Use of multiple T cell-directed intact ricin immunotoxins for autologous bone marrow transplantation

The monoclonal antibodies (MoAb) T101, G3.7, 35.1, and TA-1 were conjugated to intact ricin using a thioether linkage. These MoAb detect, respectively, the CD5[gp67], CD7[p41], CD2[p50], and [gp95, 170] determinants that are found in the vast majority of cases of T cell acute lymphocytic leukemia (T-ALL). The resulting immunotoxins (ITs) and an equimolar mixture of these ITs were evaluated as potential purgative reagents for autologous transplantation in T-ALL. Leukemic cell lines were used to compare the kinetics of protein synthesis inactivation mediated by each IT. The cells were treated with IT in the presence of lactose in order to block the native binding of ricin. The observed rates of protein synthesis inactivation correlated with target antigen expression detected by fluorescence-activated cell sorter analysis. Of the four ITs, T101-ricin (T101-R) exhibited the fastest rate of inactivation, followed in order by G3.7-ricin, TA-1-ricin, and 35.1-ricin. At concentrations greater than 300 ng/mL, a cocktail containing an equimolar amount of all four ITs (referred to as the four- IT cocktail) exhibited kinetics that were as fast or faster than those of T101-R. The long-term cytotoxic effects of individual ITs and the four-IT cocktail were evaluated using a sensitive clonogenic assay. Each IT was specifically cytotoxic and inhibited 1 to 4 logs of clonogenic leukemic cells at doses (300 to 600 ng/mL) that can be used clinically. The four-IT cocktail was highly cytotoxic; a concentration of 300 ng/mL inhibited greater than 4 logs of leukemic cells while sparing the majority of committed (CFU-GM, CFU-E) and pluripotent (CFU- GEMM) hematopoietic stem cells. The determination of both short-term kinetics of protein synthesis inactivation and longer-term inhibition of clonogenic growth allowed new insight into cell killing by IT. Our results suggest that ITs continue to act on clonogenic target cells for a period of three to five days. Interestingly, the four-IT cocktail was not as potent against clonogenic leukemic cells as T101-R alone, although it exhibited kinetics of protein synthesis inhibition that were as fast as those of T101-R alone. This finding suggests that internalized ITs may differ in the length of time they remain active within the cell. Our results also demonstrate the importance of using several different assays to evaluate IT reagents.     

Arthroscopy of the first metatarsophalangeal joint in 59 consecutive cases

The authors analyzed the results of 59 consecutive cases of the first metatarsophalangeal (MTP-I) joint arthroscopy to verify the efficacy and safety of the procedure. Fifty-nine patients were followed for >18 months after MTP-I joint arthroscopic procedures. The mean duration of follow-up was 25 months. Clinically, the American Orthopaedic Foot and Ankle Society (AOFAS) hallux metatarsophalangeal-interphalangeal scale and the satisfaction of the patients were evaluated. Hallux valgus angle, the first intermetatarsal angle, and medial sesamoid position were analyzed in cases of hallux valgus. The American Orthopaedic Foot and Ankle Society hallux metatarsophalangeal-interphalangeal scale score was increased from 69 points preoperatively to 92 points postoperatively (p < .05). Radiologically, the mean hallux valgus angle was decreased from 29.2° preoperatively to 9.7° postoperatively (p < .05). The mean first intermetatarsal angle was decreased from 14.8° preoperatively to 7.7° postoperatively (p < .05). The medial sesamoid position was improved from 4.8 preoperatively to 2.0 postoperatively (p < .05). Ninety-five percent of the patients were satisfied with the procedures. There was 1 case of a wound problem and 1 case of temporary digital nerve injury as complications. Based on our experience, arthroscopy of MTP-I joint appears to be a safe and reproducible procedure for selected cases of MTP-I joint disorders.     

Factors associated with non-orthotopic urinary diversion after radical cystectomy

Introduction

Preoperative factors favoring the performance of non-orthotopic bladder substitution (OBS) after radical cystectomy for muscle-invasive bladder cancer were identified.

Patients and methods

We retrospectively reviewed the medical records of 730 patients who underwent radical cystectomy for urothelial carcinoma of the bladder. After excluding 75 patients who were unable to undergo OBS due to the tumor location or elevated serum creatinine level, we assessed the preoperative factors in the remaining 655 patients. Multivariate logistic regression analysis was performed to identify the independent preoperative predictors of type of urinary diversion.

Results

Of the 655 patients, 171 (26.1%) underwent non-OBS. Patients who underwent non-OBS were more likely to be older and females, to have a lower educational status, non-organ confined disease, more comorbid medical conditions, more impaired performance status, lower body mass index, anemia, azotemia, and hypoalbuminemia, and to be treated by less-experienced surgeons (P?<?0.05 each). After adjusting for provider-based factors, multivariate analysis showed that factors independently associated with non-OBS included advanced age (odds ratio [OR] 4.10, P?<?0.001), female gender (OR 2.08, P?=?0.027), ECOG performance status (??1 vs 0, OR 5.20, P?<?0.001), low educational status (OR 1.59, P?=?0.042), clinically node-positive disease (OR 2.36, P?=?0.003), anemia (OR 1.67, P?=?0.041), azotemia (OR 3.97, P?<?0.001), and hypoalbuminemia (OR 1.84, P?=?0.046).

Conclusion

Several patient-based as well as provider-based factors were associated with the type of urinary diversion after radical cystectomy. Advanced age, female gender, low performance status, low education level, clinically node-positive disease, anemia, hypoalbuminemia, and azotemia were associated with non-OBS, as surgery was performed by relatively inexperienced surgeons.     

Pitfalls and Important Issues in Testing Reliability Using Intraclass Correlation Coefficients in Orthopaedic Research

Background

Intra-class correlation coefficients (ICCs) provide a statistical means of testing the reliability. However, their interpretation is not well documented in the orthopedic field. The purpose of this study was to investigate the use of ICCs in the orthopedic literature and to demonstrate pitfalls regarding their use.

Methods

First, orthopedic articles that used ICCs were retrieved from the Pubmed database, and journal demography, ICC models and concurrent statistics used were evaluated. Second, reliability test was performed on three common physical examinations in cerebral palsy, namely, the Thomas test, the Staheli test, and popliteal angle measurement. Thirty patients were assessed by three orthopedic surgeons to explore the statistical methods testing reliability. Third, the factors affecting the ICC values were examined by simulating the data sets based on the physical examination data where the ranges, slopes, and interobserver variability were modified.

Results

Of the 92 orthopedic articles identified, 58 articles (63%) did not clarify the ICC model used, and only 5 articles (5%) described all models, types, and measures. In reliability testing, although the popliteal angle showed a larger mean absolute difference than the Thomas test and the Staheli test, the ICC of popliteal angle was higher, which was believed to be contrary to the context of measurement. In addition, the ICC values were affected by the model, type, and measures used. In simulated data sets, the ICC showed higher values when the range of data sets were larger, the slopes of the data sets were parallel, and the interobserver variability was smaller.

Conclusions

Care should be taken when interpreting the absolute ICC values, i.e., a higher ICC does not necessarily mean less variability because the ICC values can also be affected by various factors. The authors recommend that researchers clarify ICC models used and ICC values are interpreted in the context of measurement.     

Prediction of Recurrence after Curative Resection of Hepatocellular Carcinoma using Liver Stiffness Measurement (FibroScan?)

Background

The purpose of this study was to investigate whether preoperative liver stiffness measurement (LSM) can predict recurrence after curative resection of hepatocellular carcinoma (HCC). LSM using FibroScan^? can assess the severity of liver fibrosis, which is significantly associated with recurrence after curative resection of HCC.

Methods

Between February 2006 and March 2009, 133 patients who underwent preoperative LSM and curative resection for HCC were enrolled in this prospective study. LSM values were analyzed for association with recurrence, together with other clinical variables.

Results

The mean age of the patients (117 men and 16 women) was 57?years. During the follow-up period (median, 25.0 (range, 3.0?C54.6) months), HCC recurred in 62 (46.6?%) patients. In multivariate analysis, together with satellite nodule and Edmonson-Steiner grade III?CIV, LSM was selected as an independent predictor of recurrence (P?<?0.05; hazard ratio, 1.034; 95?% confidence interval, 1.007?C1.061). When the study population was stratified into two groups using the optimal cutoff value (13.4?kPa) that maximized the sum of sensitivity (64.7?%) and specificity (76.1?%) from time-dependent receiver operating characteristic curves (area under the receiver operating characteristic curve?=?0.676), patients with LSM values >13.4?kPa were at a significantly greater risk for recurrence with a hazard ratio of 1.925 (P?=?0.01; 95?% confidence interval, 1.17?C3.168) compared with those with LSM values ??13.4?kPa.

Conclusions

Our data suggest that LSM can be a useful predictor of recurrence after curative resection of HCC.     

Reappraisal of Percutaneous Transhepatic Biliary Drainage Tract Recurrence After Resection of Perihilar Bile Duct Cancer

Background

The high incidence of percutaneous transhepatic biliary drainage (PTBD) tract recurrence after resection of perihilar bile duct cancer (BDC) at a reference single center has suggested the need for endoscopic biliary drainage (EBD) to prevent PTBD-related tumor recurrence. To determine the general applicability of these findings, we validated the risk of PTBD tract recurrence in patients with resected BDC in our high-volume center.

Methods

The medical records of 306 patients with perihilar BDC who underwent hepatobiliary resection with curative intent over 10?years were reviewed retrospectively.

Results

Of the 306 patients, 293 (95.8%) underwent biliary decompression, 171 (56.1%) by preoperative PTBD, 62 (20.3%) by EBD alone, and 60 (19.7%) by both. Of the 231 patients who underwent PTBD, 160 (69.3%), 62 (26.8%), and 9 (3.9%) had one, two, or three catheters, respectively (mean of 1.3 catheters per patient for a median 23?days). No patient experienced synchronous PTBD tract metastasis, whereas 4 (1.7%) experienced PTBD tract recurrence a median 13.5?months after surgery, with 3 of these patients having an intraabdominal recurrence soon afterward. Only one patient had a solitary tract recurrence without intraabdominal metastasis. These patients survived for a median 25?months, which is comparable to survival outcomes after noncurative resection. No risk factor was significantly associated with PTBD tract recurrence.

Conclusions

We think that the risk of PTBD tract recurrence after resection of perihilar BDC is not negligible but is much lower than previously reported. There is no definitive reason to avoid PTBD when it is indicated.     

Evaluation of registration methods used in frameless stereotactic surgery for the lumbar and cervical regions of the spine

Computer-assisted pedicle screw insertion is feasible but has proved to be problematic. The purpose of this study was to detail the accuracy of registration techniques and pedicle screw insertion using a frameless stereotactic system. Two registration techniques were evaluated on a model spine. The frameless stereotactic system was then used to insert 26 pedicle and 8 lateral mass screws in human cadavers. For posterior vertebral elements, trajectory accuracy was 2.5 +/- 1.0 mm between T12 and L5 and 2.2 +/- 0.9 mm between C2 and T1. Registration of the anterior elements, however, was less accurate. Despite this flaw, all screws were inserted without penetrating the cortex. Screw trajectory was accurate to 2 degrees. The main limitation of frameless stereotactic surgery in the spine stems from the fact that only the posterior vertebral elements are used during registration. Despite this flaw, the system placed all screws correctly. Given these limitations, we believe that this system is most useful for locating the screw insertion point and providing a trajectory in the pedicle.     

Duodenal-preserving resection of the head of the pancreas and pancreatic head resection with second-portion duodenectomy for benign lesions,low-grade malignancies,and early carcinoma involving the periampullary region

HYPOTHESIS: Duodenal-preserving resection of the head of the pancreas (DPRHP) and pancreas head resection with segmental duodenectomy (PHRSD) can be alternatives to standard pancreaticoduodenectomy for benign periampullary lesions. DESIGN: Retrospective analysis of patients requiring surgery for benign and borderline malignant tumors of the periampullary region. SETTING: Tertiary care referral center. PATIENTS: Duodenal-preserving resection of the head of the pancreas (n = 8) and PHRSD (n = 7) were performed in 15 patients with a preoperative diagnosis of benign and borderline malignant tumors of the periampullary region (ie, 11 pancreas head lesions [2 intraductal papillary mucinous tumors, 4 serous cystadenomas, 2 insulinomas, 1 epidermal cyst, 1 metastatic renal cell carcinoma, 1 nonfunctioning islet cell tumor/parapaillary] and 4 duodenal lesions [3 adenomas and 1 adenocarcinoma]). MAIN OUTCOME MEASURES: Surgical factors (operation time and blood loss), postoperative complication, postoperative pancreatic insufficiency (eg, development of diabetes mellitus and steatorrhea or elevated stool elastase values), weight change, and recurrence of disease. RESULTS: No differences were noted in the mean operation time and estimated blood loss between the 2 procedures. Major postoperative complication constituted the following: bile duct stricture (n = 1) in DPRHP and delayed gastric emptying (n = 1) and postoperative bleeding (n = 1) in PHRSD. Newly developed diabetes mellitus occurred in 1 patient. Exocrine pancreatic insufficiency (steatorrhea) was observed in 1 patient after PHRSD. Patients with early duodenal carcinoma and intraductal papillary mucinous tumors with a borderline malignancy are still alive without evidence of recurrence. There was no hospital or long-term mortality. CONCLUSIONS: Duodenal-preserving resection of the head of the pancreas is recommended first for a benign or low-grade, early malignant pancreatic head lesion; PHRSD can be an option for a lesion of the ampullary-parapapillary duodenal area as well as the pancreatic head. Duodenal-preserving resection of the head of the pancreas can be converted to PHRSD if ischemia of the second portion of the duodenum occurs. We found benign periampullary lesions could be conservatively treated with DPRHP and PHRSD, which could substitute for classic pancreaticoduodenectomy.     

The etiology of adolescent idiopathic scoliosis

The etiology of adolescent idiopathic scoliosis (AIS), the most common form of scoliosis, is unclear. Researchers with divergent perspectives have tried to better define this etiology. Genetics, growth hormone secretion, connective tissue structure, muscle structure, vestibular dysfunction, melatonin secretion, and platelet microstructure are major areas of focus. In this article, we review the literature in these areas and present the consensus on proposed hypotheses. Studies that simplify the etiology to a single factor have been inconclusive or unsuccessful. Most likely, the etiology is multifactorial, and reported associations are links in pathogenesis rather than etiologic factors. Research is needed to better define the role of all factors in AIS development.