The Impact of Nozzle Opening Thickness on Flow Characteristics and Primary Electron Beam Scattering in an Environmental Scanning Electron Microscope.

This paper describes the methodology of combining experimental measurements with mathematical-physics analyses in the investigation of flow in the aperture and nozzle. The aperture and nozzle separate the differentially pumped chamber from the specimen chamber in an environmental scanning electron microscope (ESEM). Experimental measurements are provided by temperature and pressure sensors that meet the demanding conditions of cryogenic temperature zones and low pressures. This aperture maintains the required pressure difference between the chambers. Since it separates the large pressure gradient, critical flow occurs on it and supersonic gas flow with the characteristic properties of critical flow in the state variables occurs behind it. As a primary electron beam passes through the differential pumped chamber and the given aperture, the aperture is equipped with a nozzle. The shape of the nozzle strongly influences the character of the supersonic flow. The course of state variables is also strongly influenced by this shape; thus, it affects the number of collisions the primary beam's electrons have with gas molecules, and so the resulting image. This paper describes experimental measurements made using sensors under laboratory conditions in a specially created experimental chamber. Then, validation using mathematical-physical analysis in the Ansys Fluent system is described.

Prospective Evaluation of Circulating Tumor DNA using Next Generation Sequencing as a Biomarker during Neoadjuvant Chemotherapy in Localized Pancreatic Cancer.

OBJECTIVE: In this prospective study, we aim to characterize the prognostic value of circulating tumor DNA (ctDNA) by next-generation-sequencing (NGS) in patients undergoing neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: Circulating tumor DNA is a promising blood-based biomarker that is prognostic in several malignancies. Detection of ctDNA by NGS may provide insights regarding the mutational profiles in PDAC to help guide clinical decisions for patients in a potentially curative setting. However, the utility of ctDNA as a biomarker in localized PDAC remains unclear. METHODS: Patients with localized PDAC were enrolled in a prospective study at Northwestern Medicine between October 2020 and October 2022. Blood samples were collected to perform targeted tumor agnostic NGS utilizing the Tempus x|F 105 gene panel at three timepoints: pre-therapy (at diagnosis), post-NAC, and after local therapy, including surgery. The relationship between ctDNA detection and CA19-9, and the prognostic significance of ctDNA detection were analyzed. RESULTS: 56 patients were included in the analysis. ctDNA was detectable in 48% at diagnosis, 33% post-NAC, and 41% after local therapy. After completion of NAC, patients with detectable ctDNA had higher CA19-9 levels versus those without (78.4 vs. 30.0, P=0.02). The presence of baseline ctDNA was associated with a CA19-9 response; those without ctDNA had a significant CA19-9 response following NAC (109.0 U/mL vs. 31.5 U/mL; P=0.01), while those with ctDNA present at diagnosis did not (198.1 U/mL vs. 113.8 U/mL; P=0.77). In patients treated with NAC, the presence of KRAS ctDNA at diagnosis was associated with and independently predicted worse progression-free-survival. CONCLUSION: This report demonstrates the prognostic value of ctDNA analysis with NGS in localized PDAC. NGS ctDNA is a biomarker of treatment response to NAC. KRAS ctDNA at diagnosis independently predicts worse survival in patients treated with NAC.

Comparative Analysis of Supersonic Flow in Atmospheric and Low Pressure in the Region of Shock Waves Creation for Electron Microscopy.

This paper presents mathematical-physics analyses in the field of the influence of inserted sensors on the supersonic flow behind the nozzle. It evaluates differences in the flow in the area of atmospheric pressure and low pressure on the boundary of continuum mechanics. To analyze the formation of detached and conical shock waves and their distinct characteristics in atmospheric pressure and low pressure on the boundary of continuum mechanics, we conduct comparative analyses using two types of inserted sensors: flat end and tip. These analyses were performed in two variants, considering pressure ratios of 10:1 both in front of and behind the nozzle. The first variant involved using atmospheric pressure in the chamber in front of the nozzle. The second type of analysis was conducted with a pressure of 10,000 Pa in front of the nozzle. While this represents a low pressure at the boundary of continuum mechanics, it remains above the critical limit of 113 Pa. This deliberate choice was made as it falls within the team's research focus on low-pressure regions. Although it is situated at the boundary of continuum mechanics, it is intentionally within a pressure range where the viscosity values are not yet dependent on pressure. In these variants, the nature of the flow was investigated concerning the ratio of inertial and viscous flow forces under atmospheric pressure conditions, and it was compared with flow conditions at low pressure. In the low-pressure scenario, the ratio of inertial and viscous flow forces led to a significant reduction in the value of inertial forces. The results showed an altered flow character, characterized by a reduced tendency for the formation of cross-oblique shockwaves within the nozzle itself and the emergence of shockwaves with increased thickness. This increased thickness is attributed to viscous forces inhibiting the thickening of the shockwave itself. This altered flow character may have implications, such as influencing temperature sensing with a tipped sensor. The shockwave area may form in a very confined space in front of the tip, potentially impacting the results. Additionally, due to reduced inertial forces, the cone shock wave's angle is a few degrees larger than theoretical predictions, and there is no tilting due to lower inertial forces. These analyses serve as the basis for upcoming experiments in the experimental chamber designed specifically for investigations in the given region of low pressures at the boundary of continuum mechanics. The objective, in combination with mathematical-physics analyses, is to determine changes within this region of the continuum mechanics boundary where inertial forces are markedly lower than in the atmosphere but remain under the influence of unreduced viscosity.

Sequential pembrolizumab and AVD are highly effective at any PD-L1 expression level in untreated Hodgkin lymphoma.

In a multicenter, phase 2, investigator-initiated trial of sequential pembrolizumab and AVD (doxorubicin, vinblastine, and dacarbazine), nearly two-thirds of patients with untreated, unfavorable, or advanced-stage classic Hodgkin lymphoma (cHL) achieved positron emission tomography (PET)-defined, complete or near-complete metabolic responses (CMRs), following pembrolizumab monotherapy. Furthermore, all patients achieved CMR after 2 cycles of AVD, with 100% of patients alive and without relapse at initial publication. We now report long-term follow-up, including the 3-year overall survival (OS) and planned correlative analyses. Thirty patients received 3 cycles of single-agent pembrolizumab, followed by AVD chemotherapy for 4 to 6 cycles depending on the stage and bulk. PET/computed tomography scan was performed after pembrolizumab monotherapy, 2 cycles of AVD, and at the end of therapy. Baseline biopsy samples were analyzed for genomic alterations of chromosome 9p24.1 and programmed cell death protein 1 (PD-1) pathway markers. At a median follow-up of 33.1 months (range, 26.0-43.0), progression-free survival and OS remained 100%. All patients had genomic alterations in 9p24.1 and were positive for programmed death ligand 1 (PD-L1) by immunohistochemistry. There was no relationship between depth of response to single-agent pembrolizumab and 9p24.1 alterations or PD-1 pathway H-scores. After additional follow-up, sequential pembrolizumab and AVD remained highly effective. The high response rates observed at all PD-L1 levels suggest that even low levels of PD-L1 expression are sufficient for response to PD-1 blockade in untreated cHL. An international phase 2 trial (registered at www.clinicaltrials.gov as #NCT03226249) is ongoing to confirm our findings.

Slip Flow Analysis in an Experimental Chamber Simulating Differential Pumping in an Environmental Scanning Electron Microscope.

This paper describes the combination of experimental measurements with mathematical-physical analysis during the investigation of flow in an aperture at low pressures in a prepared experimental chamber. In the first step, experimental measurements of the pressure in the specimen chamber and at its outlet were taken during the pumping of the chamber. This process converted the atmospheric pressure into the operating pressure typical for the current AQUASEM II environmental electron microscope at the ISI of the CAS in Brno. Based on these results, a mathematical-physical model was tuned in the Ansys Fluent system and subsequently used for mathematical-physical analysis in a slip flow regime on a nozzle wall at low pressure. These analyses will be used to fine-tune the experimental chamber. Once the chamber is operational, it will be possible to compare the results obtained from the experimental measurements of the nozzle wall pressure, static pressure, total pressure and temperature from the nozzle axis region in supersonic flow with the results obtained from the mathematical-physical analyses. Based on the above comparative analyses, we will be able to determine the realistic slip flow at the nozzle wall under different conditions at the continuum mechanics boundary.

Optimization of contrast material administration for coronary CT angiography using a software-based test-bolus evaluation algorithm.

OBJECTIVES: To evaluate the benefit of a prototype circulation time-based test bolus evaluation algorithm for the individualized optimal timing of contrast media (CM) delivery in patients undergoing coronary CT angiography (CCTA). METHODS: Thirty-two patients (62 ± 16 years) underwent CCTA using a prototype bolus evaluation tool to determine the optimal time-delay for CM administration. Contrast attenuation, signal-to-noise ratio (SNR), objective, and subjective image quality were evaluated by two independent radiologists. Results were compared to a control cohort (matched for age, sex, body mass index, and tube voltage) of patients who underwent CCTA using the generic test bolus peak attenuation +4 s protocol as scan delay. RESULTS: In the study group, the mean time delay to CCTA acquisition was significantly longer (26.0 ± 2.9 s) compared to the control group (23.1 ± 3.5 s; p < 0.01). In the study group, SNR improvement was seen in the right coronary artery (17.5 vs 13; p = 0.028), the left main (15.3 vs 12.3; p = 0.027), and the left anterior descending artery (18.5 vs 14.1; p = 0.048). Subjective image quality was rated higher in the study group (4.75 ± 0.7 vs 3.64 ± 0.5; p < 0.001). CONCLUSIONS: The prototype test bolus evaluation algorithm provided a reliable patient-specific scan delay for CCTA that ensured homogenous vascular attenuation, improvement in objective and subjective image quality, and avoidance of beam hardening artifacts. ADVANCES IN KNOWLEDGE: The prototype contrast bolus evaluation and optimization tool estimated circulation time-based time-delay improves the overall quality of CCTA.

Application of Prandtl's Theory in the Design of an Experimental Chamber for Static Pressure Measurements.

Pumping in vacuum chambers is part of the field of environmental electron microscopy. These chambers are separated from each other by a small-diameter aperture that creates a critical flow in the supersonic flow regime. The distribution of pressure and shock waves in the path of the primary electron beam passing through the differentially pumped chamber has a large influence on the quality of the resulting microscope image. As part of this research, an experimental chamber was constructed to map supersonic flow at low pressures. The shape of this chamber was designed using mathematical-physical analyses, which served not only as a basis for the design of its geometry, but especially for the correct choice of absolute and differential pressure sensors with respect to the cryogenic temperature generated in the supersonic flow. The mathematical and physical analyses presented here map the nature of the supersonic flow with large gradients of state variables at low pressures at the continuum mechanics boundary near the region of free molecule motion in which the Environmental Electron Microscope and its differentially pumped chamber operate, which has a significant impact on the resulting sharpness of the final image obtained by the microscope. The results of this work map the flow in and behind the Laval nozzle in the experimental chamber and are the initial basis that enabled the optimization of the design of the chamber based on Prandtl's theory for the possibility of fitting it with pressure probes in such a way that they can map the flow in and behind the Laval nozzle.

Energy Harvesting Using Thermocouple and Compressed Air.

In this paper, we describe the possibility of using the energy of a compressed air flow, where cryogenic temperatures are achieved within the flow behind the nozzle, when reaching a critical flow in order to maximize the energy gained. Compared to the energy of compressed air, the energy obtained thermoelectrically is negligible, but not zero. We are therefore primarily aiming to maximize the use of available energy sources. Behind the aperture separating regions with a pressure difference of several atmospheres, a supersonic flow with a large temperature drop develops. Based on the Seebeck effect, a thermocouple is placed in these low temperatures to create a thermoelectric voltage. This paper contains a mathematical-physical analysis for proper nozzle design, controlled gas expansion and ideal placement of a thermocouple within the flow for best utilization of the low temperature before a shockwave formation. If the gas flow passes through a perpendicular shockwave, the velocity drops sharply and the gas pressure rises, thereby increasing the temperature. In contrast, with a conical shockwave, such dramatic changes do not occur and the cooling effect is not impaired. This article also contains analyses for proper forming of the head shape of the thermocouple to avoid the formation of a detached shockwave, which causes temperature stagnation resulting in lower thermocouple cooling efficiency.

Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma.

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

Plastic pollution affects American lobsters, Homarus americanus.

This paper provides the first record of ingestion of plastic debris by American lobster, Homarus americanus. Plastics particles, identified as rubber pieces, were found in the stomachs of 3 from 17 individuals of lobsters kept in laboratory conditions. Debris had evidence of cuts, what suggest they were actively consumed.

Long-Term Effectiveness of Strattice in the Laparoscopic Closure of Paraesophageal Hernias.

Prosthetic reinforcement reduces the recurrence rate of large paraesophageal hernias (PEH), but the use of synthetic or biosynthetic mesh in the repair remains controversial. PEH repair has reported recurrence rates of 12% to 42%, and primary repair of PEH by suture closure under tension is at high risk of disruption. Synthetic mesh use in large PEH repair has shown to reduce recurrence but can lead to problems including mesh erosion, ulceration, stricture, and dysphagia. The objective of this study was to examine the long-term safety and efficacy of Strattice biologic mesh, a porcine acellular dermal matrix, in crural reinforcement of laparoscopic large PEH repair. Thirty-five patients with symptomatic PEH (>5 cm) were consented to receive Strattice for PEH repair. Patients were seen in clinic preoperatively, at surgery, and 2 weeks, 6 months, and 12 months postoperatively. Patients were given a standard subjective reflux test at each visit and a 12-month barium swallow X-ray to test for recurrence. Hernia recurrence was documented in 14.3% of cases by the end of the 1-year follow-up. Symptoms improved in 75% to 100% of patients by 6 months, and 33% to 100% of patients were still reporting symptom improvement at 12 months. Strattice mesh in PEH repair results in similar outcomes to other absorbable meshes, and the recurrence rate is within the 12% to 42% range of recurrences reported in studies outside of our institution. The use of Strattice mesh in large PEH repair had results similar to other biomaterial meshes and successfully decreased patients' symptom scores through surgical intervention.

Influence of glycosylation pattern on the molecular properties of monoclonal antibodies.

Glycosylation is an important post-translational modification during protein production in eukaryotic cells, and it is essential for protein structure, stability, half-life, and biological functions. In this study, we produced various monoclonal antibody (mAb) glycoforms from Chinese hamster ovary (CHO) cells, including the natively glycosylated antibody, the enriched G0 form, the deglycosylated form, the afucosylated form, and the high mannose form, and we compared their intrinsic properties, side-by-side, through biophysical and biochemical approaches. Spectroscopic analysis indicates no measureable secondary or tertiary structural changes after in vitro or in vivo modification of the glycosylation pattern. Thermal unfolding experiments show that the high mannose and deglycosylated forms have reduced thermal stability of the CH2 domain compared with the other tested glycoforms. We also observed that the individual domain's thermal stability could be pH dependent. Proteolysis analysis indicates that glycosylation plays an important role in stabilizing mAbs against proteases. The stability of antibody glycoforms at the storage condition (2-8 °C) and at accelerated conditions (30 and 40 °C) was evaluated, and the results indicate that glycosylation patterns do not substantially affect the storage stability of the antibody we studied.

Production, characterization, and pharmacokinetic properties of antibodies with N-linked mannose-5 glycans.

The effector functions of therapeutic antibodies are strongly affected by the specific glycans added to the Fc domain during post-translational processing. Antibodies bearing high levels of N-linked mannose-5 glycan (Man5) have been reported to exhibit enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) compared with antibodies with fucosylated complex or hybrid glycans. To better understand the relationship between antibodies with high levels of Man5 and their biological activity in vivo, we developed an approach to generate substantially homogeneous antibodies bearing the Man5 glycoform. A mannosidase inhibitor, kifunensine, was first incorporated in the cell culture process to generate antibodies with a distribution of high mannose glycoforms. Antibodies were then purified and treated with a mannosidase for trimming to Man5 in vitro. This 2-step approach can consistently generate antibodies with > 99% Man5 glycan. Antibodies bearing varying levels of Man5 were studied to compare ADCC and Fcγ receptor binding, and they showed enhanced ADCC activity and increased binding affinity to the FcγRIIIA. In addition, the clearance rate of antibodies bearing Man8/9 and Man5 glycans was determined in a pharmacokinetics study in mice. When compared with historical data, the antibodies bearing the high mannose glycoform exhibited faster clearance rate compared with antibodies bearing the fucosylated complex glycoform, while the pharmacokinetic properties of antibodies with Man8/9 and Man5 glycoforms appeared similar. In addition, we identified the presence of a mannosidase in mouse serum that converted most Man8/9 to Man6 after 24 h.

Characterization of the basic charge variants of a human IgG1: effect of copper concentration in cell culture media.

We report a case study of an IgG1 with a unique basic charge variant profile caused by C-terminal proline amidation on either one or two heavy chains. The proline amidation was sensitive to copper ion concentration in the production media during cell culture: the higher the Cu ( 2+) ion concentration, the higher the level of proline amidation detected. This conclusion was supported by the analysis of samples that revealed direct correlation between the proline amidation level observed from peptide maps and the level of basic peaks measured by imaged capillary isoelectric focusing and a pH gradient ion-exchange chromatography method. The importance of these observations to therapeutic antibody production is discussed.

The impact of glycosylation on monoclonal antibody conformation and stability.

Antibody glycosylation is a common post-translational modification and has a critical role in antibody effector function. The use of glycoengineering to produce antibodies with specific glycoforms may be required to achieve the desired therapeutic efficacy. However, the modified molecule could have unusual behavior during development due to the alteration of its intrinsic properties and stability. In this study, we focused on the differences between glycosylated and deglycosylated antibodies, as aglycosyl antibodies are often chosen when effector function is not desired or unimportant. We selected three human IgG1 antibodies and used PNGase F to remove their oligosaccharide chains. Although there were no detected secondary or tertiary structural changes after deglycosylation, other intrinsic properties of the antibody were altered with the removal of oligosaccharide chains in the Fc region. The apparent molecular hydrodynamic radius increased after deglycosylation based on size-exclusion chromatography analysis. Deglycosylated antibodies exhibited less thermal stability for the CH2 domain and less resistance to GdnHCl induced unfolding. Susceptibility to proteolytic cleavage demonstrated that the deglycosylated version was more susceptible to papain. An accelerated stability study revealed that deglycosylated antibodies had higher aggregation rates. These changes may impact the development of aglycosyl antibody biotherapeutics.

Safety and efficacy of combination therapy with fludarabine, mitoxantrone, and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front-line therapy for patients with follicular or marginal zone lymphoma.

BACKGROUND: We conducted a single-institution phase II clinical trial evaluating the safety and efficacy of combination chemoimmunotherapy followed by radioimmunotherapy consolidation and rituximab maintenance as front-line treatment in indolent lymphomas. PATIENTS AND METHODS: We enrolled 20 patients with intermediate- to high-risk follicular lymphoma and 2 patients with marginal zone lymphoma. Treatment consisted of 4-6 cycles of FM (fludarabine 25 mg/m(2) on days 1-3, mitoxantrone 12 mg/m(2) on day 1 of each 28-day cycle). The protocol was amended after enrolling the first 4 patients to include rituximab 375 mg/m(2) on day 1. After 6-8 weeks, responders received (90)Y-ibritumomab tiuxetan (Zevalin) followed by maintenance rituximab (375 mg/m(2) weekly × 4 doses, repeated every 6 months for 2 years). RESULTS: After R-FM, the overall response rate was 95% with a complete response rate (CR) of 45% (n = 10), a partial response (PR) rate of 50% (n = 11), and stable disease in 1 patient. Nineteen patients received (90)Y-ibritumomab tiuxetan with a 60% conversion rate of PR to CR, resulting in an improved CR of 79% (n = 15) and a PR of 21% (n = 4). Fifteen patients proceeded to rituximab maintenance resulting in 3 patients with PR converting to CR. At median follow-up of 49.6 months, median progression-free survival (PFS) was 47.2 months and median overall survival (OS) was not reached in an intent-to-treat analysis. The most common adverse effects were hematologic, with 2 patients experiencing treatment-related myelodysplastic syndrome (MDS), evolving to acute myelogenous leukemia (AML) in 1 patient. CONCLUSION: R-FM with (90)Y-ibritumomab tiuxetan consolidation and rituximab maintenance is well tolerated, improving CR rates and maintaining durable responses in patients with untreated indolent lymphomas.

Effects of cell culture conditions on antibody N-linked glycosylation--what affects high mannose 5 glycoform.

The glycosylation profile of therapeutic antibodies is routinely analyzed throughout development to monitor the impact of process parameters and to ensure consistency, efficacy, and safety for clinical and commercial batches of therapeutic products. In this study, unusually high levels of the mannose-5 (Man5) glycoform were observed during the early development of a therapeutic antibody produced from a Chinese hamster ovary (CHO) cell line, model cell line A. Follow up studies indicated that the antibody Man5 level was increased throughout the course of cell culture production as a result of increasing cell culture medium osmolality levels and extending culture duration. With model cell line A, Man5 glycosylation increased more than twofold from 12% to 28% in the fed-batch process through a combination of high basal and feed media osmolality and increased run duration. The osmolality and culture duration effects were also observed for four other CHO antibody producing cell lines by adding NaCl in both basal and feed media and extending the culture duration of the cell culture process. Moreover, reduction of Man5 level from model cell line A was achieved by supplementing MnCl2 at appropriate concentrations. To further understand the role of glycosyltransferases in Man5 level, N-acetylglucosaminyltransferase I GnT-I mRNA levels at different osmolality conditions were measured. It has been hypothesized that specific enzyme activity in the glycosylation pathway could have been altered in this fed-batch process.

Recovery and purification process development for monoclonal antibody production.

Hundreds of therapeutic monoclonal antibodies (mAbs) are currently in development, and many companies have multiple antibodies in their pipelines. Current methodology used in recovery processes for these molecules are reviewed here. Basic unit operations such as harvest, Protein A affinity chromatography, and additional polishing steps are surveyed. Alternative processes such as flocculation, precipitation, and membrane chromatography are discussed. We also cover platform approaches to purification methods development, use of high throughput screening methods, and offer a view on future developments in purification methodology as applied to mAbs.

Does type of mesh used have an impact on outcomes in laparoscopic inguinal hernia?

BACKGROUND: Theoretically, a lighter and softer mesh may decrease nerve entrapment and chronic pain by creating less fibrosis and mesh contracture in laparoscopic inguinal hernia repair. METHODS: We performed a telephone survey of patients who underwent laparoscopic inguinal hernia surgery between 2001 and 2007. We recorded patient responses for chronic pain, foreign body sensation, recurrence, satisfaction, and return to work, and then studied the effect of type of mesh (polypropylene vs polyester) on these factors. RESULTS: Of 109 consecutive patients surveyed (mean age, 54.5 y), 67 eligible patients underwent 84 transabdominal extraperitoneal procedures and 2 transabdominal preperitoneal procedures. Patients with polypropylene mesh had a 3 times higher rate of chronic pain (P = .05), feeling of lump (P = .02), and foreign body perception (P = .05) than the polyester mesh group. Our overall 1-year recurrence rate was 5.9%. The recurrence rate was 9.3% for the polypropylene group and 2.9% for the polyester group (P = .26). CONCLUSIONS: A lightweight polyester mesh has better long-term outcomes for chronic pain and foreign body sensation compared with a heavy polypropylene mesh in laparoscopic inguinal hernia repair. We also saw a trend toward higher recurrence in the polypropylene group.

Phase II studies of gemcitabine and cisplatin in heavily and minimally pretreated metastatic breast cancer.

PURPOSE: Cisplatin and gemcitabine have single-agent activity in metastatic breast cancer, and preclinical data support synergy of the combination. Two parallel, phase II trials were conducted to evaluate the response rate, response duration, and toxicities of the combination. Genetic polymorphisms were analyzed for correlation with outcomes. PATIENTS AND METHODS: Eligible women had measurable disease and heavily or minimally pretreated metastatic breast cancer. The heavily pretreated protocol required prior anthracycline and taxane therapy; cisplatin as part of high-dose therapy was allowed. All patients received cisplatin 25 mg/m(2) on days 1 through 4 and gemcitabine 1,000 mg/m(2) on days 2 and 8 of a 21-day cycle with prophylactic granulocyte colony-stimulating factor in the heavily pretreated group. Sera from a subset of patients were evaluated by polymerase chain reaction restriction fragment length polymorphism for polymorphisms in 10 genes of interest. RESULTS: Of 136 women enrolled, 74 were heavily pretreated. Both protocols accrued to their two-stage design. The response rate for both the heavily and minimally pretreated cohorts was 26%, and the median durations of response were 5.3 and 5.9 months, respectively. In a multivariate analysis, hormone receptor-negative disease was associated with a higher response rate. The most common grades 3 or 4 toxicities were thrombocytopenia (71%), neutropenia (66%), and anemia (38%). In a subset of 55 patients, the xeroderma pigmentosum group D (XPD)-751, x-ray cross-complementing group 3 (XRCC3) and cytidine deaminase polymorphisms were significantly associated with clinical outcomes. CONCLUSION: Combination cisplatin and gemcitabine is active in metastatic breast cancer regardless of prior therapy. Genetic polymorphisms may tailor which patients benefit from this regimen.