Development of an instrument to analyze organizational characteristics in multidisciplinary care pathways:the case of colorectal cancer

Background: To analyze the organization of multidisciplinary care pathways such as colorectal cancer care, an instrument was developed based on a recently published framework that was earlier used in analyzing (monodisciplinary) specialist cataract care from a lean perspective. Methods: The instrument was constructed using semi-structured interviews and direct observation of the colorectal care process based on a Rapid Plant Assessment. Six lean aspects that were earlier established that highly impact process design, were investigated: operational focus, autonomous work cell, physical lay-out of resources, multi-skilled team, pull planning and non-value adding activities. To test reliability, clarity and face validity of the instrument, a pilot study was performed in eight Dutch hospitals.ResultsIn the pilot it proved feasible to apply the instrument and generate the intended information. The instrument consisted of 83 quantitative and 24 qualitative items. Examples of results show differences in operational focus, number of patient visits needed for diagnosis, numbers of staff involved with treatment, the implementation of protocols and utilization of one-stop-shops. Identification of waste and non-value adding activities may need further attention. Based on feedback from involved clinicians the face validity was acceptable and the results provided useful feedback- and benchmark data. The instrument proved to be reliable and valid for broader implementation in Dutch health care. The limited number of cases made statistical analysis not possible and further validation studies may shed better light on variation. Conclusions: This paper demonstrates the use of an instrument to analyze organizational characteristics in colorectal cancer care from a lean perspective. Wider use might help to identify best organizational practices for colorectal surgery. In larger series the instrument might be used for in-depth research into the relation between organization and patient outcomes.Although we found no reason to adapt the underlying framework, recommendations were made for further development to enable use in different tumor- and treatment modalities and in larger (international) samples that allow for more advanced statistical analysis. Waste from defective care or from wasted human potential will need further elaboration of the instrumen

Toxic iron species in lower-risk myelodysplastic syndrome patients : course of disease and effects on outcome

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Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression

Pemetrexed (ALIMTA, MTA) is a novel thymidylate synthase (TS) inhibitor and has shown activity against colon cancer, mesothelioma and nonsmall-cell lung cancer. We induced resistance to Pemetrexed in the human colon cancer cell line WiDr by using a continuous exposure to stepwise increasing Pemetrexed concentrations (up to 20 microM) as well as a more clinically relevant schedule with intermittent exposure (up to 50 microM) for 4 hr every 7 days, resulting in WiDr variants WiDr-cPEM and WiDr-4PEM, respectively. However, using the same conditions, it was not possible to induce resistance in the WiDr/F cell line, a variant adapted to growth under low folate conditions. Mechanisms of resistance to Pemetrexed were determined at the level of TS, folylpolyglutamate synthetase (FPGS) and reduced folate carrier (RFC). WiDr-4PEM and WiDr-cPEM showed cross-resistance to the polyglutamatable TS inhibitor Raltitrexed (6- and 19-fold, respectively) and the nonpolyglutamatable TS-inhibitor Thymitaq (6- and 42-fold, respectively) but not to 5-fluorouracil. The ratios of TS mRNA:beta actin mRNA in WiDr-4PEM and WiDr-cPEM were 5-fold (P=0.01) and 18-fold (P=0.04) higher, respectively, compared to WiDr (ratio: 0.012). In addition, TS protein expression in the resistant WiDr variants was elevated 3-fold compared to WiDr, while the catalytic activity of TS with 1 microM dUMP increased from 30 pmol/hr/10(6) cells in WiDr cells to 2201 and 7663 pmol/hr/10(6) cells in WiDr-4PEM and WiDr-cPEM, respectively. The activity of FPGS was moderately decreased, but not significantly different in all WiDr variants. Finally, no evidence was found that decreased catalytic activity of RFC was responsible for the obtained Pemetrexed resistance. Altogether, these results indicate that resistance to Pemetrexed in the colon cancer cell line WiDr was solely due to upregulation of TS of which all related parameters (mRNA and protein expression and TS activity) were increased, rather than alterations in FPGS or RFC activity

Antibody Response in Immunocompromised Patients With Hematologic Cancers Who Received a 3-Dose mRNA-1273 Vaccination Schedule for COVID-19.

Importance: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce. Objective: To assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Design, Setting, and Participants: This prospective observational cohort study was conducted at 4 university hospitals in the Netherlands and included 584 evaluable patients spanning the spectrum of hematologic cancers and 44 randomly selected age-matched adults without malignant or immunodeficient comorbidities. Exposures: One additional mRNA-1273 vaccination 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. Main Outcomes and Measures: Serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after a third mRNA-1273 vaccination, and antibody neutralization capacity of wild-type, Delta, and Omicron variants in a subgroup of patients. Results: In this cohort of 584 immunocompromised patients with hematologic cancers (mean [SD] age, 60 [11.2] years; 216 [37.0%] women), a third mRNA-1273 vaccination was associated with median S1-IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid cancers or multiple myeloma and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1-IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients receiving or shortly after completing anti-CD20 therapy, CD19-directed chimeric antigen receptor T-cell therapy recipients, and patients with chronic lymphocytic leukemia receiving ibrutinib were less responsive or unresponsive to the third vaccination. In the 27 patients who received cell therapy between the second and third vaccination, S1 antibodies were preserved, but a third mRNA-1273 vaccination was not associated with significantly enhanced S1-IgG concentrations except for patients with multiple myeloma receiving autologous HCT. A third vaccination was associated with significantly improved neutralization capacity per antibody. Conclusions and Relevance: Results of this cohort study support that the primary schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination. Patients with B-cell lymphoma and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Trial Registration: EudraCT Identifier: 2021-001072-41

Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG $300 binding antibody units (BAUs)/mL was considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n 5 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, .50$ 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG $300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was,2 months for multiple myeloma, 8 months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer–cell number, and number of immunosuppressants predicted S1 IgG$ 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553