third molar enamel samples were etched for 30 sec with 37% phosphoric acid prior to being viewed by SEM. Etched enamel surfaces were graded according to the Galil and Wright classification. The total surface area of etched samples was determined by the BET gas absorption method. A substantial variability in total surface area was observed between and among samples. A Pearson's Correlation Coefficient showed a lack of relationship between etch pattern and total surface area.

Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer.

Erlotinib (Tarceva, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108-329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.

Dental and skeletal changes following surgically assisted rapid maxillary expansion.

The aim of this study was to evaluate skeletal and dental changes after surgically assisted rapid maxillary expansion (SARME). Clinical trials were carried out that assessed skeletal and dental changes through cephalograms, computer tomographs or dental casts. No other simultaneous treatment during the active expansion period was accepted. Electronic databases (Pubmed, Medline, Medline In-Process & Other Non-Indexed Citations, All Evidence-based Medicine Reviews, Embase, Web of Science and Lilacs) were searched. Abstracts which appeared to fulfil the selection criteria were selected by consensus. The original articles were then retrieved and evaluated with a methodological checklist. Their references were hand searched for possible missing articles. Only 12 articles fulfilled the selection criteria. All presented methodological flaws. An individual methodological analysis of these articles was made. Expansion was greater at the molars and diminished progressively to the anterior part of the dental arch in all the evaluation periods. Vertical and sagittal skeletal changes were nil or not clinically significant. The nasal portion of the maxillary complex showed an increase in dimensions thereby improving nasal patency. An overall dental relapse of 0.5-1 mm is reported after 1 year of orthodontic treatment. The conclusions should be considered with caution because only a secondary level of evidence was found.

Zoledronic acid in the treatment of hypercalcemia of malignancy: results of the international clinical development program.

This report summarizes results of the clinical development program evaluating zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ) in the treatment of hypercalcemia of malignancy (HCM). In addition to a phase I dose escalation trial, two randomized, double-blind, double-dummy studies were conducted in parallel to investigate the clinical efficacy and safety of 4 mg and 8 mg zoledronic acid in patients with moderate to severe HCM. Patients were treated with a single dose of zoledronic acid (4 or 8 mg) via 5-minute infusion or a control treatment, 90 mg pamidronate via 2-hour infusion. Patients who relapsed or had refractory HCM after initial treatment could be re-treated with 8 mg zoledronic acid. End points included rate of complete response, defined as normalization of corrected serum calcium by day 10, change in corrected serum calcium, time to relapse, duration of response, and bone biochemical markers. Doses of > or =0.02 mg/kg were effective and nontoxic in the phase I study. In the controlled studies, 287 patients were randomized and evaluated for safety and 275 patients were evaluable for efficacy. The proportions of patients with a complete response by day 10 were 88.4% and 86.7% in the 4 mg and 8 mg zoledronic acid groups, respectively, compared with 69.7% in the 90 mg pamidronate group. Corrected serum calcium normalization occurred by day 4 in 45.3% of patients treated with 4 mg zoledronic acid, 55.6% of patients treated with 8 mg zoledronic acid, and 33.3% of patients treated with pamidronate. Mean change from baseline in corrected serum calcium also was greater with zoledronic acid than with pamidronate. Median times to relapse were significantly longer in both the zoledronic acid 4 mg and 8 mg groups compared with the pamidronate group. There were no significant differences in efficacy between the 4 mg and 8 mg zoledronic acid doses. Retreatment in 69 patients with relapsing or refractory hypercalcemia with 8 mg zoledronic acid resulted in a 52% complete response rate. Fever, hypophosphatemia, and asymptomatic hypocalcemia were the most common drug-related adverse events. These studies have shown that a short single intravenous dose of 4 mg or 8 mg zoledronic acid is effective in treating moderate to severe HCM. Zoledronic acid produced a higher rate of calcium normalization, faster onset of action, and longer time to relapse than pamidronate, while maintaining an excellent safety profile. The lower dose of 4 mg is recommended as initial therapy, with the 8 mg dose reserved for patients requiring retreatment.

Methodology for treatment evaluation in patients with cancer metastatic to bone.

BACKGROUND: Patients with cancer metastatic to bone experience several adverse and clinically important skeletal-related events, including pathologic fractures, vertebral compressions with fracture, the need for surgery to treat or prevent fractures, and the need for radiation therapy for the treatment of bone pain. We present appropriate methods for describing and modeling the clinical course of skeletal-related events and comparing treatments for such events. METHODS: On the basis of data from a recently completed randomized, placebo-controlled trial involving 380 breast cancer patients with bone metastases, we tested the validity of the "events-per-person-years" method, one of the most commonly used techniques, for the analysis of skeletal-related events. We then used more robust methods of analysis that are based on fewer assumptions, including a random-effects Poisson model, and contrasted the inferences about skeletal-related event rates and treatment effects for the different analytic methods. All statistical tests were two-sided. RESULTS: The events-per-person-years analysis underestimated substantially the variation in the data and is not appropriate to summarize the incidence rate of skeletal-related events. A random-effects Poisson model did provide a valid basis for analyzing such data. CONCLUSIONS: The underestimation of variability in data associated with the use of the events-per-person-years analysis leads to unduly narrow confidence intervals for complication rates and inflated false-positive error rates in treatment comparisons. A random-effects Poisson model provides a valid, robust basis for describing the clinical course of bone complications and evaluating treatment effects.