Societal costs of ovarian cancer in a population-based cohort - a cost of illness analysis.

BACKGROUND: The societal cost associated with ovarian cancer (OC) is not well known. Increasing costs for new treatments and/or the impact of organizational changes motivates these costs to be described and communicated. This study aims to evaluate the cost of illness of OC in a population-based cohort. MATERIAL AND METHODS: All patients diagnosed with ovarian, fallopian tube, primary peritoneal cancer, and serous cancer of undesignated primary site (UPS) in 2011-2012 were followed for six years. Direct costs, i.e., costs for health care expenditures, were gathered from the regional healthcare database. Information on indirect costs, i.e., costs of loss of production due to sick leave, was retrieved from Statistics Sweden. Sub-group analyses were conducted regarding stage, income levels, residential area, and diagnosis. RESULTS: The cost of illness for all stages during the six years of follow-up was €201,086 per patient, where indirect costs constituted 43.7%. The mean cost of illness per year per patient for all stages was €33,514. Direct costs were higher in advanced stages compared to early stages for every year from diagnosis. During the first two years, there were no differences in indirect costs between early and advanced stages. However, during the third year there was a difference with higher indirect costs in advanced stages. There was no difference in direct costs depending on income levels. Regarding residential area, there was a difference in the outpatient cost during the index and second year with higher costs when chemotherapy and follow-up were provided at county hospitals, compared to at the tertiary hospital. CONCLUSIONS: Indirect costs constituted a large part of the cost of illness over 6 years from diagnosis. This could indicate that even though treatment costs can be expected to rise with the introduction of new therapies, the societal cost may decrease when survival increase.

Instantaneous wave-free ratio compared with fractional flow reserve in PCI: A cost-minimization analysis.

BACKGROUND: Coronary physiology is a routine diagnostic tool when assessing whether coronary revascularization is indicated. The iFR-SWEDEHEART trial demonstrated similar clinical outcomes when using instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) to guide revascularization. The objective of this analysis was to assess a cost-minimization analysis of iFR-guided compared with FFR-guided revascularization. METHODS: In this cost-minimization analysis we used a decision-tree model from a healthcare perspective with a time-horizon of one year to estimate the cost difference between iFR and FFR in a Nordic setting and a United States (US) setting. Treatment pathways and health care utilizations were constructed from the iFR-SWEDEHEART trial. Unit cost for revascularization and myocardial infarction in the Nordic setting and US setting were derived from the Nordic diagnosis-related group versus Medicare cost data. Unit cost of intravenous adenosine administration and cost per stent placed were based on the average costs from the enrolled centers in the iFR-SWEDEHEART trial. Deterministic and probabilistic sensitivity analyses were carried out to test the robustness of the result. RESULTS: The cost-minimization analysis demonstrated a cost saving per patient of $681 (95% CI: $641 - $723) in the Nordic setting and $1024 (95% CI: $934 - $1114) in the US setting, when using iFR-guided compared with FFR-guided revascularization. The results were not sensitive to changes in uncertain parameters or assumptions. CONCLUSIONS: IFR-guided revascularization is associated with significant savings in cost compared with FFR-guided revascularization.

Hospital costs and health-related quality of life from complications after esophagectomy.

BACKGROUND: Approximately 50% of all patients undergoing esophagectomy experience complications. This paper estimates the costs due to complications after esophagectomy in a Swedish context. MATERIAL AND METHODS: The Swedish National Register for Esophageal and Gastric Cancer (NREV) and the Healthcare Consumption Register in Region Skåne (RSVD) were crossmatched for patients undergoing esophagectomy between 2010 and 2015 in Region Skåne, Sweden (n = 132). Multivariable linear regression analysis was performed on the logarithm of total healthcare cost. HRQoL was presented descriptively. RESULTS: The mean total healthcare costs were 335,016 SEK (€33,502) for the group with no complications and 438,320 SEK (€43,832) and 808,461 SEK (€80,846) for minor and major complications (p < 0.001), respectively. Pneumonia (p < 0.001), laryngeal nerve paresis (p = 0.002) and other complications (p < 0.001) showed significant associations with increased healthcare cost. No significant difference was found in QALY-weights between the complication grades. Patients that underwent esophagectomy reported poorer HRQoL than the scores valued by the general background population. CONCLUSION: Complications following esophagectomy incrementally increase the healthcare costs, where more severe complications led to higher healthcare costs. The severity of complications did not affect the mean QALY-weights.

Cost-effectiveness analysis of voice rehabilitation for patients with laryngeal cancer: a randomized controlled study.

INTRODUCTION: Voice problems are common following radiotherapy for laryngeal cancer. Few studies exist covering the effect of voice rehabilitation, and no previous studies exist regarding the cost of said rehabilitation. This randomized controlled study aimed to analyze the cost-effectiveness of voice rehabilitation after radiotherapy for patients with laryngeal cancer. MATERIAL AND METHODS: A total of 66 patients with laryngeal cancer with follow-up data 12 months post-radiotherapy were included. Patients were randomized into receiving either voice rehabilitation (n = 32) or no voice rehabilitation (n = 34). The patient outcome was measured as quality-adjusted life years (QALYs). The index range between 0 and 1, where 0 equals death and 1 represents perfect health. The QALYs were assessed with the European Organization for Research and Treatment of Cancer questionnaire QLQ-C30 mapped to EuroQoL 5 Dimension values. The cost of rehabilitation and other healthcare visits was derived from hospital systems. The patients reported the total amount of sick leave days during the first 12 months following radiotherapy. The cost-effectiveness of the voice rehabilitation was compared with no rehabilitation intervention based on the incremental cost-effectiveness ratio. RESULTS: The cost per gained QALY with voice rehabilitation compared to no rehabilitation from a societal perspective was - 27,594 € (SEK - 250,852) which indicates that the voice rehabilitation is a cost-saving alternative compared to no rehabilitation due to lower costs and a slightly better health outcome. From a healthcare perspective, the voice rehabilitation indicates a cost 60,800 € (SEK 552,725) per gained QALY. CONCLUSION: From a societal perspective, i.e., including the costs of production loss, voice rehabilitation compared to no voice rehabilitation following radiotherapy for laryngeal cancer seems to be cost-saving. When analyzing only the healthcare costs in relation to health outcomes, voice rehabilitation indicates an incremental cost of 60,800 € per gained QALY, which is just above the threshold of the maximum willingness to pay level.

Characterization of Ring-Opening Reaction of Succinimide Linkers in ADCs.

A new class of highly potent biopharmaceutical drugs, antibody-drug conjugates (ADCs), has been proven to be clinically effective to treat oncologic diseases. ADCs contain 3 major components: the monoclonal antibody, cytotoxic drug, and chemical linker. THIOMAB™ drug conjugates and interchain-cysteine ADCs are common ADC platforms that apply thiol-maleimide chemistry via Michael addition to conjugate linker-drugs to cysteine residues. However, the resulting succinimide ring in the linker is susceptible to ring-opening reactions via hydrolysis, especially at high pH and elevated temperatures. Once the succinimide ring is opened, in vivo stability of the ADCs can be changed and the therapeutic activity will be altered. In this study, we investigated the impact of conjugation sites on succinimide ring opening for ADCs. A new methodology based on imaged capillary isoelectric focusing was developed to monitor the formation of succinimide ring-opened products. In addition, a reverse-phase high-performance liquid chromatography method was used to monitor site-specific ring-opening reactions. Our data confirmed that succinimide ring-opening rates in ADCs are conjugation-site dependent. With a good understanding of the conjugation site impact on final product's stability, it is potentially feasible to modify ring-opening rates in vitro to achieve desirable in vivo stability and biological activity.

Shunt surgery in idiopathic normal pressure hydrocephalus is cost-effective-a cost utility analysis.

BACKGROUND: The objective was to evaluate the cost-effectiveness of shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Health-related quality of life was evaluated before and 6 months after surgery using the EQ-5D-3 L (EuroQOL group five-dimensions health survey) in 30 patients (median age, 71 years; range, 65-89 years) diagnosed with iNPH. The costs associated with shunt surgery were assessed by a detailed survey with interviews and extraction of register data concerning the cost of hospital care, primary care, residential care, home-care service and informal care. The cost of untreated patients was derived from the cost of dementia disorders in Sweden in 2012, as reported by the National Board of Health and Welfare. The cost effectiveness analysis used a decision-analytic Markov model. We used a societal perspective and a lifelong time horizon to estimate costs and effects. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to test the robustness of the model. RESULTS: The shunt surgery model as the standard treatment in iNPH resulted in a gain of 2.2 life years and 1.7 quality-adjusted life years (QALY), along with an incremental cost per patient of €7,500/QALY. The sensitivity analysis showed that the results were not sensitive to changes in uncertain parameters or assumptions. CONCLUSIONS: Shunt surgery in iNPH, an underdiagnosed condition severely impairing elderly patients, is not only an effective medical treatment, it is also cost-effective, adding 2.2 additional life years and 1.7 QALYs at a low cost, a remarkable gain for an individual aged around 70 years.

[Robot-assisted surgery on a broad front--without evidence for being cost-effective]. / Robotkirurgi på bred front ­ utan evidensbaserad grund - Tekniken används allt mer, trots att den är dyr och att vetenskapliga bevis för patientnytta saknas.

Robot-assisted surgery on a broad front - without evidence for being cost-effective Robot-assisted surgery is currently heavily marketed. The HTA centre in Region Västra Götaland has produced five HTA reports regarding use of robot-assisted surgery in different clinical situations (prostatic cancer, benign gynaecological surgery, pediatric pyeloplasty and fundoplication, and rectal cancer), finding weak evidence for a patient value. The current report by Per Carlsson et al confirms that robot-assisted surgery indeed leads to increased costs that are not balanced by augmented patient value, i.e. robot-assisted surgery cannot be regarded as cost efficient. We comment critically on the capricious introduction of new techniques/devices, a procedure that stands in sharp contrast to the strictly formalized system for approval of new drugs.

Improved assembly of bispecific antibodies from knob and hole half-antibodies.

A process was developed for large-scale assembly of IgG1 and IgG4 bispecific antibodies from knob and hole half-antibodies. We optimized assembly conditions such as pH, temperature, stabilizers, and reducing agent. We also identified and exploited structural changes unique to knob and hole half-antibodies with the result of improving assembly outcome, specifically storing half-antibodies at higher pH will condition them to assemble more rapidly and produce fewer high molecular-weight species (HMWS). Application of heat to the assemblies resulted in an acceleration of assembly rate, with optimal formation of bispecific achieved at 37°C. IgG4 half-antibodies were unusually sensitive to temperature-dependent formation of HMWS in pre-assembly conditioning as well as during assembly. We selected l-histidine and Polyvinylpyrrolidone (PVP) as stabilizers to prevent HMWS formation in IgG4 , and achieved rapid and high-efficiency assemblies. Using optimized assembly conditions, we developed and scaled up a method for assembling bispecific antibody with 90% assembly efficiency over 6 h with minimal impact to product quality, generating a pool with bispecific antibody for downstream processing.

Development of a human IgG4 bispecific antibody for dual targeting of interleukin-4 (IL-4) and interleukin-13 (IL-13) cytokines.

Human bispecific antibodies have great potential for the treatment of human diseases. Although human IgG1 bispecific antibodies have been generated, few attempts have been reported in the scientific literature that extend bispecific antibodies to other human antibody isotypes. In this paper, we report our work expanding the knobs-into-holes bispecific antibody technology to the human IgG4 isotype. We apply this approach to generate a bispecific antibody that targets IL-4 and IL-13, two cytokines that play roles in type 2 inflammation. We show that IgG4 bispecific antibodies can be generated in large quantities with equivalent efficiency and quality and have comparable pharmacokinetic properties and lung partitioning, compared with the IgG1 isotype. This work broadens the range of published therapeutic bispecific antibodies with natural surface architecture and provides additional options for the generation of bispecific antibodies with differing effector functions through the use of different antibody isotypes.

Nasal and skin delivery of IC31(®)-adjuvanted recombinant HSV-2 gD protein confers protection against genital herpes.

Genital herpes caused by herpes simplex virus type 2 (HSV-2) remains the leading cause of genital ulcers worldwide. Given the disappointing results of the recent genital herpes vaccine trials in humans, development of novel vaccine strategies capable of eliciting protective mucosal and systemic immune responses to HSV-2 is urgently required. Here we tested the ability of the adjuvant IC31(®) in combination with HSV-2 glycoprotein D (gD) used through intranasal (i.n.), intradermal (i.d.), or subcutaneous (s.c.) immunization routes for induction of protective immunity against genital herpes infection in C57BL/6 mice. Immunization with gD plus IC31(®) through all three routes of immunization developed elevated gD-specific serum antibody responses with HSV-2 neutralizing activity. Whereas the skin routes promoted the induction of a mixed IgG2c/IgG1 isotype profile, the i.n. route only elicited IgG1 antibodies. All immunization routes were able to induce gD-specific IgG antibody responses in the vaginas of mice immunized with IC31(®)-adjuvanted gD. Although specific lymphoproliferative responses were observed in splenocytes from mice of most groups vaccinated with IC31(®)-adjuvanted gD, only i.d. immunization resulted in a significant splenic IFN-γ response. Further, immunization with gD plus IC31(®) conferred 80-100% protection against an otherwise lethal vaginal HSV-2 challenge with amelioration of viral replication and disease severity in the vagina. These results warrant further exploration of IC31(®) for induction of protective immunity against genital herpes and other sexually transmitted infections.

Intranasal immunization with a proteoliposome-derived cochleate containing recombinant gD protein confers protective immunity against genital herpes in mice.

The purpose of this study was to investigate the potential of intranasal (IN) immunization with Neisseria meningitides B proteoliposome (AFPL1) and AFPL1-derived cochleate (AFCo1), containing glycoprotein D (gD) of herpes simplex virus type 2 (HSV-2) for induction of protective immunity against genital herpes infection in mice. We could show that IN immunization with both AFPL1 and AFCo1 containing gD induced gD-specific IgG antibody and lymphoproliferative responses. However, IFN-gamma response could only be detected in CD4(+) splenic cells and genital lymph node cells of the AFCo1gD immunized mice upon recall antigen stimulation in vitro. Importantly, IN immunization with AFCo1gD could elicit a complete protection against an otherwise lethal vaginal challenge with HSV-2, while the AFPL1gD immunized mice were only partially protected. Further, we could show that the IFN-gamma response and protective immunity observed after IN immunization with AFCo1gD are mediated via the adaptor molecule myeloid differentiation factor 88. These data may have implications for the development of a mucosal vaccine against genital herpes.

The mucosal adjuvant effect of alpha-galactosylceramide for induction of protective immunity to sexually transmitted viral infection.

Development of mucosal adjuvants to generate immunity in the female genital tract may have important implications for the development of vaccines to counter sexually transmitted infections. alpha-Galactosylceramide (alpha-GalCer) is presented by CD1d molecule on APCs to invariant Valpha14(+) NKT (iNKT) cells, which upon activation rapidly produce large amounts of immunomodulatory cytokines, leading to activation of a variety of innate and adaptive immune cells. Here, we assessed whether alpha-GalCer could act as a mucosal adjuvant for induction of protective immunity against genital herpes. We found that intranasal immunization with HSV-2 glycoprotein D (gD) in combination with alpha-GalCer elicits strong systemic gD-specific IgG Ab response as well as lymphoproliferative response with a mixed Th1/Th2 cytokine profile in the spleen, mediastinal lymph nodes, and genital lymph nodes. Importantly, such an immunization scheme conferred complete protection against an otherwise lethal vaginal HSV-2 challenge. We could also show that intravaginal immunization with gD plus alpha-GalCer generates potent gD-specific lymphoproliferative and IFN-gamma responses in the genital lymph nodes and spleen. Furthermore, the vaginally immunized mice developed a strong systemic and mucosal IgG Ab response and protection against vaginal HSV-2 challenge. The mucosal adjuvant effect of alpha-GalCer was found to be mediated via CD1d molecule and appeared to be independent of the usage of the adaptor molecule MyD88. To our knowledge, this is the first report on the mucosal adjuvant effect of alpha-GalCer for induction of protective immunity against a sexually transmitted pathogen.

Primary recovery of a genetically engineered Trichoderma reesei endoglucanase I (Cel 7B) fusion protein in cloud point extraction systems.

Here we present data to demonstrate how partitioning of a hydrophilic enzyme can be directed to the hydrophobic detergent-enriched phase of an aqueous two-phase system by addition of short stretches of amino acid residues to the protein molecule. The target enzyme was the industrially important endoglucanase I, EGI (endo-1,4-beta-D-glucan-4-glucanohydrolase, EC 3.2.1.4, Cel7B) of Trichoderma reesei. We investigated the partitioning of three EGI variants containing various C-terminal peptide extensions including Trp-Pro motifs of different lengths and localizations. Additionally, a recently developed system composed of the thermoseparating copolymer HM-EOPO was utilized to study the effects of fusion tags. The addition of peptides containing tryptohan residues enhanced the partitioning of EGI to the HM-EOPO-rich phase. The system composed of a nonionic detergent (Agrimul NRE1205) resulted in the highest partition coefficient (K = 31) and yield (90%) with the construct EGI(core-P5)(WP)(4) containing (Trp-Pro)(4) after a short linker stretch. A recombinant strain of T. reesei Rut-C30 for large-scale production was constructed in which the fusion protein EGI(core-P5)(WP)(4) was expressed from the strong promoter of the cellulase gene cbh1. The fusion protein was successfully expressed and secreted from the fungus during shake-flask cultivations. Cultivation in a 28-L bioreactor however, revealed that the fusion protein is sensitive to proteases. Consequently, only low production levels were obtained in large-scale production trials.