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Debate persists regarding the need for shaking during hyperthermic intraperitoneal chemotherapy. Studies assessing the thermal behaviors of the perfusate throughout the abdomen during hyperthermic intraperitoneal chemotherapy are limited.A closed hyperthermic intraperitoneal chemotherapy technique was performed in an institutional International Animal Care and Use Committee approved porcine model targeting a 41°C outflow temperature. Continuous temperature monitoring was conducted. Abdominal shaking was performed for 60 second intervals and temperatures were allowed to equilibrate without shaking between intervals. Temperature distributions and changes due to shaking were evaluated. These findings were validated against human subjects' data.The experimental procedure was conducted in 2 different animals and with 6 total shaking intervals assessed. Without shaking, temperatures were highly variable ranging between 38.0 to 42.2°C. Shaking the abdomen reduced the mean range of temperatures across all locations observed from 3.9°C to 0.8°C (P.01). The locations of the most divergent temperatures varied based on perfusion cannula position. The point of minimum temperature heterogeneity was achieved in 28.3 (19.1-37.5) seconds. After shaking stopped, heterogeneity equal to the baseline measurements was seen on average within 25.7 (13.3-38.0) seconds. The outflow catheter differed from the system mean temperature by 1.4°C and from the coldest-reading probe by 2.8°C and outperformed the inflow catheter for all time points. With shaking these were significantly reduced to 0.4°C (P.01) and 0.6°C (P.01). The patient data mirrored that of the pig data.Shaking significantly reduces temperature variability within the abdomen during hyperthermic intraperitoneal chemotherapy, and significantly improves the ability of the outflow catheter to estimate internal temperatures.

The aim of this study is to present radiologically designated LAPC found to be resectable upon surgical exploration and evaluate the outcomes of such resections.Sequential LAPC patients between 2013 and 2019 were staged and underwent resection were included in the analysis of both perioperative and long-term outcomes.Twenty-eight patients with radiologically-designated LAPC underwent surgical resection after chemotherapy with a median follow-up of 31.7 m,75% underwent pancreaticoduodenectomy. The margin positivity and local recurrence rates were 21.4% and 35.7%, respectively. When compared to the 30 BRPC controls, the LAPC group had a higher rates of an arterial resection (11vs.1; p = 0.002), but the groups were similar with regard to all other preoperative and intraoperative variables (p 0.05). Perioperative morbidity rates were similar (25.9%vs21.4%; p = 0.53). The LAPC and BRPC groups were also equivalent with respect to median recurrence-free survival (9.0mo; 95%CI 6.3, 11.7vs.8.3mo; 95%CI 5.4, 11.2) and median overall survival (19.9mo; 95%CI 17.0, 22.7 vs. 19.9mo; 95%CI 14.8, 25.1), respectively.Despite a radiologic designation of locally advanced pancreatic cancer, certain subtypes of LAPC warrant surgical exploration provided the operative surgeon is prepared for major arterial and/or venous resection. Pancreatectomy in these patients has acceptable morbidity and oncologic outcomes, similar to patients who are radiologically borderline resectable.

BACKGROUND This study aims to compare the LACE + readmission index to a novel hepatopancreatobiliary readmission risk score (HRRS) in predicting post-operative hepatopancreatobiliary (HPB) cancer patient readmissions. METHODS A retrospective review of 104 postoperative HPB cancer patients from January 2017 to July of 2019 was performed. Univariable and multivariable analyses were utilized. RESULTS The LACE + index did not predict 30-day (OR 1.01, 95% CI, 0.97-1.05, p = 0.81, c-statistic = 0.52) or 90-day (OR 1.02, 95% CI, 0.98-1.05, p = 0.43) readmission. Patients readmitted within 30 days had significantly increased HRRS scores compared to those who were not (0 vs 34, p

Background Although completion lymph node dissection (CLND) is not routinely performed for a positive sentinel lymph node (SLN) anymore, adjuvant therapy depends on the risk factors available from SLN biopsy, including the risk of nonsentinel node metastases (NSNM). A systematic review and meta-analysis was performed in an attempt to identify risk factors that could be used to predict the risk of NSNM. Materials and methods Medline, Web of Science, Embase, and Cochrane were searched for articles discussing predictive factors for NSNM. PRISMA guidelines were followed, and RevMan software was used to calculate pooled odds ratios (OR) using the Mantel-Haenszel test. Results Fifty publications were suitable for additional analysis. The clinical and primary tumor factors that were consistently identified as risk factors for NSNMs were: age >50, T stage 3 or 4, Clark level IV/V, ulceration, microsatellitosis, lymphovascular invasion, nodular histology, and extremity versus trunk primary tumor location. SLN factors that predicted NSNMs were >1 positive SLN, SLN micrometastatic tumor burden, diameter >2 mm, extracapsular extension, nonsubcapsular location (Dewar), and Rotterdam > 1 mm or ≥ 0.1 mm. Conclusions The findings in this study support that many clinical and pathologic risk factors that can be assessed with SLN biopsy alone can be used to predict the risk of NSNMs. The factors identified in this review should be evaluated in clinical prediction models to predict the risk of NSNMS, a prediction that may be used to select patients for adjuvant therapy in high-risk melanoma.

The optimal timing of treatment of liver metastases from low-grade neuroendocrine tumors (LG-NELM) varies significantly due to numerous treatment modalities and the literature supporting various treatment(s). This study sought to create and validate a literature-based treatment algorithm for LG-NELM.A treatment algorithm to maximize overall survival (OS) was designed using peer-reviewed articles evaluating treatment of LG-NELM. This algorithm was retrospectively applied to patients treated for LG-NELM at our institution. Deviation was determined based on whether or not a patient received treatment consistent with that recommended by the algorithm. Patients who did and did not deviate from the algorithm were compared with respect to OS and number of treatments.Applying our algorithm to a 149-patient cohort, 57 (38%) deviated from recommended treatment. Deviation occurred in the form of alternative (28, 49%) versus additional procedures (29, 51%). Algorithm deviators underwent significantly more procedures than non-deviators (median 1 vs. 2, p 0.001). Cox model indicated no difference in OS associated with algorithm deviation (HR 1.19, p = 0.58) when controlling for age and tumor characteristics.This literature-based algorithm helps standardize treatment protocols in patients with LG-NELM and can reduce cost and risk by minimizing unnecessary procedures. Prospective implementation and validation is required.

Background Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is a common treatment for peritoneal surface malignancies but no standard carrier solution currently exists for the procedure. This study compared a standard low-dextrose perfusate to a higher-dextrose dialysate that has previously shown favorable impact on perioperative patient outcomes in trauma settings. Materials and methods A single-center retrospective study identified patients undergoing CRS/HIPEC from 2008 to 2019 with recorded dextrose concentration of administered perfusate. An institutional shift to a higher-dextrose solution was made in late 2015. Comparisons of preoperative factors, intraoperative and postoperative glucose levels, and postoperative outcomes were made using the chi-square test, Fisher's exact test, Wilcoxon rank sum test, or repeated measures analysis of variance. Results There were 97 patients in the study, 73 (75%) in the low-dextrose group and 24 (25%) in the high-dextrose group. There was no significant difference in peak intraoperative blood glucose levels between the 1.5% (mean 230 mg/dL) and the 2.5% group (mean 199 mg/dL, P = 0.15). Daily postoperative glucose values were also not statistically different (repeated measures analysis of variance, P = 0.18). Median length of stay was slightly lower for the high-dextrose group (10 d, interquartile range 8-15) than that for the low-dextrose group (12 d, interquartile range 9-17), but was not statistically significant (P = 0.29). Return of bowel function and resumption of diet were similar between the groups. The high-dextrose group had a lower rate of overall complications (20.8%) than the low-dextrose group (49.3%, P = 0.0143). Ninety-day mortality was equivalent between the two groups (2.7% low-dextrose, 4.2% high-dextrose, P = 1.0). Conclusions Use of 2.5% dextrose-containing perfusate appears safe for CRS/HIPEC operations, does not negatively impact intraoperative or postoperative glucose levels, and may be associated with a decreased risk of complications.

Few studies have assessed the relationship between serum alpha-fetoprotein (AFP) and yttrium-90 (Y-90) radioembolization response in hepatocellular carcinoma (HCC). The objective of the study was to evaluate whether peri-procedural serum AFP was correlated with Y-90 therapy response in HCC.Patients undergoing Y-90 radioembolization with glass microspheres (TheraSphere™) for HCC between 2006 and 2013 at a single center were evaluated. The relationship between AFP and 6-month radiographic improvement (complete or partial response by modified RECIST criteria), overall (OS), and disease-specific survival (DSS) were analyzed.Seventy-four patients underwent a total of 124 Y-90 infusions. Median age was 65 years, median AFP was 37 ng/mL (range: 2-112,593 ng/mL) and median model for end-stage liver disease score was 6.2 (range:1.8-11.2). Increased AFP was not associated with radiographic improvement (odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.75-1.30, p = 0.92). Median OS was 15.2 months and was increased in patients with low AFP compared to high AFP (30.8 months vs. 7.8 months, p 0.001). On multivariable regression analysis, increased AFP was associated with worse OS (OR = 1.11, 95%CI = 1.01-1.22, p = 0.034) and DSS (OR = 1.13, 95%CI = 1.03-1.25, p = 0.018).Pre-infusion AFP independently predicted survival after Y-90 treatment for HCC, but not radiographic response, and can help guide treatment decisions.

Background The preoperative and intraoperative factors that could predict a higher risk of anastomotic/staple line leak for gastric cancer patients has not been accurately defined. Methods Patients who underwent surgery with curative intent for gastric malignancies between 2002 and 2018 were evaluated from a single prospective database. Results A total of 195 patients were evaluated with an overall complication rate of 40%. Anastomotic/staple line leak occurred in 13%, with 4% undergoing reoperation during the same hospitalization. Significant risk factors affecting postoperative complications (POC) were identified in the patients including number of comorbidities (≥2) (HR, 5.30; 95% CI, 1.1–15.3; P = 0.037) and operation type (Total vs Distal) (HR, 2.5; CI 1.08–8.5; p = 0.048). Subset analysis of gastric adenocarcinoma patients demonstrates a five-year overall survival (OS) for patients without perioperative complications was 68%, compared with 41% for patients with POCs (p 0.001). Conclusions In a large single-institutional study, POCs were associated with decreased survival in patients undergoing surgery for gastric adenocarcinoma. Optimizing these patients post-operatively with limited anastomotic stress and enteral feeding tube may allow for a less complicated course.

Broad patterns of use of the gene signature panel Oncotype DX DCIS and its large-scale impact on postoperative administration of radiation therapy in women with ductal carcinoma in situ of the breast remain unclear. This study sought to evaluate the patterns of use of this gene signature panel in women with ductal carcinoma in situ and the impact of these tools on postoperative radiation therapy administration.The National Cancer Database was queried for women with ductal carcinoma in situ treated with breast-conserving therapy who had information regarding whether a gene signature panel was performed between 2010 and 2015. Demographic characteristics, the characteristics of their ductal carcinoma in situ, and whether they received postoperative radiation therapy were compared among patients who did have a gene signature panel performed and those who did not. Patterns of radiation therapy administration were also evaluated based on the recurrence risk score by the gene signature panel.Gene signature panel use increased over time, with a sharp increase in utilization occurring in 2015 (8.0% in 2015 vs 4.4% in 2014, P.001). Patients with estrogen receptor-positive ductal carcinoma in situ were somewhat more likely to have a gene signature panel ordered (3.9% estrogen receptor positive vs 1.7% estrogen receptor negative, P.001), as were patients with lower-grade ductal carcinoma in situ (4.5% grade I/II vs 3.1% grade III, P.001). Gene signature panel utilization was associated with a decrease in the administration of postoperative radiation therapy (48.6% gene signature panel vs 83.4% no gene signature panel, P.001). Among patients in whom a gene signature panel was performed, postoperative radiation therapy was administered in 81.9%, 72.0%, and 35.9% of patients with high-, intermediate-, and low-recurrence scores, respectively.Gene signature panel use in patients with ductal carcinoma in situ has increased over time and is more commonly used in women with lower-risk, clinicopathologic features to determine the magnitude of benefit afforded by radiation therapy. Gene signature panel use is associated with decreased rates of postoperative radiation therapy administration, particularly among patients with scores suggesting a low rate of recurrence.

The presence of neutralizing antibodies against SARS-CoV-2 in a large number of people is – besides cellular immunity – important to overcome the SARS-CoV-2 pandemic. While determination of neutralizing antibodies via virus neutralization tests are laborious, assays to determine the antibody levels serologically are fully automated and widely available. Correlations between these methodologies were recently given by the manufacturers, however performance in samples close to the cut off value have not yet been fully validated. Thus, we analysed 22 borderline and low positive (

Ductal carcinoma in situ (DCIS) is a non-obligate precursor, non-invasive malignancy confined within the basement membrane of the breast ductal system. There is a wide variation in the natural history of DCIS with an estimated incidence of progression to invasive ductal carcinoma being at least 13%-50% over a range of 10 or more years after initial diagnosis. Regardless of the treatment strategy, long-term survival is excellent. The controversy surrounding DCIS relates to preventing under-treatment, while also avoiding unnecessary treatments. In this article, we review the incidence, presentation, management options and surveillance of DCIS. Furthermore, we address several current controversies related to the management of DCIS, including margin status, sentinel node biopsy, hormonal therapy, the role of radiation in breast conservation surgery, and various risk stratification schemes.

Background The benefit of adjuvant chemotherapy occurs with early initiation, but is commonly delayed due to postoperative complications. Minimally invasive surgery is proven to significantly reduce complications and hospital length of stay. This study compares open versus laparoscopic liver resection in patients requiring adjuvant chemotherapy. Methods 120 consecutive patients with metastatic colorectal liver cancer who underwent liver resection between 2007 through 2012 were reviewed from an IRB prospective database. Results 44 laparoscopic cases were compared to 76 open cases having equivalent resections. Laparoscopic liver resection patients had lower blood loss (276 ml) than patients with open resection (614 ml). Patients with laparoscopy had shorter length of hospital stay (5 days) than patients with open resection (9 days). Patients with laparoscopic resection had a shorter time of chemotherapy initiation postoperatively (24 days v 39 days). Overall complication rates were higher, but statistically insignificant in patients with open resection. Conclusions Our data showed that the shorter LOS with laparoscopic major hepatectomies allows earlier initiation of chemotherapy compared to the open group, without jeopardizing surgical margins or extent of resection. Summary Over the past decade multiple authors have established that, despite occasional longer operating times, laparoscopic liver surgery is associated with reduced blood loss, reduced postoperative morbidity and shorter hospital stay. The purpose of this analysis was to determine if the advantages of a minimally invasive approach correspond to shorter initiation of adjuvant chemotherapy versus an open approach.

We enumerate the broad range of anesthetic considerations that affect the outcome of patients undergoing laparoscopic liver resection. Key elements for excellent outcomes after laparoscopic liver resection are careful patient selection and risk stratification, appropriate monitoring, techniques to reduce blood loss and transfusion, and active recovery management. Although some of these key elements are the same for open liver operation, there are specific anesthetic considerations of which both the surgical and anesthesia teams must be aware to achieve optimal patient outcomes after laparoscopic liver resection. While unique advantages of laparoscopic liver resection typically include decreased intraoperative bleeding, transfusion requirements, and a lower incidence of postoperative ascites, specific challenges include management of the complicated interplay between low-volume anesthesia and increased intraabdominal pressure due to pneumoperitoneum, with additional considerations regarding circulatory support to treat acute blood loss with need for emergent conversion in some cases. This article will address in detail the preoperative, intraoperative, and postoperative anesthetic considerations for patients undergoing laparoscopic liver resection that both the surgical and anesthesia team should be aware of to optimize outcomes.

Background Antibody tests are essential tools to investigate humoral immunity following SARS-CoV-2 infection or vaccination. While first-generation antibody tests have primarily provided qualitative results, accurate seroprevalence studies and tracking of antibody levels over time require highly specific, sensitive and quantitative test setups. Methods We have developed two quantitative, easy-to-implement SARS-CoV-2 antibody tests, based on the spike receptor binding domain and the nucleocapsid protein. Comprehensive evaluation of antigens from several biotechnological platforms enabled the identification of superior antigen designs for reliable serodiagnostic. Cut-off modelling based on unprecedented large and heterogeneous multicentric validation cohorts allowed us to define optimal thresholds for the tests’ broad applications in different aspects of clinical use, such as seroprevalence studies and convalescent plasma donor qualification. Findings Both developed serotests individually performed similarly-well as fully-automated CE-marked test systems. Our described sensitivity-improved orthogonal test approach assures highest specificity (99.8%); thereby enabling robust serodiagnosis in low-prevalence settings with simple test formats. The inclusion of a calibrator permits accurate quantitative monitoring of antibody concentrations in samples collected at different time points during the acute and convalescent phase of COVID-19 and disclosed antibody level thresholds that correlate well with robust neutralization of authentic SARS-CoV-2 virus. Interpretation We demonstrate that antigen source and purity strongly impact serotest performance. Comprehensive biotechnology-assisted selection of antigens and in-depth characterisation of the assays allowed us to overcome limitations of simple ELISA-based antibody test formats based on chromometric reporters, to yield comparable assay performance as fully-automated platforms. Funding WWTF, Project No. COV20–016; BOKU, LBI/LBG

Background Sentinel lymph node (SLN) biopsy for melanoma results in accurate nodal staging, which guides treatment decisions. Patients with a negative SLN biopsy in general have a favorable prognosis, but certain subsets are at increased risk for recurrence and death. This study aimed to identify risk factors predictive of prognosis in patients with a tumor-negative SLN biopsy for cutaneous melanoma. Methods In this post-hoc analysis of data from a multicenter prospective randomized trial, clinicopathologic data of patients with cutaneous melanoma ≥1.0 mm Breslow thickness and tumor-negative SLN were analyzed. Disease-free survival, overall survival (OS), and local and in-transit recurrence-free survival were compared by Kaplan-Meier analysis. Risk factors for worse survival were identified with Cox proportional hazard models. Results This analysis included 1,998 patients with tumor-negative SLN with a median follow-up of 70 months. Ulceration, Breslow thickness, nonextremity tumor location, and age ≥45 years were independent risk factors for worse disease-free survival and OS. Breslow thickness and ulceration were the only factors on multivariate analysis that predicted local and in-transit recurrence-free survival. Estimated 5-year OS rates ranged from 55.5 to 95.4% on the basis of the defined risk factors. Conclusion There is a wide range of prognosis among patients with tumor-negative SLN. Breslow thickness, ulceration, age, and anatomic location of the primary melanoma are important independent factors predicting survival and recurrence among such patients. These factors can be used to stratify prognosis among patients with tumor-negative SLN to formulate rational long-term follow-up strategies as well as identify high-risk, SLN-negative patients for clinical trials of adjuvant therapy.

We have designed and tested software for the acquisition and analysis of high-resolution gamma-ray spectra during on-site inspections under the Comprehensive Nuclear-Test-Ban Treaty (CTBT). The On-Site Inspection RadioIsotopic Spectroscopy—OSIRIS—software filters the spectral data to display only radioisotopic information relevant to CTBT on-site inspections, e.g., 131 I. A set of over 100 fission-product spectra was employed for OSIRIS testing. These spectra were measured where possible, or generated by modeling. The test spectral compositions include non-nuclear-explosion scenarios, e.g., a severe nuclear reactor accident, and nuclear-explosion scenarios such as a vented underground nuclear test. Comparing its computer-based analyses to expert visual analyses of the test spectra, O SIRIS correctly identifies CTBT-relevant fission product isotopes at the 95% level or better.

Background The BRAF inhibitor vemurafenib (PLX) has shown promise in treating metastatic melanoma, but most patients develop resistance to treatment after 6 mo. We identified a transmembrane protein, extracellular matrix metalloproteinase inducer (EMMPRIN) as a cell surface receptor highly expressed by PLX-resistant melanoma. Using an S100A9 ligand, we created an EMMPRIN targeted probe and liposome that binds to melanoma cells in vivo, thus designing a novel drug delivery vehicle. Methods PLX-resistant cells were established through continuous treatment with PLX-4032 over the course of 1 y. Both PLX-resistant and sensitive melanoma cell lines were evaluated for the expression of unique cell surface proteins, which identified EMMPRIN as an overexpressed protein in PLX0-resistant cells and S100A9 is a ligand for EMMPRIN. To design a probe for EMMPRIN, S100A9 ligand was conjugated to a CF-750 near-infrared (NIR) dye. EMMPRIN targeted liposomes were created to encapsulate CF-750 NIR dye. Liposomes were characterized by scanning electron microscopy, flow cytometry, and in vivo analysis. A2058PLX and A2058 cells were subcutaneously injected into athymic mice. S100A9 liposomes were intravenously injected and tumor accumulation was evaluated using NIR fluorescent imaging. Results Western blot and flow cytometry demonstrated that PLX sensitive and resistant A2058 and A375 melanoma cells highly express EMMPRIN. S100A9 liposomes were 200 nm diameter and uniformly sized. Flow cytometry demonstrated 100X more intracellular dye uptake by A2058 cells treated with S100A9 liposomes compared with untargeted liposomes. In vivo accumulation of S100A9 liposomes within subcutaneous A2058 and A2058PLX tumors was observed from 6–48 h, with A2058PLX accumulating significantly higher levels (P = 0.001626). Conclusions EMMPRIN-targeted liposomes via an S100A9 ligand are a novel, targeted delivery system which could provide improved EMMPRIN specific drug delivery to a tumor.

Gender is an established prognostic factor in cutaneous melanoma; women as a group have a better overall prognosis than men. However, the investigators hypothesized that melanoma in young women may have distinct clinicopathologic features and biologic behavior compared with melanoma in older women, possibly related to tanning bed use and excessive acute episodes of sun exposure.A retrospective analysis was performed of a large multicenter study that accrued patients between 1996 and 2003 and included patients aged 18 to 70 years with cutaneous melanoma ≥1 mm Breslow thickness and no evidence of regional or distant metastatic disease. All women with follow-up data were included. Univariate and multivariate analyses as well as Kaplan-Meier (KM) analysis were performed to test for differences in clinicopathologic variables, disease-free survival (DFS), and overall survival (OS) between female patients ≤40 and40 years of age.A total of 1,056 female patients were divided into 2 groups: those40 years of age (n = 757 [71.7%]) and those ≤40 years of age (n = 299 [28.3%]). Overall, there were no differences in Breslow thickness, ulceration, or sentinel lymph node status between groups. Compared with older women, younger women were more likely to have truncal melanomas (39.5% vs 29.5%, P = .0017) and less likely to have regression of the primary tumor (6.4% vs 11.5%, P = .0208). The mean number of sentinel lymph nodes removed was 2.82 for younger women and 2.29 for older women (P.0001). Multivariate analysis revealed that Breslow thickness, ulceration, and tumor-positive sentinel lymph node were associated with worse DFS in both the younger and older groups; truncal location was associated with worse DFS in the younger group only. The same factors were predictive of OS in both groups, except that ulceration was not significant in the younger patient group. In the younger patient group, the 5-year KM DFS rates were 78.1% for truncal melanomas and 92.5% for nontruncal melanoma locations (P = .0009); the corresponding 5-year KM OS rates were 76.6% and 93.9% (P = .0003). In the older patient group, the 5-year KM DFS rates were 84.1% for truncal and 82.8% for nontruncal melanomas (P = NS), and the corresponding 5-year KM OS rates were 81.6% and 87.5% (P = .0049).Although women with cutaneous melanoma tend to have a better prognosis than men, women ≤40 years of age with primary melanoma of the trunk may represent a subgroup at higher risk for disease recurrence and metastasis.

Background The purpose of this study was to evaluate and compare the incidence of wound complications after laparoscopic component separation (LCS) vs open component separation (OCS) in patients with complex abdominal wall hernias. Methods A retrospective review was performed of all patients who underwent LCS or OCS for repair of a complex abdominal wall hernia at a single institution between 2009 and 2011. Charts were reviewed to identify postoperative wound complications. A computed tomographic scan or physical examination was used for the determination of hernia recurrence. Categoric variables were compared using the Fisher exact test. Univariate and multivariate analyses were performed using linear and Cox regression. Recurrence rates were compared using log-rank tests (Kaplan-Meier method). Results A total of 44 patients underwent LCS (n = 18) or OCS (n = 26). There was no statistically significant difference between categoric variables. Multivariate analysis using wound complications as the dependent variable showed a statistically significantly lower rate of wound complications in the LCS group. Conclusions LCS is associated with a lower rate of wound complications when compared with OCS but yields comparable recurrence rates.

Background The importance of the lymph node ratio (LNR) after regional lymphadenectomy for cutaneous melanoma is unknown. Materials and methods A post hoc analysis was performed for patients after the completion of lymphadenectomy for cutaneous melanoma. LNR was calculated as the number of tumor-positive nodes divided by the total number of lymph nodes. Comparison of disease-free survival (DFS) and overall survival (OS) and univariate and multivariate analyses with regard to LNR was performed. Comparison of the performance of LNR to other measurements of lymph node disease was performed. Results A LNR of 0.10 was a significant cutoff point for determining DFS and OS. On multivariate analysis, LNR >0.10 was an independent predictor of DFS and OS without other measures of lymph node disease burden. Patients with LNR >0.10 had worse DFS and OS. Absolute counts of tumor-positive lymph nodes differentiated survival differences better than LNR. LNR was not a significant predictor of survival in patients with neck or axillary dissections but was for inguinal dissections. In multivariate analysis of alternative nodal measures, LNR was an inferior prognostic factor. Conclusions A LNR >0.10 has a negative prognostic significance when it is the only measurement of lymph node disease considered but is an inferior prognostic factor to alternative measures of lymph node disease.

Background This study was performed to identify clinicopathologic factors associated with survival in acral lentiginous melanoma. Methods A post hoc analysis of a prospective clinical trial and local database was performed in all patients with acral lentiginous melanomas. Multivariate analyses of factors associated with a tumor-positive sentinel lymph node (SLN) biopsy, disease-free survival (DFS), overall survival (OS), and local and in-transit recurrence-free survival (LITRFS) were performed. Kaplan–Meier survival analyses were performed. Results Eighty-five patients were identified. Age younger than 59 years and Breslow thickness (BT) of 2.0 mm or greater were independent risk factors for a positive SLN. SLN status was the only independent risk factor for DFS and LITRFS on multivariate analysis. A BT of 2.0 mm or greater was the only independent risk factor for OS. SLN status distinguished differences in DFS, OS, and LITRFS on Kaplan–Meier analysis. Conclusions SLN status is the dominant factor for recurrence and survival in acral lentiginous melanoma. BT and ulceration are less important in this histologic subtype.

Metal complexes bearing phosphine ligands are attracting increasing attention for their applications in medicinal chem. In particular, organometallic ruthenium-phosphine complexes have been found to exhibit promising antitumor activity. The synthesis, anticancer activity and reactivity of a novel bis-phosphine complex, [Ru(η6-cymene)(PPh2(o-C6H4O)-κ2-P,O)(pta)]Cl (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1.]decane), is presented. The complex appears to exhibit its anticancer effect via a different mechanism to other ruthenium-arene pta complexes with labile co-ligands.

Seismic reflection profiling demonstrates that the active, significant-offset Surprise Valley Fault that marks the western boundary of the Basin-and-Range Province in northernmost California dips at a moderate angle, only ~ 30° to ~ 2 km depth. A nearby seismic refraction/wide-angle reflection profile, albeit of lower-resolution, shows the fault-plane remains approximately planar to at least 7 km depth. Variably-tilted volcanic strata of known ages within the Surprise Valley basin demonstrate that ≥ 7 km of normal slip occurred along the Surprise Valley Fault within the past 8–4 Myr at a time-averaged slip rate of ~ 1–2 mm/yr, and that the fault rotated from an initial dip of as much as 60° to its present dip of 30°. The rotation of this isolated fault was not accomplished by domino-style rotation as seen elsewhere in the Basin-and-Range province, but rather by flexural rift-shoulder uplift aided by mid-crustal flow.

Surprise Valley in northeastern California offers an ideal opportunity to examine the structural setting of a developing extensional basin due to its late Miocene to recent activity in isolation from other major normal fault-bound basins. Seismic velocity and potential field modeling help determine the nature of basin fill and identify intra-basin faults. Based on a detailed gravity and magnetic profile, we identify shallow subsurface basalt flows and several faults within the valley that may accommodate hundreds of meters of vertical offset, possibly cutting and offsetting the ~ 30° east-dipping Surprise Valley fault that rotated during footwall tilting of the adjacent Warner Mountains. Some of these intra-basin faults correspond with mapped Quaternary fault scarps, but others have no surface expression. These faults may represent the currently active fault system within the basin. If so, they would indicate that basin development is transitioning away from the main range-front normal fault to a new set of steep intra-basin faults that are more favorable for accommodating regional transtensional strain.

Objective Presentation of a large series of patients with metastatic melanoma involving the eye and orbit. Design Retrospective clinical study. Participants Thirteen cases of metastatic melanoma involving intraocular tissues, 6 cases of metastatic melanoma in the orbit, and 1 case of metastatic melanoma involving both the eye and the orbit, treated in Lausanne between 1986 and 2002, were identified from the computer files of the ocular oncology and orbitopalpebral surgery units of Jules Gonin Hospital. Methods The analysis is based on the demographic data concerning these patients, clinical data concerning the tumor, the treatment applied, the outcome, and the follow-up. Main outcome measures Clinical presentation of intraocular and orbital metastasis, interval between primary tumor and ocular metastasis, survival of the patients, evaluation of various therapeutic protocols. Results Intraocular metastases (14 cases, 15 eyes) were situated in the choroid in 11 cases (isolated lesion, 6 cases; multiple lesions, 3 cases; diffuse involvement, 2 cases), in the iris and ciliary body in 2 cases, and in the retina and vitreous in 2 other cases. The primary tumor was a cutaneous melanoma in 8 cases, a melanoma of the contralateral eye in 3 cases, a mucosal melanoma in 1 case, and was unknown in 2 cases. The mean interval between the diagnosis of ocular metastases and the patient's death was 8.8 months (range, 1–48 months). The primary tumor in the 7 cases of orbital metastases was a cutaneous melanoma in 5 cases, a uveal melanoma in the contralateral eye in 1 case, and was unknown in 1 case. The mean interval between the diagnosis of orbital metastases and death was 19.7 months (range, 5–48 months). The patients were treated by various protocols. The best results, in terms of both local tumor control and preservation of visual function, were obtained with circumscribed proton beam radiotherapy or external beam irradiation, depending on the site and extent of the tumor. Conclusions Metastatic melanomas to the eye and orbit are rare and generally occur in patients with disseminated metastases during the terminal stages of the disease, with a short life expectancy. Treatment is palliative and, among the various possible treatment options, circumscribed proton beam radiotherapy or global photon beam radiotherapy, at relatively high irradiation doses, seems to achieve the most favorable results.

A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and alpha-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50 approximately 1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.

Purpose: This study reports local tumor control and survival after proton beam radiotherapy (PBRT) of uveal melanoma. It identifies the risk factors for local tumor-control failure and for ocular tumor-related death. It presents the improvements implemented to increase the rate of local tumor control, and compares the survival rate of patients with locally controlled tumors to those of patients who had to receive a second treatment. Patients and Methods: We have treated 2,435 uveal melanomas with PBRT between March 1984 and December 1998. Data were analyzed as of September 1999. Patients’ age ranged from 9 to 89 years; there were 1,188 men and 1,247 women. The largest tumor diameter ranged from 4 to 26 mm, and tumor thickness from 0.9 to 15.6 mm. Median follow-up time was 40 months. Results: Local tumor control probability at 5 years was improved from 90.6 ± 1.7% for patients treated before 1988, to 96.3 ± 0.6% for patients treated between 1989 and 1993, and became 98.9 ± 0.6% for patients treated after 1993. Among 2,435 treated patients, 73 (3%) had to receive a second treatment because of tumor regrowth. Cause-specific survival at 10 years was calculated to 72.6 ± 1.9% for patients with controlled tumors compared to 47.5 ± 6.5% for those with recurrent tumors. Conclusion: Reduced safety margins, large ciliary body tumors, eyelids within the treatment field, inadequate positioning of tantalum clips, and male gender were identified to be the main factors impairing local tumor control. The improvement of local tumor control rate after 1993 is attributed to changes implemented in the treatment procedure. Our data strongly support that the rate of death by metastases is influenced by local tumor control failure: improvement of the local tumor control rate results in a better survival rate.

The physical and radiobiological features of the fully-modulated 72 MeV proton beam of the therapy unit of the Paul Scherrer Institut (Switzerland) were analyzed in deep detail by adopting both an experimental and theoretical approach. The spatial distribution of the physical dose was calculated by using the FLUKA MC transport code; the role of nuclear interactions was taken into account and the geometry of the apparatus was faithfully reproduced. The contributions of the various beam components were analysed separately. The simulation results were compared with measured depth–dose distributions and very good agreement was found. The depth-dependence of cell survival along the completely spread-out Bragg peak (SOBP) was simulated with a biophysical model, based on the assumption that clustered DNA damage is a relevant step of the process leading to cell inactivation. Experiments on clonogenic survival of V79 cells were performed at PSI and the results were compared with the simulations, showing very good agreement. Simulated and experimental results consistently confirm that the RBE along most of the SOBP is ≈1.2, whereas it increases dramatically at the distal part. The peak in biological effect is therefore shifted downstream from the physical dose peak.

Fricke-agarose gels have been irradiated with a proton beam. Then samples have been extracted at different depths with respect to the beam penetration distance, corresponding to different irradiation doses. Relaxation times T1 and T2, measured at 17 MHz, appear sensitive to this kind of radiation. In particular, T2 exhibits three components T2a, T2b and T2c, the first two being sensitive to proton irradiation. At 1% agarose concentration, the relaxation rates R1 = 1/T1, R2a = 1/T2a and R2b = 1/T2b of samples irradiated with both modulated and unmodulated beams, increase with the dose, irrespective of the beam energy. The yield G of Fe3+ ions per 100 eV of absorbed energy is always higher than that obtained for gamma irradiated samples.

The performance of two different alanine-ESR systems (1 mm ISS pellets and NRI films) in therapy proton beams was checked against reference dosimetery provided by a Markus parallel plate ionization chamber. Irradiations were performed at the OPTIS facility of the PSI with a 62 MeV proton beam. The energy dependence of the response was derived from the analysis of film stacks irradiated with pristine beams. In fact, 250 μm films allowed for a high resolution sampling of the proton slowing down mechanisms. Moreover pellets were irradiated in unmodulated and modulated beams. Alanine dose distributions were always in good agreement with the PSI Markus chamber results. Simple density scaling allowed for the conversion of the results to the dose distributions in water, consistently with the good tissue equivalence properties of these detectors.

Purpose We investigated the therapeutic possibilities of gamma brachytherapy to improve the final functional results of eyes with choroidal hemangiomas, which are benign vascular tumors that can induce progressive impairment of visual acuity. Methods We treated 41 patients with choroidal hemangioma with cobalt-60 applicators. The lesions consisted of 39 circumscribed hemangiomas and two diffuse hemangiomas in patients with Sturge-Weber syndrome. Before treatment, visual acuity in the affected eye was 20/200 in ten patients, 20/200 to 20/50 in 17 patients, 20/40 to 20/25 in 11 patients, and 20/20 in three patients. All patients were symptomatic. The macula was infiltrated by the tumor in 12 eyes (29.3%). There was retinal detachment in 40 eyes (97.6%), cystoid edema in ten eyes (24.4%), subretinal fibrosis in eight eyes (19.5%), and areolar atrophy in two eyes (4.9%). Results After treatment, the retina was reattached in all eyes, and the tumor progressively transformed into a flat scar. The postirradiation macular lesions that we identified were pigment migrations in the macular region, subretinal fibrosis, and an areolar atrophic scar. We correlated the functional results at two, five, and ten years after treatment with the initial visual acuity, and with pre-existing and posttreatment macular lesions. Conclusions Our results suggest that radiotherapy is a valuable therapeutic modality for choroidal hemangiomas, particularly in hemangiomas that involve the macula, and for tumors associated with bullous retinal detachment.

The activity of the creatine kinase isoenzyme BB was determined in the serum of 26 healthy adults and 31 children. The isoenzyme BB could be proved as a normal component in the human serum. In the adults examined, an activity of 0.56 ± 0.16 I.U./l ( x ± S.D. ) was determined. The activity of creatine kinase isoenzyme BB in the serum does not depend on sex but is subject, however, to a strong age dependence. Only at an age of more than 18 years, isoenzyme BB activities adjust to those of adults.

Non-ionic detergents such as polyoxyethylene-octylphenol or -sorbitolester were found to increase activity of horseradish peroxidase due to delay of inactivation in the course of substrate reaction. This rise in activity was investigated using different chromogens and was highest with o-dianisidine. An increasing stability of the enzyme to higher reaction temperatures was observed when detergents were added to the substrate solution, and the action of detergents also is enhanced with increasing reaction temperature and time. Different degrees of activation were found when comparing substrate conversion with and without detergents using free peroxidase (2.7-fold) and conjugated peroxidase bound to the solid phase by antigen antibody reaction (1.8-fold). In enzyme-immunoassay, detection limit and analytical sensitivity can be doubled.

The suitability of thirteen commercially available control sera for measuring alkaline phosphatase (EC 3.1.3.1; orthophosphoric acid monoester phosphohydrolase, ALP) activity in human serum was tested. Apart from differences in ALP activity observed in some reconstituted commercial sera, the behaviour of control materials towards experimental variables such as the nature and concentration of the substrate, pH and type of buffer (or PO4-acceptor) together with the composition of the isoenzymes present in human serum highlights the problems and difficulties if commercial materials are to be used as control sera. The half-saturation constants in control sera were in all cases smaller than those of ALP isoenzymes from bone and liver. The shape of substrate activity curves and the pH optimum in most of control sera differed from that of human serum. The discrepant kinetic data of control materials and human serum may mask or suggest changes relevant to commercial quality control serum but not to samples of human serum.

1. 1. The red blood cell lipids in different forms of human muscular dystrophy (m.d., 29 cases) were estimated and a significant increase of the sphingomyelin content was found in x-chromosomal and autosomal malignant m.d. In these cases sphingomyelin was the main fraction of the phospholipids. Plasmalogens showed no variation. 2. 2. The fatty acid pattern of phosphatidylethanolamine (PE) and sphingomyelin (Sph) from erythrocytes in m.d. was significantly altered: in PE of m.d. the dimethyl acetals were increased, arachidonic acid was diminished. In Sph of m.d., the fatty acids 16:0, 24:2 and 18:2 were decreased and the percentage of stearic acid was increased. The composition of fatty acids in the corresponding fractions in the serum was not altered. 3. 3. The influx of linoleic acid and the incorporation of this fatty acid in phosphatidylcholine (PCh) and PE in erythrocytes of m.d. during incubation in vitro was increased, the reactivity of palmitic and stearic acids was not different from the controls. 4. 4. In the pooled bioptic samples of three cases of m.d., the fatty acid pattern of PCh, PE, Sph and lyso-PCh was estimated. Remarkable differences as compared to normal muscle were found. 5. 5. The results are discussed in the light of the thesis that the primary defect in m.d. concerns the specific incorporation of linoleic acid during the de novo synthesis of PCh in muscle. Possible mechanism of variation of the pattern of fatty acids in red blood cell phospholipids are discussed considering the fact that Sph has a lower turnover than PCh and PE.

Zusammenfassung Menschlicher Mischspeichel wurde nach Konzentrierung der Proteine mittels Ultrafiltration bzw. Lyophilisierung in freier, Horizontalstreifen- und kontinuierlicher Elektrophorese untersucht. Es wurden 5–7 reproduzierbare Fraktionen gefunden, welche durch ihre Beweglichkeit, verglichen mit zugesetzten reinen Serumproteinfraktionen, ihre Anfarbbarkeit mit Amidoschwarz, mit der Perjodat-Schiff-Reaktion, mit Sudanschwarz, Mucicarmin und Toluidinblau charakterisiert wurden. Die Amylaseaktivitat wurde am Horizontalstreifen und nach kontinuierlicher Elektrophorese lokalisiert. Alkoholgefalltes Mucin aus Mischspeichel erwies sich elektrophoretisch als uneinheitlich. Bei Myelomfallen mit Paraproteinurie konnte eine entsprechende Eiweissfraktion im Speichel nachgewiesen werden.