Severe and prolonged hypocalcemia after a single dose of denosumab for metastatic breast cancer with diffuse bone involvement without prior calcium/vitamin D supplementations.

INTRODUCTION: Denosumab is a human monoclonal antibody antiresorptive agent used for the treatment of bone metastasis in different cancer types, including breast cancer. Hypocalcemia is a known adverse effect of denosumab, and early supplementation plays an important role in the prevention and management of hypocalcemia. CASE REPORT: A 63-year-old female with stage IV estrogen receptor-positive breast cancer with diffuse bone metastasis experienced severe, prolonged hypocalcemia following a single dose of denosumab. The patient also had several risk factors for denosumab-associated hypocalcemia. Despite not receiving additional doses of denosumab, the patient required multiple hospitalizations and outpatient infusions of calcium to resolve her symptomatic hypocalcemia.Management and outcome: Severe hypocalcemia associated with denosumab can be prevented or mitigated by recognizing the risk factors for hypocalcemia and supplementing with vitamin D/calcium. Proposed risk factors include poor renal function, hypoparathyroidism, insufficient calcium intake, and diffuse metastatic bone disease. Studies suggest that early supplementation before starting denosumab can lower this risk. DISCUSSION: Several cases of severe hypocalcemia associated with denosumab have been reported. However, to the authors' knowledge, this is the first report that highlights the importance of early vitamin D/calcium supplementations for a patient with diffuse metastatic bone disease with pre-existing low levels of calcium.

Characteristics Associated with Confidential Consultation for Adolescents in Primary Care.

OBJECTIVE: To examine how provider report of confidential consultation in the electronic health record is associated with adolescent characteristics, health risk factors, and provider training. STUDY DESIGN: This prospective cohort study was conducted as part of a larger study implementing computerized clinical decision support in 2 urban primary care clinics. Adolescents used tablets to complete screening questions for specified risk factors in the waiting room. Adolescent-reported risk factors included sexual activity, substance use, and depressive symptoms. Providers were prompted on encounter forms to address identified risk factors and indicate whether confidential consultation was provided. Provider types included adolescent medicine board certified pediatrics and general pediatrics. Differences in proportions of adolescents reporting risk factors by provider type were assessed using χ2 tests. Associations between adolescent characteristics, risk factors, and provider-reported confidential consultation were examined using logistic regression analyses. RESULTS: The sample included 1233 English and Spanish-speaking adolescents 12-20 years of age (52% female; 60% black; 50% early adolescent). Patients seen by adolescent medicine board certified providers reported sexual activity, depressive symptoms, and substance use significantly more often than those seen by general pediatric providers. Among patients seen by board certified adolescent medicine providers, confidential consultation was provided to 90%. For those seen by general pediatric providers, confidential consultation was provided to 53%. Results of multiple logistic regression demonstrated that female sex, later adolescence, and clinic location were significantly associated with confidential consultation. CONCLUSIONS: Provider training is needed to reinforce the importance of confidential consultation for all adolescents.

B12 deficiency leading to marked poikilocytosis versus true schistocytosis, a pernicious problem.

Severe vitamin B12 deficiency is caused most commonly by autoimmune atrophic gastritis leading to loss of intrinsic factor. Vitamin B12 deficiency leading to megaloblastic anemia and demyelinating central nervous system disease is well known; however, a rare presentation of B12 deficiency described as pseudothrombotic microangiopathy is not well known. This complication presents with signs of mechanical hemolysis, elevated lactate dehydrogenase (LDH), thrombocytopenia, and a low reticulocyte count, which can be incorrectly diagnosed as thrombotic thrombocytopenic purpura and managed incorrectly. Decreased reticulocyte count and an LDH >2500IU/L is more commonly seen in B12 deficiency. However, recognizing the differences in marked poikilocytosis can be challenging, as seen with megaloblastic changes and true schistocytosis. To illustrate the challenge in differentiating between megaloblastic changes and true schistocytosis, we present the case of a 27-year-old woman who presented to her physician for symptomatic anemia and complaints of nausea, vomiting, and loose stool. She had a hemoglobin of 5.1g/dL, platelet count of 39×109/L, LDH of 9915IU/L, haptoglobin below assay limit, and a reticulocyte count of 2.5%. Peripheral smear showed macrocytic anemia, rare hypersegmented neutrophils, and schistocytes. Vitamin B12 level was less than 50pg/mL, methylmalonic acid was 0.33µmol/L, anti-parietal cell antibody was >1:640, and intrinsic factor blocking antibody was positive-confirming the diagnosis of pernicious anemia. While hospitalized, she was treated with vitamin B12 1000µg intramuscular injections daily and thereafter continued with monthly injections, which ultimately resolved her severe macrocytic anemia.

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.

Pembrolizumab-Induced Immune-Mediated Glossitis.

Pembrolizumab (Keytruda), an anti-PD-1 antibody used in the treatment of several different malignancies has been identified to cause adverse effects pertaining to multiple body systems which include respiratory, gastrointestinal, dermatologic, and endocrine manifestations known as immune-related adverse events (IRAEs). Skin manifestations have been most described in current literature highlighting the most common adverse effects of this agent. However, adverse outcomes involving the oral mucosa have been rarely identified in the PD-1 and PD-L1 inhibitor classes of immunotherapeutic agents. We present a case of a 71-year-old male who was treated with a chemotherapeutic regimen including pembrolizumab for newly diagnosed squamous cell carcinoma of the lung, who later developed ulcerations on his tongue that were consistent with glossitis. Upon determining that this adverse effect may be immune-related, the patient was treated with oral prednisone 40 mg with a 10 mg taper each subsequent week, which resulted in significant improvement in the patient's symptoms following one month of treatment.

Agent Orange Exposure, Transformation From MGUS to Multiple Myeloma, and Outcomes in Veterans.

Background: Multiple myeloma (MM) accounts for 1% to 2% of all cancers. Exposure to the pesticide Agent Orange (AO) has been established as a potential risk factor for the development of monoclonal gammopathy of undetermined significance (MGUS) and, subsequently, MM in Vietnam War veterans. Methods: This study explored variation in survival related to AO exposure, transformation from MGUS to MM, and covariates. Vietnam War veterans with MM or MGUS were identified in Veterans Health Administration (VHA) health records data. Cox proportional hazards models analyzed survival as a function of AO, race, ethnicity, body mass index, nicotine dependence, alcohol use disorder, Charlson Comorbidity Index, and treatment. Autologous hematopoietic cell transplantation for MM was defined by procedure codes. Results: In the VHA 16,366 patients were identified: 11,112 patients diagnosed with MGUS and 7261 with MM during fiscal years 2010 to 2015 were identified; 12% (n = 2007) had both diagnoses. No statistically significant difference in the rate of transformation from MGUS to MM in the AO exposed and AO not exposed groups was found. In survival models, AO exposure was associated with slightly lower mortality. Alcohol use disorder, nicotine dependence, older age, and greater comorbidity burden increased mortality risk. Black race, female sex, obesity/overweight, and hematopoietic cell transplantation for patients with MM were protective factors. AO exposure was associated with decreased mortality for both MM/MGUS groups. Transformation increased mortality risk for patients with MGUS and decreased mortality risk for patients with MM. Conclusions: Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and drug use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies should examine the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to best identify their disease course and optimize their care in the latter part of their life.

Longitudinal monitoring of disease burden and response using ctDNA from dried blood spots in xenograft models.

Whole-genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA from minute volumes of blood in PDX mice. We developed a xenograft Tumour Fraction (xTF) metric using shallow WGS of dried blood spots (DBS), and demonstrate its application to quantify disease burden, monitor treatment response and predict disease outcome in a preclinical study of PDX mice. Further, we show how our DBS-based ctDNA assay can be used to detect gene-specific copy number changes and examine the copy number landscape over time. Use of sequential DBS ctDNA assays could transform future trial designs in both mice and patients by enabling increased sampling and molecular monitoring.

Reviewing the Outcomes of Different Treatment Approaches in Elderly Pancreatic Cancer Patients.

OBJECTIVES: The incidence of pancreatic cancer is age dependent. Ninety percent of new diagnoses occur in patients older than 55 years. Despite the association with age and cancer, elderly patients are historically underrepresented in clinical trials. Thus, optimal management of elderly patients has a lack of data. The purpose of this retrospective study was to investigate the outcomes of palliative chemotherapy in elderly patients with pancreatic cancer compared with supportive care alone. METHODS: Unicentric data were reviewed on all elderly patients (defined as age >65 years) with a diagnosis of pancreatic cancer from 2008 through 2019 to compare outcomes in those who received chemotherapy versus supportive care alone. RESULTS: The study reviewed 665 patients with a median age of 75 years (mean, 75.7 years) and average Charlson Comorbidity Score of 5.74. Of them, 291 received chemotherapy and 363 received supportive care only. Chemotherapy was associated with a median overall survival of 250 versus 93 days with supportive care (P < 0.0001). Analysis showed improved survival for all age ranges, cancer stages, and Charlson Comorbidity Scores. CONCLUSIONS: Elderly pancreatic cancer patients can benefit from palliative chemotherapy, and it should be considered, especially in patients with fewer medical comorbidities and better functional status.

Hemophagocytic lymphohistiocytosis due to pembrolizumab therapy for adenocarcinoma of the lung.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of dysregulated inflammation. It is most commonly seen in children who have a predisposing genetic mutation. However, adults can contract an acquired version of the disorder secondary to an infectious, neoplastic, or other inflammatory insult. There have been several documented cases of HLH being induced by treatment with immunotherapy. Here, we present the case of a 71-year-old man who was receiving pembrolizumab for lung adenocarcinoma when he developed HLH following his 14th cycle of therapy. Although bone marrow biopsy was negative, he nevertheless fulfilled the diagnostic criteria of the HLH 2004 report and was treated with high-dose steroids followed by a prolonged taper, with resolution of his symptoms and normalization of his blood counts.

The STarT Back stratified care model for nonspecific low back pain: a model-based evaluation of long-term cost-effectiveness.

ABSTRACT: The STarT Back approach comprises subgrouping patients with low back pain (LBP) according to the risk of persistent LBP-related disability, with appropriate matched treatments. In a 12-month clinical trial and implementation study, this stratified care approach was clinically and cost-effective compared with usual, nonstratified care. Despite the chronic nature of LBP and associated economic burden, model-based economic evaluations in LBP are rare and have shortcomings. This study therefore produces a de novo decision model of this stratified care approach for LBP management to estimate the long-term cost-effectiveness and address methodological concerns in LBP modelling. A cost-utility analysis from the National Health Service perspective compared stratified care with usual care in patients consulting in primary care with nonspecific LBP. A Markov state-transition model was constructed where patient prognosis over 10 years was dependent on physical function achieved at 12 months. Data from the clinical trial and implementation study provided short-term model parameters, with extrapolation using 2 cohort studies of usual care in LBP. Base-case results indicate this model of stratified care is cost-effective, delivering 0.14 additional quality-adjusted life years at a cost saving of £135.19 per patient over a time horizon of 10 years. Sensitivity analyses indicate the approach is likely to be cost-effective in all scenarios and cost saving in most. It is likely this stratified care model will help reduce unnecessary healthcare usage while improving the patient's quality of life. Although decision-analytic modelling is used in many conditions, its use has been underexplored in LBP, and this study also addresses associated methodological challenges.

The alcohol detoxification protocol and creation of the e-consult at Central Texas Veterans health care system.

Within the Central Texas Veterans Health Care System, the alcohol-related disorder readmission rate has been recognized as an area that needs improvement. The aim of this quality improvement initiative was to develop an alcohol detoxification protocol. This protocol assesses the need for inpatient vs outpatient management of alcohol withdrawal and provides guidance pertaining to medication options, with emphasis on prescribing gabapentin for treatment of alcohol withdrawal. The protocol also contains the alcohol detox e-consult, which prompts a physician to call the patient daily to assess alcohol withdrawal, ability to abstain from alcohol, medication compliance, interest in substance abuse treatment programs, and appropriate follow-up. After implementing the protocol and e-consult, we saw a reduction in the admission rate of alcohol-related disorders and patients found the consult helpful.

Relationship between splenomegaly and transfusion requirements in patients with cirrhosis.

Patients with cirrhosis and splenomegaly commonly develop cytopenias and require the transfusion of blood products. In this study, we evaluated spleen size as a clinical indicator for red blood cell transfusion effectiveness and hypothesized that transfusion would be less effective in patients with splenomegaly. Our retrospective cohort study compared 215 cirrhotic patients with splenomegaly and 114 cirrhotic patients without splenomegaly and measured their respective change in hemoglobin concentration after a unit of transfused red blood cells. The primary endpoint was the percent difference between the measured rise in hemoglobin after transfusion in these cohorts. Patient sex (P < 0.0035), body mass index (P < 0.0001), and the change in hemoglobin concentration after a leukocyte-reduced red blood transfusion (P < 0.0001) were found to be significantly related to spleen size. When compared to the nonsplenomegaly cohort, it was found that the splenomegaly cohort experienced 79.70% (95% CI 71.26%-89.14%) of the change in hemoglobin concentration after red blood cell transfusion when adjusted for patient sex and body mass index. In conclusion, in patients with cirrhosis, increased spleen size was correlated with a decreased responsiveness to red blood cell transfusion when adjusted for patient sex and body mass index.

Iowa Case Management for Rural Drug Abuse.

OBJECTIVE: The purpose of this research was to evaluate the effectiveness of a comprehensive, strengths-based model of case management for clients in drug abuse treatment. METHOD: 503 volunteers from residential or intensive outpatient treatment were randomly assigned to one of three conditions of Iowa Case Management (ICM) plus treatment as usual (TAU), or to a fourth condition of TAU only. All were assessed at intake and followed at 3, 6, and 12 months. RESULTS: Clients in all four conditions significantly decreased substance use by 3 months after intake and maintained most gains over time. However, the addition of ICM to TAU did not improve substance use outcomes. CONCLUSION: Overall, the addition of case management did not significantly improve drug treatment as hypothesized by both researchers and clinicians. Some results were mixed, possibly due to the heterogeneous sample, wide range of case management activities, or difficulty retaining participants over time.

Systematic Review of Decision Analytic Modelling in Economic Evaluations of Low Back Pain and Sciatica.

BACKGROUND: Low back pain (LBP) and sciatica place significant burden on individuals and healthcare systems, with societal costs alone likely to be in excess of £15 billion. Two recent systematic reviews for LBP and sciatica identified a shortage of modelling studies in both conditions. OBJECTIVES: The aim of this systematic review was to document existing model-based economic evaluations for the treatment and management of both conditions; critically appraise current modelling techniques, analytical methods, data inputs, and structure, using narrative synthesis; and identify unresolved methodological problems and gaps in the literature. METHODS: A systematic literature review was conducted whereby 6512 records were extracted from 11 databases, with no date limits imposed. Studies were abstracted according to a predesigned protocol, whereby they must be economic evaluations that employed an economic decision model and considered any management approach for LBP and sciatica. Study abstraction was initially performed by one reviewer who removed duplicates and screened titles to remove irrelevant studies. Overall, 133 potential studies for inclusion were then screened independently by other reviewers. Consensus was reached between reviewers regarding final inclusion. RESULTS: Twenty-one publications of 20 unique models were included in the review, five of which were modelling studies in LBP and 16 in sciatica. Results revealed a poor standard of modelling in both conditions, particularly regarding modelling techniques, analytical methods, and data quality. Specific issues relate to inappropriate representation of both conditions in terms of health states, insufficient time horizons, and use of inappropriate utility values. CONCLUSION: High-quality modelling studies, which reflect modelling best practice, as well as contemporary clinical understandings of both conditions, are required to enhance the economic evidence for treatments for both conditions.

The "nursing cheat sheet," a guide to aid nursing in management of patient care.

The aim of this study was to promote nursing and practitioner satisfaction by improving communication and reducing rapid response team (RRT) activations and code blues hospitalwide by implementing the nursing cheat sheet, a list of key steps to be done before calling the primary provider. This prospective observational study took place over a year at a 636-bed teaching hospital in Central Texas. Education regarding the nursing cheat sheet was provided to nurses at monthly meetings, unit huddles, and interdisciplinary rounds. Units received monthly follow-up education and reminders, and the nursing cheat sheet was posted at nursing work areas. RRT activations and code blues were counted daily. After implementing the nursing cheat sheet, RRT activations were lower than the pre-intervention average and were outside the control band for July, August, and November. The number of code blues did not deviate from the control bands. The authors did not see a reduction in code blues after implementation of the nursing cheat sheet, but the average number of RRT activations decreased, indicating a significant difference in the number of RRT activations. It is not clear that this decrease was due to the intervention.

Sepsis as the primary admitting diagnosis of transferred patients who died within 48 hours of arrival at a Central Texas hospital.

Interhospital transfers are independently associated with inpatient mortality, and transferred patients have worse outcomes. The aim of this study was to retrospectively assess the 48-hour mortality rate in interhospital transfer cohorts of all transfers to a Central Texas teaching hospital and to identify a primary admitting diagnosis for potential intervention. A total of 15,435 patients with 19,161 transfers over the course of the study were retrospectively reviewed and placed in 18 different categories based upon the primary admitting diagnosis. There were about 5000 transfer patients yearly with ∼1.4% deaths within 48 hours of arrival. The three leading categories for transferred patients were cardiovascular, neurologic, and psychiatric. In this group, 268 of 19,161 transfers died within 48 hours of arrival. Despite being the 10th leading category for transfer, sepsis was the leading primary admitting diagnosis of patients who died within 48 hours of arrival, accounting for nearly 22% of those patients. Given the significant association found between sepsis and 48-hour mortality after transfer, we devised a novel interhospital transfer checklist based upon the Surviving Sepsis guidelines in an attempt to decrease mortality associated with these transfers.

Rescue angioplasty after failed fibrinolysis for acute myocardial infarction: predictors of a failed procedure and 1-year mortality.

BACKGROUND: Rescue angioplasty (rPCI) for failed fibrinolysis is associated with a low mortality if successful, but a high mortality if it fails. The latter may reflect a high-risk group or harm in some patients. Predictors of success or failure of rPCI may aid selection of patients to be treated. METHODS: Unselected patients referred for rPCI from March 1994 to March 2005 were studied to determine the predictors of a failed procedure and 1-year mortality. RESULTS: Of 440 patients undergoing emergency coronary angiography for failed fibrinolysis (1-year mortality 18%), 101 had thrombolysis in myocardial infarction flow grade (TFG) 3 in the infarct-related vessel. rPCI was attempted in 318 of 339 patients with 75 years, shock, and final TFG < 3 were independent predictors of 1-year mortality. CONCLUSIONS: Cardiogenic shock is an independent predictor of a failed rPCI. Age group >75 years and shock were the only independent clinical predictors of 1-year mortality. These clinical variables may help in selecting patients for either a strategy of rescue angioplasty after failed fibrinolysis, or in selecting specific patients who might do better with a policy of primary angioplasty.

Clinical outcomes of traumatized youth in adolescent substance abuse treatment: a longitudinal multisite study.

The purpose of this study was to evaluate the effectiveness of outpatient substance abuse treatment for youth with high traumatic stress compared to youth without high traumatic stress in substance abuse treatment centers across the United States. The data for this study were gathered using a longitudinal survey design with purposive sampling from nine drug treatment delivery systems across the United States participating in the cooperative grant Strengthening Communities for Youth (SCY) awarded by SAMHSA's Center for Substance Abuse Treatment (CSAT) between September 2002 and June 2006. Follow-up assessments were conducted with the youth at three,six, and 12 months following intake. Traumatized youth responded to outpatient treatment in a similar pattern when compared to nontraumatized youth, although the traumatized youth had consistently higher scores on substance use frequency and substance problems scales than nontraumatized youth throughout the study. Current empirically validated treatments for adolescent substance abuse do not prepare the practitioner for trauma-informed practice or specifically address trauma-informed recovery. Based on our results, we advocate for the development and integration of trauma-informed practice within substance abuse treatment for adolescents to help them recover from trauma and substance abuse issues.

Substance abuse treatment with rural adolescents: issues and outcomes.

This study compared the characteristics and treatment outcomes of rural adolescents with urban adolescents in substance abuse treatment programs in CSAT's Strengthening Communities for Youth (SCY) initiative. Using data from ten SCY programs nationally, the authors classified adolescents as rural or urban using Rural-Urban Commuting Area (RUCA) codes. We then evaluated changes in substance use frequency and substance-related problems at three, six, and 12 months after baseline assessments for the two sites that treated rural (n = 59) and urban (n = 345) youth in outpatient settings. Data were analyzed using a two-part mixed effects model for zero-saturated dependent variables. At treatment intake, rural youth exhibited greater problem severity on a number of substance abuse and mental health indices. From intake to the 12-month follow-up point, the percentages of both urban and rural youth who reported abstinence increased significantly. Both rural and urban youth also reported fewer problems due to substance use over time, but differences between groups were not consistent. Overall, treatment appears equally effective for both rural and urban adolescents. As few rural youth obtained treatment, we encourage funding agencies and treatment providers to consider innovative ways for providing services in rural areas and addressing gaps in primary prevention, early identification, and continuing care.

Disseminated methicillin-susceptible Staphylococcus aureus infection.

INTRODUCTION: When clinicians think about Staphylococcus aureus bacteria, what comes to the mind of most is the dreaded methicillin-resistant form. However, clinicians should not forget the methicillin-susceptible type, which is just as virulent. CASE PRESENTATION: The authors present the case of a 20-year-old woman who was admitted with septic shock and multi-organ failure and was found to have disseminated methicillin-susceptible Staphylococcus aureus (MSSA) infection. The patient had persistent blood cultures positive for MSSA. A transesophageal echocardiogram showed a 1.1 cm vegetation in the mitral valve, and the patient had bilateral pleural effusions that grew MSSA. An MRI of the brain showed multiple areas consistent with infarctions thought to be secondary to septic emboli. The patient underwent a mitral valve replacement and was treated with a prolonged course of parenteral nafcillin. DISCUSSION: This case illustrates a severe clinical presentation and management of MSSA infections.