Antineoplastic Drug Synergy of Artesunate with Navitoclax in Models of High-Grade Serous Ovarian Cancer.

Artesunate belongs to a class of medications derived from the sweet wormwood plant (Artemisia annua) known as artemisinins. Artesunate has traditionally been used as a frontline treatment for severe malaria but has also demonstrated antineoplastic activity against various malignancies, including ovarian cancer. Data suggest that artesunate exacerbates cellular oxidative stress, triggering apoptosis. In the current study, we investigated the ability of navitoclax, an inhibitor of the antiapoptotic Bcl-2 protein family, to enhance artesunate efficacy in ovarian cancer cells. Artesunate and navitoclax both demonstrated antiproliferative effects on 2D and 3D ovarian cancer cell models as single agents. Upon combination of navitoclax with artesunate, antineoplastic drug synergy was also observed in each of the 2D cell lines and ovarian tumor organoid models tested. Further investigation of this drug combination using intraperitoneal CAOV3 xenograft models in BALB/scid mice showed that the artesunate/navitoclax doublet was superior to single-agent artesunate and vehicle control treatment. However, it did not outperform single-agent navitoclax. With optimization, this drug combination could provide a new therapeutic option for ovarian cancer and warrants further preclinical investigation.

Artesunate acts through cytochrome c to inhibit growth of pediatric AML cells.

Artesunate is a derivative of artemisinin, an active compound isolated from Artemisia annua which has been used in Traditional Chinese Medicine and to treat malaria worldwide. Artemisinin derivatives have exhibited anti-cancer activity against both solid tumors and leukemia. The direct target(s) of artesunate are controversial; although, heme-bound proteins in the mitochondria have been implicated. We utilized computational modeling to calculate the predicted binding score of artesunate with heme-bound mitochondrial proteins and identified cytochrome c as potential artesunate target. UV-visible spectroscopy showed changes in the absorbance spectrum, and thus protein structure, when cytochrome c was incubated with artesunate. Artesunate induces apoptosis, disrupts mitochondrial membrane potential, and is antagonized by methazolamide in pediatric AML cells indicating a probable mechanism of action involving cytochrome c. We utilized a multi-disciplinary approach to show that artesunate can interact with and is dependent on cytochrome c release to induce cell death in pediatric AML cell lines.

Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers.

DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt-resistant cancers are a major cause of mortality. To combat Pt-resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin. The conjugates displayed both the Mg2+ -dependent noncovalent DNA binding characteristic of mithramycin and the covalent crosslinking to DNA of the Pt. The conjugate was three times as potent as cisplatin against ovarian cancer cells. The DNA lesions caused by the conjugate led to the generation of DNA double-strand breaks, as also observed with cisplatin. Nevertheless, the conjugate was highly active against both Pt-sensitive and Pt-resistant ovarian cancer cells. This study paves the way to developing mithplatins to combat Pt-resistant ovarian cancers.

Human macrophage-engineered vesicles for utilization in ovarian cancer treatment.

Background: Ovarian cancer is a deadly female malignancy with a high rate of recurrent and chemotherapy-resistant disease. Tumor-associated macrophages (TAMs) are a significant component of the tumor microenvironment and include high levels of M2-protumor macrophages that promote chemoresistance and metastatic spread. M2 macrophages can be converted to M1 anti-tumor macrophages, representing a novel therapeutic approach. Vesicles engineered from M1 macrophages (MEVs) are a novel method for converting M2 macrophages to M1 phenotype-like macrophages. Methods: Macrophages were isolated and cultured from human peripheral blood mononuclear cells. Macrophages were stimulated to M1 or M2 phenotypes utilizing LPS/IFN-γ and IL-4/IL-13, respectively. M1 MEVs were generated with nitrogen cavitation and ultracentrifugation. Co-culture of ovarian cancer cells with macrophages and M1 MEVs was followed by cytokine, PCR, and cell viability analysis. Murine macrophage cell line, RAW264.7 cells were cultured and used to generate M1 MEVs for use in ovarian cancer xenograft models. Results: M1 MEVs can effectively convert M2 macrophages to an M1-like state both in isolation and when co-cultured with ovarian cancer cells in vitro, resulting in a reduced ovarian cancer cell viability. Additionally, RAW264.7 M1 MEVs can localize to ovarian cancer tumor xenografts in mice. Conclusion: Human M1 MEVs can repolarize M2 macrophages to a M1 state and have anti-cancer activity against ovarian cancer cell lines. RAW264.7 M1 MEVs localize to tumor xenografts in vivo murine models.

KEAP1 Is Required for Artesunate Anticancer Activity in Non-Small-Cell Lung Cancer.

Artesunate is the most common treatment for malaria throughout the world. Artesunate has anticancer activity likely through the induction of reactive oxygen species, the same mechanism of action utilized in Plasmodium falciparum infections. Components of the kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which regulates cellular response to oxidative stress, are mutated in approximately 30% of non-small-cell lung cancers (NSCLC); therefore, we tested the hypothesis that KEAP1 is required for artesunate sensitivity in NSCLC. Dose response assays identified A549 cells, which have a G333C-inactivating mutation in KEAP1, as resistant to artesunate, with an IC50 of 23.6 µM, while H1299 and H1563 cells were sensitive to artesunate, with a 10-fold lower IC50. Knockdown of KEAP1 through siRNA caused increased resistance to artesunate in H1299 cells. Alternatively, the pharmacological inhibition of NRF2, which is activated downstream of KEAP1 loss, by ML385 partially restored sensitivity of A549 cells to artesunate, and the combination of artesunate and ML385 was synergistic in both A549 and H1299 cells. These findings demonstrate that KEAP1 is required for the anticancer activity of artesunate and support the further development of NRF2 inhibitors to target patients with mutations in the KEAP1/NRF2 pathway.

Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment.

BACKGROUND: Ovarian cancer is the deadliest gynecologic malignancy despite current first-line treatment with a platinum and taxane doublet. Artesunate has broad antineoplastic properties but has not been investigated in combination with carboplatin and paclitaxel for ovarian cancer treatment. METHODS: Standard cell culture technique with commercially available ovarian cancer cell lines were utilized in cell viability, DNA damage, and cell cycle progression assays to qualify and quantify artesunate treatment effects. Additionally, the sequence of administering artesunate in combination with paclitaxel and carboplatin was determined. The activity of artesunate was also assessed in 3D organoid models of primary ovarian cancer and RNAseq analysis was utilized to identify genes and the associated genetic pathways that were differentially regulated in artesunate resistant organoid models compared to organoids that were sensitive to artesunate. RESULTS: Artesunate treatment reduces cell viability in 2D and 3D ovarian cancer cell models. Clinically relevant concentrations of artesunate induce G1 arrest, but do not induce DNA damage. Pathways related to cell cycle progression, specifically G1/S transition, are upregulated in ovarian organoid models that are innately more resistant to artesunate compared to more sensitive models. Depending on the sequence of administration, the addition of artesunate to carboplatin and paclitaxel improves their effectiveness. CONCLUSIONS: Artesunate has preclinical activity in ovarian cancer that merits further investigation to treat ovarian cancer.

PTPN11 Plays Oncogenic Roles and Is a Therapeutic Target for BRAF Wild-Type Melanomas.

Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten- and Cdkn2a-null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence, and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K -mutant melanoma. Using a quantitative tyrosine phosphoproteomics approach, we identified GSK3α/ß as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3ß signaling pathways. IMPLICATIONS: This study identifies PTPN11 as an oncogenic driver and a novel and actionable therapeutic target for BRAF wild-type melanoma.

Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation.

Inactivation of Ras GTPase activating proteins (RasGAPs) can activate Ras, increasing the risk for tumor development. Utilizing a melanoma whole genome sequencing (WGS) data from 13 patients, we identified two novel, clustered somatic missense mutations (Y472H and L481F) in RASA1 (RAS p21 protein activator 1, also called p120RasGAP). We have shown that wild type RASA1, but not identified mutants, suppresses soft agar colony formation and tumor growth of BRAF mutated melanoma cell lines via its RasGAP activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. Moreover, R-Ras increased and RASA1 suppressed Ral-A activation among Ras downstream effectors. In addition to mutations, loss of RASA1 expression was frequently observed in metastatic melanoma samples on melanoma tissue microarray (TMA) and a low level of RASA1 mRNA expression was associated with decreased overall survival in melanoma patients with BRAF mutations. Thus, these data support that RASA1 is inactivated by mutation or by suppressed expression in melanoma and that RASA1 plays a tumor suppressive role by inhibiting R-Ras, a previously less appreciated member of the Ras small GTPases.

Quality of life outcomes in proton and photon treated pediatric brain tumor survivors.

BACKGROUND: Radiotherapy can impair Health Related Quality of Life (HRQoL) in survivors of childhood brain tumors, but proton radiotherapy (PRT) may mitigate this effect. This study compares HRQoL in PRT and photon (XRT) pediatric brain tumor survivors. METHODS: HRQoL data were prospectively collected on PRT-treated patients aged 2-18 treated at Massachusetts General Hospital (MGH). Cross-sectional PedsQL data from XRT treated Lucile Packard Children's Hospital (LPCH) patients provided the comparison data. RESULTS: Parent proxy HRQoL scores were reported at 3 years for the PRT cohort (PRT-C) and 2.9 years (median) for the XRT cohort (XRT-C). The total core HRQoL score for the PRT-C, XRT-C, and normative population differed from one another and was 75.9, 65.4 and 80.9 respectively (p=0.002; p=0.024; p<0.001). The PRT-C scored 10.3 and 10.5 points higher than the XRT-C in the physical (PhSD) and psychosocial (PsSD) summary domains of the total core score (TCS, p=0.015; p=0.001). The PRT-C showed no difference in PhSD compared with the normative population, but scored 6.1 points less in the PsSD (p=0.003). Compared to healthy controls, the XRT-C scored lower in all domains (p<0.001). CONCLUSIONS: The HRQoL of pediatric brain tumor survivors treated with PRT compare favorably to those treated with XRT and similar to healthy controls in the PhSD.

PKCι maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis.

UNLABELLED: Protein kinase Cι (PKCι) has oncogenic potential and is an attractive therapeutic target for treatment of lung cancer, particularly those tumors that express elevated PKCι. However, whether PKCι is a viable target in ovarian cancer is unknown, and virtually nothing is known about the mechanism by which PKCι drives ovarian tumorigenesis. Here, it is demonstrated that PKCι maintains a tumor-initiating cell (TIC) phenotype that drives ovarian tumorigenesis. A highly tumorigenic population of cells from human ovarian cancer cell lines exhibit cancer stem-like TIC properties, including self-renewal, clonal expansion, expression of stem-related genes, enhanced transformed growth in vitro, and aggressive tumor-initiating activity in vivo. Genetic disruption of PKCι inhibits the proliferation, clonal expansion, anchorage-independent growth, and enhanced tumorigenic properties of ovarian TICs. Biochemical analysis demonstrates that PKCι acts through its oncogenic partner Ect2 to activate a MEK/ERK signaling axis that drives the ovarian TIC phenotype. Genomic analysis reveals that PKCι and Ect2 are coordinately amplified and overexpressed in the majority of primary ovarian serous tumors, and these tumors exhibit evidence of an active PKCι-Ect2 signaling axis in vivo. Finally, this study reveals that auranofin, a potent and selective inhibitor of oncogenic PKCι signaling, inhibits the tumorigenic properties of ovarian TIC cells in vitro and in vivo. These data demonstrate that PKCι is required for a TIC phenotype in ovarian cancer, and that auranofin is an attractive therapeutic option to target deadly ovarian TICs in ovarian cancer patients. IMPLICATIONS: PKCι drives a tumor-initiating cell phenotype in ovarian cancer cells that can be therapeutically targeted with auranofin, a small molecule inhibitor of PKCι signaling.

Regulation of HGF expression by ΔEGFR-mediated c-Met activation in glioblastoma cells.

The hepatocyte growth factor receptor (c-Met) and a constitutively active mutant of the epidermal growth factor receptor (ΔEGFR/EGFRvIII) are frequently overexpressed in glioblastoma (GBM) and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF) production in GBM are not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes) GBMs, a subtype associated with poor treatment response and shorter overall survival. In an HGF/c-Met-dependent GBM cell line, HGF expression declined upon silencing of c-Met using RNAi or by inhibiting its activity with SU11274. Silencing c-Met decreased anchorage-independent colony formation and increased the survival of mice bearing intracranial GBM xenografts. Consistent with these findings, c-Met activation by ΔEGFR also elevated HGF expression, and the inhibition of ΔEGFR with AG1478 reduced HGF levels. Interestingly, c-Met expression was required for ΔEGFR-mediated HGF production, anchorage-independent growth, and in vivo tumorigenicity, suggesting that these pathways are coupled. Using an unbiased mass spectrometry-based screen, we show that signal transducer and activator of transcription 3 (STAT3) Y705 is a downstream target of c-Met signaling. Suppression of STAT3 phosphorylation with WP1193 reduced HGF expression in ΔEGFR-expressing GBM cells, whereas constitutively active STAT3 partially rescued HGF expression and colony formation in c-Met knockdown cells expressing ΔEGFR. These results suggest that the c-Met/HGF signaling axis is enhanced by ΔEGFR through increased STAT3-dependent HGF expression and that targeting c-Met in Mes GBMs may be an important strategy for therapy.

Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.

At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.

Prospective study of health-related quality of life for children with brain tumors treated with proton radiotherapy.

PURPOSE: We describe the health-related quality of life (HRQoL) of a cohort of children with brain tumors treated with proton radiotherapy. PATIENTS AND METHODS: We recruited 142 pediatric patients with brain tumors (age 2 to 18 years) and parents of such patients treated with proton radiation at Massachusetts General Hospital from 2004 to 2010. HRQoL was assessed using the PedsQL core, brain tumor, and cancer modules (range, 0 to 100). Assessments took place during radiation and annually thereafter. We examined correlations of HRQoL with disease, treatment, and cognitive and behavioral data. RESULTS: Overall reports of HRQoL during treatment were 74.8 and 78.1 for child self-report (CSR) and 67.0 and 74.8 for parent proxy report (PPR) for the core and brain tumor modules, respectively. PPR demonstrated lower HRQoL scores than CSR, but the two were highly correlated. Higher HRQoL scores were significantly associated with Wechsler Full Scale Intelligence Quotient scores (administered via the age-appropriate version) and better scores on two behavioral measures. Disease type also correlated with PPR core total HRQoL score at the beginning of treatment: medulloblastoma or primitive neuroectodermal tumors, 57.8; germ cell tumors, 63.5; ependymoma or high-grade glioma, 69.8; low-grade glioma, 71.5; and other low-grade neoplasms, 78.0 (P = .001). Craniospinal irradiation and chemotherapy were negatively correlated with HRQoL. CONCLUSION: This is the first study to our knowledge of HRQoL in a cohort of children with brain tumors treated with proton radiation. This prospective study demonstrates the effect of disease type and intensity of treatment on HRQoL. It further suggests that where CSR is not possible, PPR is appropriate in most circumstances.

Altered down regulation of the receptor tyrosine kinase met in pancreatic adenocarcinoma cells.

Increased signaling from Met, the receptor for Hepatocyte Growth Factor, promotes pancreatic tumorigenesis and poor patient prognosis by enhancing tumor cell growth, survival and motility. Increased Met levels can result from gene amplification or increased transcription. However, receptor down regulation--a process that normally functions to attenuate Met signaling in vivo--could if impaired, amplify Met signaling in pancreatic tumor cells. Here we report that the lysosomal down regulation of Met is uncoupled in pancreatic adenocarcinoma cell lines. Interestingly, different endocytic mechanisms are employed to escape receptor down regulation and prolong Met signaling. Specifically, ligand treatment does not result in Met retention on the plasma membrane. Rather impaired binding of the E3 ubiquitin ligase Cbl to internalized Met in pancreatic Suit-2 cells causes reduced receptor ubiquitination and enhances Met recycling to the cell surface. Conversely, transient ligand-induced Met ubiquitination in pancreatic BxPC-3 cells correlates with prolonged Met stability and signaling. Moreover, increased Met stability and signaling enhances Suit-2 and BxPC-3 cell viability and chemotaxis towards Hepatocyte Growth Factor. Together our data indicate that uncoupled Met down regulation likely functions to amplify the oncogenic signaling of Met in pancreatic tumor cells.

The well-being of parental caregivers of children with activity limitations.

This paper describes well-being (health status/quality of life, healthcare utilization, employment, and financial status) of parental caregivers of children with activity limitations and compares their well-being to parental caregivers with children without activity limitations. Using Medical Expenditure Panel Survey data from 1996 to 2001, we examined the well-being of parents of children with and without an activity limitation. Children were considered as having an activity limitation if they reported a limitation in school, play or social activities. Analyses include weighted descriptive statistics and multivariable regressions. Seventy-five percentage of parents of children with activity limitations experienced at least one adverse outcome compared to 66% of parents of children without activity limitations. Parents of children with activity limitations exhibited poorer reported quality of life as indicated by lower SF-12 physical health scores (coefficient = -2.24 CI -3.38 to -1.11) and lower EuroQol scores (coefficient = -.07 CI -.10 to -.03). Parents of children with activity limitations have slightly higher utilization of sick visits. One measure of preventive care use was not significant and one showed a slight increase in use among parents of children with activity limitations. Employment and financial outcomes were less favorable for parents of children with activity limitations. Across a variety of domains, parental caregivers of children with activity limitations are at a disadvantage compared to other parents suggesting that public and private parental supports might be helpful.

Met receptor tyrosine kinase degradation is altered in response to the leucine-rich repeat of the Listeria invasion protein internalin B.

Entry of the bacterial pathogen Listeria monocytogenes into host epithelial cells is critical for infection and virulence. One major pathway for Listeria entry involves binding of the bacterial protein Internalin B to the host receptor tyrosine kinase Met (hepatocyte growth factor receptor). Activation of Met and downstream signaling cascades is critical for Listeria entry. Internalin B is composed of several structural domains including an N-terminal leucine-rich repeat that is sufficient for binding Met and stimulating downstream signal transduction. Internalin B is monomeric, whereas the leucine-rich repeat is dimeric when expressed as an isolated fragment. The different quaternary states of Internalin B and the leucine-rich repeat suggest that these two Met ligands might cause distinct biological effects. Here we demonstrate that Internalin B and the leucine-rich repeat fragment exhibit agonist properties that differentially influence Met down-regulation in lysosomes. Specifically, Met stability is increased in response to the leucine-rich repeat fragment compared with Internalin B. Interestingly, Internalin B and the leucine-rich repeat stimulate equivalent rates of clathrin-mediated Met internalization. However, the leucine-rich repeat is defective in promoting lysosomal down-regulation of Met and instead enhances receptor recycling to the cell surface. In addition, the leucine-rich repeat causes prolonged Met activation (phosphorylation) and increased cell motility compared with Internalin B. Taken together, our findings indicate that individual domains of Internalin B differentially regulate Met trafficking. The ability of the leucine-rich repeat fragment to promote Met recycling could account for the increased cell motility induced by this ligand.

Analysis of receptor tyrosine kinase internalization using flow cytometry.

The internalization of activated receptor tyrosine kinases (RTKs) by endocytosis and their subsequent down regulation in lysosomes plays a critical role in regulating the duration and intensity of downstream signaling events. Uncoupling of the RTK cMet from ligand-induced degradation was recently shown to correlate with sustained receptor signaling and increased cell tumorigenicity, suggesting that the corruption of these endocytic mechanisms could contribute to increased cMet signaling in metastatic cancers. To understand how cMet signaling for normal cell growth is controlled by endocytosis and how these mechanisms are dysregulated in metastatic cancers, we developed flow cytometry-based assays to examine cMet internalization.

Medicaid managed care and the unmet need for mental health care among children with special health care needs.

OBJECTIVE: To determine the association between Medicaid managed care pediatric behavioral health programs and unmet need for mental health care among children with special health care needs (CSHCN). DATA SOURCE: The National Survey of CSHCN (2000-2002), using subsets of 4,400 CSHCN with Medicaid and 1,856 CSHCN with Medicaid and emotional problems. Additional state-level sources were used. STUDY DESIGN: Multilevel models investigated the association between managed care program type (carve-out, integrated) or fee-for-service (FFS) and reported unmet mental health care need. DATA COLLECTION/EXTRACTION METHODS: The National Survey of CSHCN conducted telephone interviews with a sample representative at both the national and state levels. PRINCIPAL FINDINGS: In multivariable models, among CSHCN with only Medicaid, living in states with Medicaid managed care (odds ratio [OR]=1.81; 95 percent confidence interval: 1.04-3.15) or carve-out programs (OR=1.93; 1.01-3.69) were associated with greater reported unmet mental health care need compared with FFS programs. Among CSHCN on Medicaid with emotional problems, the association between managed care and unmet need was stronger (OR=2.48; 1.38-4.45). CONCLUSIONS: State Medicaid pediatric behavioral health managed care programs were associated with greater reported unmet mental health care need than FFS programs among CSHCN insured by Medicaid, particularly for those with emotional problems.

Unmet need among children with special health care needs in Massachusetts.

OBJECTIVES: We partnered with a Massachusetts family workgroup to analyze state level data that would be most useful to consumers and advocates in Massachusetts. METHODS: Massachusetts' and US data from the 2001 National Survey of Children with Special Health Care Needs (NSCSHCN) were analyzed. We examined types of need and prevalence of unmet need for all CSHCN and for more severely affected CSHCN. We also correlated unmet need to child and family characteristics using multivariate logistic regression. RESULTS: In Massachusetts, 17% of CSHCN and 37% of children more severely affected did not receive needed care. CSHCN who were uninsured anytime during the previous year were nearly 5 times more likely to experience an unmet need (OR = 4.95, CI: 1.69-14.51). Children with more functional limitations (OR = 3.15; CI: 1.59-6.24) and unstable health care needs (OR = 3.26; CI: 1.33-8.00) were also more likely to experience an unmet need. Receiving coordinated care in a medical home (OR = 0.46; CI: 0.23-0.90) was associated with reduced reports of unmet need. CONCLUSIONS: With input from families of CSHCN, researchers can direct their analyses to answering the questions and concerns most meaningful to families. We estimate that 1 in 6 CSHCN in Massachusetts did not receive needed care, with more than 1 in 3 CSHCN with a more severe condition experiencing an unmet need. Enabling factors were predictors of unmet need suggesting solutions such as expanding insurance coverage and improving services systems for CSHCN.