Initial Safety and Feasibility Results From a Phase 1, Diagnose-and-Treat Trial of Neoadjuvant Intratumoral Cisplatin for Stage IV NSCLC.

Neoadjuvant intratumoral cisplatin has the potential to generate substantial cytotoxicity and immune priming within the tumor environment, while minimizing systemic, off-target, adverse events. We initiated a phase 1A, 3+3 dose-ranging study of neoadjuvant, intratumoral cisplatin, delivered through endobronchial ultrasound bronchoscopy, in the same procedure as the initial diagnosis. There were no dose-limiting toxicity identified at the 20mg level.

Endobronchial ultrasound-guided transbronchial needle injection of cisplatin results in dynamic changes in the tumor immune microenvironment.

RATIONALE: Direct intratumoral delivery of cisplatin via endobronchial ultrasound guided-transbronchial needle injections (EBUS-TBNI) is a novel approach for salvage treatment of advanced stage non-small cell lung cancer (NSCLC). The goal of this study was to evaluate changes in the tumor immune microenvironment during the course of EBUS-TBNI cisplatin therapy. METHODS: Under an IRB approved protocol, patients with recurrence after radiation therapy who were not receiving other cytotoxic therapy, were prospectively enrolled, and underwent weekly treatments with EBUS-TBNI with additional biopsies obtained for research. Needle aspiration was performed prior to cisplatin delivery at each procedure. Samples were evaluated by flow cytometry for the presence of immune cell types. RESULTS: Three of the six patients responded to the therapy based on RECIST criteria. Compared to the pre-treatment baseline, intratumoral neutrophils increased in 5 of the 6 patients (p = 0.041), with an average increase of 27.1%, but was not associated with response. A lower pre-treatment CD8+/CD4+ ratio at baseline was associated with response (P = 0.01). Responders demonstrated a lower final proportion of PD-1+ CD8+ T cells compared to non-responders (8.6% vs. 62.3%, respectively, P<0.001. Lower doses of intratumoral cisplatin were associated with subsequent increases in CD8+ T cells within the tumor microenvironment (P = 0.008). CONCLUSIONS: EBUS-TBNI cisplatin resulted in significant alterations in the tumor immune microenvironment. Further studies are needed to determine if the changes seen here generalize to larger cohorts.

Visualizing intratumoral injections in lung tumors by endobronchial ultrasound.

Real-time endobronchial ultrasound images are crucial for the accurate placement of the needle in peribronchial lung tumors and lymph nodes for diagnostic sampling. Beyond its role as a diagnostic tool, ultrasound-guided bronchoscopy can also aid the delivery of anti-cancer agents intratumorally, enabling diagnosis, staging, and treatment to occur within the same anesthesia, reducing the patient's burden. However, determining drug retention and distribution in situ remains challenging, albeit pivotal in assessing the success or failure of the therapeutic intervention. We hypothesized that ultrasound images acquired by the bronchoscope during the injection can provide qualitative and quantitative real-time information about drug transport. As a proof-of-concept, we retrospectively analyzed 13 videos of intratumoral cisplatin injections in advanced non-small cell lung cancers. We identified the injection and performed quantitative analysis through image processing and segmentation algorithms and mathematical models in 5 of them. We were able to infer the unlikeliness of a laminar flow through interstitial pores in favor of the emergence of tissue fractures. These data imply that the structural integrity of the tumor is a critical determinant of the ultimate distribution of an intratumorally delivered agent.

Identification of novel MurA inhibitors using in silico approach, their validation and elucidation of mode of inhibition.

UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is an important enzyme involved in the first cytosolic step of bacterial cell wall synthesis. In this study a combination of ligand based and structure based in silico virtual screening methods were utilised for screening of more than 50,000 drug-like compounds from CSIR-IIIM in-house compound library in order to identify potent inhibitors of MurA. The identified hits were validated in vitro under various incubation conditions using Malachite green phosphate assay, and two potent hits viz 3772-9534 and D396-0012 were identified. Among these hits, compound 3772-9534 showed significant changes in the activity values in different assay conditions. The MD simulation study of 3772-9534 suggested a novel binding site in MurA enzyme, independent of the two-substrate binding sites. Binding of inhibitors at the allosteric site induces conformational changes in the enzyme, which leads to inhibition of enzymatic activity. Overall, the study offers new insight for targeting MurA, which may promote the discovery of novel MurA allosteric site inhibitors.

Prevalence and Impact of Acute Pancreatitis on Hospitalization Outcomes in a Cohort of Patients With Crohn's Disease.

Background: Few studies evaluated the risk of acute pancreatitis (AP) in patients with Crohn's disease (CD). It's controversial if AP can be considered as an extraintestinal manifestation of CD. We studied this potential association in a retrospective cohort of patients with CD. Methods: We draw our cohort from the Nationwide Readmission Databases 2016 - 2018. We used the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes to identify all adult patients admitted with a diagnosis of CD. Patient with a comorbid AP were identified. We analyzed the significant impact of AP on hospitalization outcomes. A multivariate regression analysis was used to identify factors associated with AP. Results: We included 214,622 patients discharged from an index hospitalization for CD, 1.1% had AP. AP was independently associated with higher odds of inpatient mortality (odds ratio (OR): 1.831; 95% confidence interval (CI): 1.345 - 2.492, P < 0.001), gallstone disease (OR: 4.047; 95% CI: 3.343 - 4.9, P < 0.001), nonalcoholic fatty liver disease (NAFLD) (OR: 3.568; 95% CI: 3.08 - 4.133, P < 0.001), and hypercalcemia (OR: 1.964; 95% CI: 1.302 - 2.965, P = 0.001). Thirty-day readmission analysis showed that CD patients with AP were more commonly to be readmitted for AP than for any other reason. Conclusions: In our nationwide cohort of CD patients, there was a significant association between AP and worse hospitalization outcomes. Additionally, we found independent associations for having AP that may help identify patients at high risk.

Use of Focus Groups to Inform a New Community-Based Youth Diabetes Prevention Program.

There have been few youth-led diabetes prevention programs. Our objective was to conduct focus groups to explore peer influences on adolescent lifestyle behaviors and strategies for implementing a youth peer education model for diabetes prevention. We conducted six focus groups with 52 youth (ages 13-22; 62% male, 38% female; 64% Hispanic, 36% non-Hispanic Black) from East Harlem, NYC. We used a Thematic Analysis approach to identify major themes, compared findings, and resolved differences through discussion and consensus. Three dominant themes arose: (1) Adolescents generally encounter more unhealthy peer influences on diet and more healthy peer influences on physical activity; (2) Adolescents endorse youth-led diabetes prevention strategies and describe ideal qualities for peer leaders and methods to support and evaluate leaders; (3) Adolescents prefer text messaging to monitor behaviors, track goals, and receive personalized guidance. Using study findings, our Community Action Board developed a peer-led diabetes prevention program for prediabetic adolescents.

Boswellic acids, as novel inhibitor targeting peptidoglycan biosynthetic enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) in Escherichia coli.

UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is an essential cytosolic enzyme in the biosynthesis of peptidoglycan. It becomes a potential bacterial target for screening promising antibacterial compounds as it is associated with the early phases of peptidoglycan production. MurA enzyme is conserved and necessary for bacterial viability with no mammalian homolog, which is a well-proven therapeutic research target. The present study reports the natural compounds from Boswellia serrata targeting the MurA enzyme. The identified inhibitors against MurA Escherichia coli (E. coli): ß-boswellic acid (IC50 33.65 µM), Acetyl-ß-boswellic acid (IC50 30.17 µM), and Acetyl-11-keto-ß-boswellic acid (IC50 37.67 µM). Inhibitors showed a fourfold decrease in IC50 values on pre-incubation with substrate-UDP-N-acetyl-glucosamine (UDP-GlcNAc). Mode-of-inhibition studies revealed their uncompetitive nature with both the substrates. Although these boswellic acids have been explored for their pharmacological potential, this is the first study reporting these compounds' E. coli MurA inhibiting potential.

Burden and Predictors of Non-Alcoholic Fatty Liver Disease in a Retrospective Cohort of Patients With Crohn's Disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is an emerging extraintestinal manifestation (EIM) of Crohn's disease (CD). We aimed to investigate the prevalence and comorbid predictors of NAFLD in patients with CD. Methods: We conducted a nationwide retrospective cohort study to determine the prevalence, characteristics, comorbidities, and hospitalization outcomes associated with NAFLD in patients with CD. Comparison between groups was performed by Mann-Whitney test for continuous variables and Chi-square test for categorical variables. We performed a binary logistic regression analysis for predictors of NAFLD among patients with CD. Results: We extracted 215,049 index hospital discharges with CD; 2.4% had NAFLD. CD patients, with NAFLD, had increased length of stay (4 days; interquartile range (IQR): 2 - 6 vs. 3; IQR: 2 - 6, P < 0.01), and increased median total charges ($32,305.5; IQR: $18,600 - $61,599 vs. $30,782; IQR: $16,847 - $58,667, P < 0.01), compared to CD patients without NAFLD. Non-alcoholic steatohepatitis (NASH) was found to be independently associated with increased mortality (odds ratio (OR): 1.7; 95% confidence interval (CI): 1.1 - 2.6, P = 0.03) and a higher odd for all-cause 30-day non-elective readmission (OR: 1.6: 95% CI: 1.3 - 1.9, P < 0.001). Factors independently associated with NAFLD in patients with CD included portal hypertension (OR: 5.347; 95% CI: 4.604 - 6.211, P < 0.001), vitamin A deficiency (OR: 9.89; 95% CI: 4.49 - 21.76, P < 0.001) and vitamin B12 deficiency (OR: 1.56; 95% CI: 1.098 - 2.209, P = 0.013). Conclusions: NAFLD is associated with worse hospitalization outcomes in patients with CD. Study findings suggest the need for early identification and effective management of NAFLD predictors to reduce complications.

Iron Deficiency Anemia: An Overlooked Complication of Crohn's Disease.

Background: There are few studies to evaluate the association between iron deficiency anemia (IDA) and Crohn's disease (CD). We examined this association in a USA-based cohort of patients with CD. Methods: We queried the Nationwide Readmission Databases 2018 using the International Classification of Disease, 10th Revision, and Clinical Modification (ICD-10-CM) codes to identify all adult patients admitted with a diagnosis of CD. Primary outcomes were the prevalence of IDA among patients with CD. Secondary outcomes included inpatient mortality, the length of stay, all-cause 30-day non-elective readmission rate, and total cost of hospitalization. Multivariate regression analysis was performed to study the impact of IDA on inpatient mortality and non-elective readmissions. Results: Of the 72,076 patients discharged from an index hospitalization for CD, 8.1% had IDA. CD patients with IDA had increased length of stays in days (4, interquartile range (IQR): 2 - 6 vs. 3, IQR: 2 - 5; P < 0.001), increased median total charges ($35,160, IQR: $19,786 - $64,126 vs. $31,299, IQR: $17,226 - $59,561; P < 0.001), and were more common to require blood transfusion during hospitalization (13.6% vs. 3.4%, P < 0.001) compared to CD patients without IDA, respectively. IDA was independently associated with increased odds of all-cause 30-day non-elective readmission (odds ratio (OR): 1.254, 95% confidence interval (CI): 1.154 - 1.363, P < 0.001) and increased odds of all-cause 90-day non-elective readmission (OR: 1.396, 95% CI: 1.302 - 1.498, P < 0.001). Conclusions: In a large nationwide cohort of patients hospitalized for CD, we observed a significant burden of IDA. Additionally, we found a significant association between IDA and worse hospitalization outcomes.

Cancer Care in the Wake of a Cyberattack: How to Prepare and What to Expect.

PURPOSE: Cyberattacks targeting health care organizations are becoming more frequent and affect all aspects of care delivery. Cancer care is particularly susceptible to major disruptions because of the potential of immediate and long-term consequences for patients who often rely on timely diagnostic testing and regular administration of systemic therapy in addition to other local treatment modalities to cure or control their diseases. On October 28, 2020, a cyberattack was launched on the University of Vermont Health Network with wide-ranging consequences for oncology, including loss of access to all network intranet servers, e-mail communications, and the electronic medical record (EMR). METHODS: This review details the immediate challenges faced by hematology and oncology during the cyberattack. The impact and response on inpatient, outpatient, and special patient populations are described. Steps that other academic- and community-based oncology practices can take to lessen the brunt of such an assault are suggested. RESULTS: The two areas of immediate impact after the cyberattack were communications and lack of EMR access. The oncology-specific impact included loss of the individualized EMR chemotherapy plan templates and electronic safeguards built into multistep treatment preparation and delivery. With loss of access to schedules, basic patient information, encrypted communications platforms and radiology, and laboratory and pharmacy services, clinical outpatient care delivery was reduced by 40%. The infusion visit volume dropped by 52% in the first week and new patients could not access necessary services for timely diagnostic evaluation, requiring the creation of command centers to oversee ethical and transparent triage and allocation of systemic therapies and address new patient referrals. This included appropriate transfer of patients to alternate sites to minimize delays. Inpatient care including transitions of care was particularly challenging and addressing patient populations whose survival might be affected by delays in care. CONCLUSION: Oncology health care leaders and providers should be aware of the potential impact of a cyberattack on cancer care delivery and preventively develop processes to mitigate the impact.

Screening of compound library identifies novel inhibitors against the MurA enzyme of Escherichia coli.

Bacterial cell has always been an attractive target for anti-infective drug discovery. MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) enzyme of Escherichia coli (E.coli) is crucial for peptidoglycan biosynthetic pathway, as it is involved in the early stages of bacterial cell wall biosynthesis. In the present study we aim to identify novel chemical structures targeting the MurA enzyme. For screening purpose, we used in silico approach (pharmacophore based strategy) for 52,026 library compounds (Chembridge, Chemdiv and in house synthetics) which resulted in identification of 50 compounds. These compounds were screened in vitro against MurA enzyme and release of inorganic phosphate (Pi) was estimated. Two compounds (IN00152 and IN00156) were found to inhibit MurA enzyme > 70% in primary screening and IC50 of 14.03 to 32.30 µM respectively. These two hits were further evaluated for their mode of inhibition studies and whole-cell activity where we observed 2-4 folds increase in activity in presence of Permeabilizer EDTA (Ethylenediaminetetraacetic acid). Combination studies were also performed with known antibiotics in presence of EDTA. Hits are reported for the first time against this target and our report also support the use of OM permeabilizer in combination with antibacterial compounds to address the permeability and efficacy issue. These lead hits can be further optimized for drug discovery. KEY POINTS: • Emerging Gram negative resistant strains is a matter of concern. • Need for new screening strategies to cope with drying up antibiotics pipeline. • Outer membrane permeabilizers could be useful to improve potency of molecules to reach its target.

Detection of the in vitro modulation of Plasmodium falciparum Arf1 by Sec7 and ArfGAP domains using a colorimetric plate-based assay.

The regulation of human Arf1 GTPase activity by ArfGEFs that stimulate GDP/GTP exchange and ArfGAPs that mediate GTP hydrolysis has attracted attention for the discovery of Arf1 inhibitors as potential anti-cancer agents. The malaria parasite Plasmodium falciparum encodes a Sec7 domain-containing protein - presumably an ArfGEF - and two putative ArfGAPs, as well as an Arf1 homologue (PfArf1) that is essential for blood-stage parasite viability. However, ArfGEF and ArfGAP-mediated activation/deactivation of PfArf1 has not been demonstrated. In this study, we established an in vitro colorimetric microtiter plate-based assay to detect the activation status of truncated human and P. falciparum Arf1 and used it to demonstrate the activation of both proteins by the Sec7 domain of ARNO, their deactivation by the GAP domain of human ArfGAP1 and the inhibition of the respective reactions by the compounds SecinH3 and QS11. In addition, we found that the GAP domains of both P. falciparum ArfGAPs have activities equivalent to that of human ArfGAP1, but are insensitive to QS11. Library screening identified a novel inhibitor which selectively inhibits one of the P. falciparum GAP domains (IC50 4.7 µM), suggesting that the assay format is suitable for screening compound collections for inhibitors of Arf1 regulatory proteins.

Progress Toward Polio Eradication - Worldwide, January 2016-March 2018.

In 1988, when an estimated 350,000 cases of poliomyelitis occurred in 125 countries, the World Health Assembly resolved to eradicate polio globally. Transmission of wild poliovirus (WPV) continues uninterrupted in only three countries (Afghanistan, Nigeria, and Pakistan) (1), and among the three serotypes, WPV type 1 (WPV1) remains the only confirmed circulating type. This report describes global progress toward polio eradication during January 2016-March 2018, and updates previous reports (2). In 2017, 22 WPV1 cases were reported, a 41% decrease from the 37 WPV1 cases reported in 2016. As of April 24, 2018, eight WPV1 cases have been reported (seven in Afghanistan and one in Pakistan), compared with five cases during the same period in 2017. In Pakistan, continuing WPV1 transmission has been confirmed in multiple areas in 2018 by isolation from wastewater samples. In Nigeria, ongoing endemic WPV1 transmission was confirmed in 2016 (3); although WPV was not detected in 2017 or in 2018 to date, limitations in access for vaccination and surveillance in insurgent-held areas in northeastern Nigeria might permit continued undetected poliovirus transmission. Substantial progress toward polio eradication has continued in recent years; however, interruption of WPV transmission will require overcoming remaining challenges to reaching and vaccinating every missed child. Until poliovirus eradication is achieved, all countries must remain vigilant by maintaining high population immunity and sensitive poliovirus surveillance.

Small-cell transformation of ALK-rearranged non-small-cell adenocarcinoma of the lung.

Anaplastic lymphoma kinase (ALK) gene rearrangements are present in ∼5% of non-small-cell lung cancers (NSCLCs). These rearrangements occur because of a chromosomal inversion within the short arm of Chromosome 2, which results in the formation of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion oncogene. Whereas NSCLC transformation to SCLC is a rare phenomenon described in epidermal growth factor receptor (EGFR) mutant cancers primarily after treatment with targeted therapy, it is exceedingly rare in ALK-rearranged adenocarcinomas. It is currently unclear what the therapeutic significance of the rearrangement is in this transformed tumor as there is a paucity of medical literature describing follow-up care and outcomes of patients in this rare scenario. We describe a unique case in which a patient with ALK-rearranged adenocarcinoma underwent small-cell transformation at a metastatic site with retained ALK rearrangement and was provided clinical follow-up after treatment with second-generation tyrosine kinase inhibiter (TKI) therapy.

Assessment of an Innovative Voluntary Substance Abuse Treatment Program Designed to Replace Compulsory Drug Detention Centers in Malaysia.

BACKGROUND: As part of an ongoing initiative by the Malaysian government to implement alternative approaches to involuntary detention of people who use drugs, the National Anti-Drug Agency has created new voluntary drug treatment programs known as Cure and Care (C&C) Centers that provide free access to addiction treatment services, including methadone maintenance therapy, integrated with social and health services. OBJECTIVES: We evaluated early treatment outcomes and client satisfaction among patients accessing C&C treatment and ancillary services at Malaysia's second C&C Center located in Kota Bharu, Kelantan. METHODS: In June-July 2012, a cross-sectional convenience survey of 96 C&C inpatients and outpatients who entered treatment >30 days previously was conducted to assess drug use, criminal justice experience, medical co-morbidities, motivation for seeking treatment, and attitudes towards the C&C. Drug use was compared for the 30-day-period before C&C entry and the 30-day-period before the interview. RESULTS: Self-reported drug use levels decreased significantly among both inpatient and outpatient clients after enrolling in C&C treatment. Higher levels of past drug use, lower levels of social support, and more severe mental health issues were reported by participants who were previously imprisoned. Self-reported satisfaction with C&C treatment services was high. Conclusions/Importance: Preliminary evidence of reduced drug use and high levels of client satisfaction among C&C clients provide support for Malaysia's ongoing transition from compulsory drug detention centers (CDDCs) to these voluntary drug treatment centers. If C&C centers are successful, Malaysia plans to gradually transition away from CDDCs entirely.

Genetic diversity of Glossina fuscipes fuscipes along the shores of Lake Victoria in Tanzania and Kenya: implications for management.

BACKGROUND: Tsetse flies (Diptera: Glossinidae) are sole vectors for trypanosomiasis, which affect human health and livestock productivity in Africa. Little is known about the genetic diversity of Glossina fuscipes fuscipes, which is an important species in Tanzania and Kenya. The main objective of the study was to provide baseline data to determine the genetic variability and divergence of G. f. fuscipes in the Lake Victoria basin of Tanzania and Kenya in order to guide future vector control efforts in the region. FINDINGS: Two hundred and seventy five G. f. fuscipes from 8 sites along the shores of Lake Victoria were screened for genetic polymorphisms at 19 microsatellite loci. Samples were collected from two sites in Kenya and six sites in Tanzania. Four of the Tanzanian sites were located in the Rorya district, on the eastern shores of Lake Victoria, while the other two sites were from Ukerewe and Bukoba districts from the southern and western Lake Victoria shores, respectively. Four genetically distinct allopatric clusters were revealed by microsatellite analysis, which sorted the sampling sites according to geography, with sites separated by as little as ~65 km belonging to distinct genetic clusters, while samples located within ~35 km from each other group in the same cluster. CONCLUSION: Our results suggest that there is ongoing genetic admixture within sampling sites located ~35 km from each other, while sites located ~65 km apart are genetically isolated from each other. Similar patterns emerged from a parallel study on G. f. fuscipes analyzed from the Lake Victoria Uganda shores. From a control perspective these results suggest that for sites within the same genetic cluster, control efforts should be carried out in a coordinated fashion in order to avoid re-invasions. Future work should focus on better quantifying the extent and spatial patterns of the observed genetic discontinuities of the G. f. fuscipes populations along the Tanzanian shores. This will aid in their control by providing guidelines on the geographical extent of the area to be treated at the same time.

Strengthening value-based medication management in a free clinic for the uninsured: Quality interventions aimed at reducing costs and enhancing adherence.

Skyrocketing costs of prescription medications in the USA pose a significant threat to the financial viability of safety net clinics that opt to supply medications at low to no out-of-pocket costs to patients. At the East Harlem Health Outreach Partnership clinic of the Icahn School of Medicine at Mount Sinai, a physician-directed student-run comprehensive primary care clinic for uninsured adults of East Harlem, expenditures on pharmaceuticals represent nearly two-thirds of annual costs. The practice of minimising costs while maintaining quality, referred to as high-value care, represents a critical cost-saving opportunity for safety net clinics as well as for more economical healthcare in general. In this paper, we discuss a series of quality improvement initiatives aimed at reducing pharmacy-related expenditures through two distinct yet related mechanisms: (A) promoting value-conscious prescribing by providers and (B) improving patient adherence to medication regimens. Interventions aimed at promoting value-conscious prescribing behaviour included blacklisting a costly medication on our clinic's formulary and adding a decision tree in our mobile clinician reference application to promote value-conscious prescribing. Interventions targeted to improving patient adherence involved an automated text messaging system with English and Spanish refill reminders to encourage timely pick-up of medication refills. As a result of these processes, the free clinic experienced a 7.3%, or $3768, reduction in annual pharmacy costs. Additionally, medication adherence in patients with diabetes on oral antihyperglycaemic medications increased from 55% to 67%. Simultaneous patient-based and provider-based interventions may be broadly applicable to addressing rising pharmacy costs in healthcare across the USA.

Access to Care in Vermont: Factors Linked With Time to Chemotherapy for Women With Breast Cancer-A Retrospective Cohort Study.

PURPOSE: In the rural United States, there are multiple potential barriers to the timely initiation of chemotherapy. The goal of this study was to identify factors associated with delays in the time from initial diagnosis to first systemic therapy (TTC) among women with breast cancer in Vermont. METHODS: Using data from the Vermont Cancer Registry, we explored TTC for 702 female Vermont residents diagnosed with stage I to III breast cancer between 2006 and 2010 who received adjuvant chemotherapy. Multivariable linear regression was used to evaluate the associations between TTC and patient, tumor, treatment, and geographic variables. RESULTS: Mean TTC was 10.2 weeks. Longer drive time (P < .001), more invasive surgery (P = .01), and breast reconstruction (P < .001) were each associated with longer TTC. Each additional 15 minutes of drive time was associated with a 0.34-week (95% CI, 0.22 to 0.46 weeks) increase in TTC. Participants age younger than 65 years whose primary payer was Medicare (n = 27) had significantly longer average TTC, by 2.37 weeks (P = .001), compared with those with private or military insurance. There was also substantial variation in TTC across hospitals (P < .001). CONCLUSION: Most female patients with stage I to III breast cancer in Vermont are receiving adjuvant chemotherapy within the National Comprehensive Cancer Network-recommended timeframe; however, improvements remain needed for certain subgroups. Novel approaches for women with long drive times need to be developed and evaluated in the community. Variation in TTC by hospital, even after adjusting for patient, tumor, and treatment factors, also suggests opportunities for process improvement.

Double trouble: para-neoplastic anti-PCA-2 and CRMP-5-mediated small fibre neuropathy followed by chorea associated with small cell lung cancer and evolving radiological features.

Patients with Purkinje cell cytoplasmic autoantibody type 2 (PCA-2) and collapsin response-mediator protein-5 (CRMP-5) autoantibody can present with multifocal elements of encephalomyeloneuropathy. Except for an anecdotal report, case descriptions of paraneoplastic small fibre neuropathy are lacking. We report paraneoplastic small fibre neuropathy followed by chorea associated with small cell lung cancer. A man aged 57 years with a 35 pack-year smoking history presented with painless subacute paresthesia and weight fluctuation. A non-length-dependent small fibre neuropathy was confirmed by skin biopsy. Further testing revealed positive serum PCA-2 and CRMP-5 autoantibodies, which after positron emission tomography-CT led to histological confirmation of a small cell lung cancer. Initially, abnormal MRI and cerebrospinal fluid studies suggested central nervous system (CNS) involvement which was subclinical; however, 6 months later during antitumour therapy, the patient became symptomatic with choreoathetosis. After combined chemoradiation as well as immunosuppressive and symptomatic therapies, the clinical course stabilised, although residual neurological deficits remained at follow-up a year later. Coexistent PCA-2 and CRMP-5 autoantibodies may occur in the setting of small fibre peripheral neuropathy and choreoathetosis and predict cancer type. Two paraneoplastic syndromes can present successively over months; subclinical CNS involvement with evolving basal ganglia abnormalities can be a paraneoplastic manifestation. In the appropriate clinical setting, paraneoplastic testing should be considered in patients presenting with small fibre neuropathy.