Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis.

Systemic immunoglobulin light-chain amyloidosis is characterized by pathologic deposition of immunoglobulin light chains as amyloid fibrils in vital organs, leading to organ impairment and eventual death. That the process is reversible was evidenced in an in vivo experimental model in which fibril-reactive chimeric monoclonal antibody (mAb) 11-1F4 directly targeted human light-chain amyloid deposits and affected their removal via a phagocyte-mediated response. To determine the tolerability and potential amyloidolytic effect of this agent (now designated mAb CAEL-101), we conducted a phase 1a/b study involving 27 patients, most of whom had manifestations of organ involvement. This was an open-label study in which phase 1a patients received mAb CAEL-101 as a single intravenous infusion with escalating dose levels from 0.5 mg/m2 to 500 mg/m2 to establish the maximum tolerated dose (MTD). In phase 1b, the antibody was administered as a graded series of 4 weekly infusions. For both phases, there were no drug-related serious adverse events or dose-limiting toxicities among recipients, and the MTD was not reached. The majority of patients had deep hematologic responses but persistent organ disease prior to treatment. Fifteen of 24 patients (63%) who manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue involvement had a therapeutic response to mAb CAEL-101 as evidenced by serum biomarkers or objective imaging modalities with a median time to response of 3 weeks. Infusions of mAb CAEL-101 were well tolerated and, for the majority, resulted in improved organ function, notably for those with cardiac impairment. This trial was registered at www.clinicaltrials.gov as #NCT02245867.

Proton pump inhibitor use and the risk of peritoneal dialysis associated peritonitis.

BACKGROUND: The use of proton-pump inhibitors (PPI) has been associated with an increased risk of developing spontaneous bacterial peritonitis in patients with cirrhosis. Whether PPI use confers a similar risk in developing peritonitis in peritoneal dialysis (PD) patients remains unclear. AIM: To assess whether PPI use is associated with an increased risk of PD peritonitis. METHODS: Patients on PD were retrospectively identified. Data such as PPI use during PD, underlying diagnoses, comorbidities, and baseline serum tests were collected. Univariable and multivariable analysis was conducted using logistic regression to assess whether PPI use and other factors were associated with PD peritonitis. RESULTS: Fifty-seven patients were identified with a median (interquartile range (IQR)) age of 65.0 (51.5-74.0) years. The median (IQR) time on PD was 29.0 (17.5-45.0) months. Twenty-eight patients were on a PPI during PD. Fifty-seven percent of the PPI group went on to develop peritonitis, compared with 31% of patients without PPI exposure (odds ratio (OR) = 2.96; 95% confidence interval (CI): 1.00, 8.78; P = 0.050). Months on PD (OR = 1.03; 95% CI: 1.00, 1.06; P = 0.026), serum urea (OR = 0.88; 95% CI: 0.80, 0.97; P = 0.017), congestive cardiac failure (OR = 5.44; 95% CI: 1.29, 23.00; P = 0.021) and renovascular disease (OR = 14.59; 95% CI: 1.68, 126.67; P = 0.015) were identified as possible risk factors for peritonitis on univariable analysis. Following adjustment for covariates, serum urea, but not PPI use, was associated with PD peritonitis (OR = 0.87; 95% CI: 0.78, 0.98; P = 0.020). CONCLUSION: PPI use during PD was not associated with peritonitis. Due to the small number of patients and the limited number of studies investigating the effect of PPI use on PD peritonitis, further research is needed.

Hip fractures in patients with chronic kidney disease admitted to Victorian hospitals.

There is a paucity of epidemiological data in Australia on fracture rates in patients with chronic kidney disease (CKD). Using data from the Victorian Admitted Episodes Dataset, we assessed the incidence of hip fractures requiring hospitalisation between 2006 and 2015, comparing those coded with and without the co-morbidity CKD. ICD-9 and ICD-10 codes were used to determine hip fractures and comorbidities. Overall, 7.4% of 77 076 Victorian hospital admissions for hip fractures had CKD as a co-morbidity, with an increasing proportion over the study period. Mortality was significantly higher in the CKD cohort compared to no CKD, perhaps in part due to increased associated comorbidities of diabetes and ischaemic heart disease.

Scarcity mindset in reproductive health decision making: a qualitative study from rural Malawi.

Poverty has widespread impacts on health. In dealing with resource scarcity, individuals' thoughts are narrowed to address immediate resource limitations, thus crowding out other information, a phenomenon called the scarcity mindset. To assess for indication of a scarcity mindset in sexual and reproductive decision making in rural Malawi, a setting with extreme resource scarcity, we collected qualitative data in the form of eight focus group discussions and 28 semi-structured, in-depth interviews with women and men of varying ages and marital status. Participants, who were of low socioeconomic status, described constant tradeoffs that they made to secure their daily needs. They articulated both the challenges of supporting many children and the need to bear many children to guarantee their own future support. While participants described wealthy people as being concerned with preserving resources (often through the practice of limiting childbearing), they described poor people as working to increase their probability of success against an uncertain economic future (without due consideration of contraceptive behaviours). We found qualitative evidence that a scarcity mindset may influence reproductive decision making among women and men in rural Malawi and may preclude the use of contraception in low-resource settings.

Inflammatory Myofibroblastic Tumor Driven by Novel NUMA1-ALK Fusion Responds to ALK Inhibition.

Inflammatory myofibroblastic tumors (IMTs) are soft tissue neoplasms with rare metastatic potential. Approximately half of IMTs are positive for an ALK rearrangement, and ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. This report describes a 21-year-old woman with an aggressive, metastatic IMT with a novel NUMA1-ALK fusion that showed a dramatic response to the ALK inhibitors crizotinib and alectinib. To our knowledge, this report provides the first published description of an IMT with a NUMA1-ALK fusion. The patient's aggressive IMT responded favorably to crizotinib and alectinib, suggesting that ALK inhibitors may be effective in IMT with NUMA1-ALK fusions. We review published reports of ALK-driven IMTs that have received ALK inhibitor therapy and suggest characteristics that may be associated with favorable response to treatment. We also discuss the strengths and limitations of immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing in the diagnosis and management of IMTs.

Correction to: The Role of Oncolytic Viruses in the Treatment of Melanoma.

A correction was made to a sentence in the original article to provide additional clarification in the "Other Oncolytic Viruses" section.

The Role of Oncolytic Viruses in the Treatment of Melanoma.

PURPOSE OF REVIEW: Oncolytic virotherapy is a new approach to the treatment of cancer and its success in the treatment of melanoma represents a breakthrough in cancer therapeutics. This paper provides a review of the current literature on the use of oncolytic viruses (OVs) in the treatment of melanoma. RECENT FINDINGS: Talimogene laherparepvec (T-VEC) is the first OV approved for the treatment of melanoma and presents new challenges as it enters the clinical setting. Several other OVs are at various stages of clinical and pre-clinical development for the treatment of melanoma. Reports from phase Ib-III clinical trials combining T-VEC with checkpoint blockade are encouraging and demonstrate potential added benefit of combination immunotherapy. OVs have recently emerged as a standard treatment option for patients with advanced melanoma. Several OVs and therapeutic combinations are in development. Immunooncolytic virotherapy combined with immune checkpoint inhibitors is promising for the treatment of advanced melanoma.

Infertility and self-rated health among Malawian women.

Infertility is prevalent and stigmatized in sub-Saharan Africa. Self-rated health, a subjective indicator that has been consistently related to objectively measured health, may be useful in evaluating the relationship between women's infertility and health. Data were from surveys conducted from July 2014 to January 2015 with women aged 15-39 years (n = 915) as part of the initial assessment in a cohort study in Lilongwe district, Malawi. We first assessed correlates of self-reported infertility among women in rural Malawi. We then used multiple logistic regression to examine associations between infertility and self-rated health. Of women surveyed, 20 percent had a history of infertility. Compared to women who had not experienced infertility, women with a history of infertility were older (p = 0.05), less educated (p = 0.01), and more likely to report depressive symptoms (p = 0.02) and forced first intercourse (p = 0.02) and to have been previously diagnosed with a sexually transmitted infection (p = 0.05). However, women with a history of infertility were not significantly more likely to report poor self-rated health (adjusted odds ratio: 1.69; 95 percent confidence interval: 0.70-4.07). Infertility was prevalent in our sample of Malawian women but was not significantly related to self-rated health, an instrument widely used in public-health research.

Intravaginal Practices and Prevalence of Sexual and Reproductive Tract Infections Among Women in Rural Malawi.

BACKGROUND: Many women engage in intravaginal practices (IVP) with a goal of improving genital hygiene and increasing sexual pleasure. Intravaginal practices can disrupt the genital mucosa, and some studies have found that IVP increases risk of acquisition of HIV and bacterial vaginosis (BV). Limited prior research also suggests significant associations between IVP, herpes simplex virus type 2 (HSV-2), and high-risk types of human papillomavirus (HPV). METHODS: We examined associations between IVP and HPV, BV, and HSV-2 among 200 women in rural Malawi participating in a clinic-based study on sexual and reproductive tract infections. We calculated prevalence ratios for the associations between frequency and type of IVP and outcomes of HPV, BV, and HSV-2. RESULTS: Intravaginal practices were commonly performed, with 95% of women reporting current use of at least 1 practice. Infections were also frequently detected: Twenty-two percent of the sample had at least 1 high-risk HPV type, 51% had BV, and 50% were HSV-2 seropositive. We observed no significant associations between type of IVP, frequency of IVP, or a combined measure capturing type and frequency of IVP-and any of the infection outcomes. CONCLUSIONS: Although both IVP and our outcomes of interest (BV, HPV, and HSV-2) were common in the study population, we did not detect associations between IVP type or frequency and any of the 3 infections. However, the high prevalence and frequency of IVP may have limited our ability to detect significant associations.

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

Comparison of Human Papillomavirus Genotype Detection in Paired Urine and Self-Collected Cervical Swabs: A Pilot Study.

OBJECTIVES: With the objective of establishing a simple, cost-effective, and effective screening tool for the screening of Human Papilloma Virus infection, the study was undertaken. MATERIAL METHODS: This pilot study was conducted on 20 urine samples of women whose cervical swabs were tested positive while screening for Human papilloma virus in asymptomatic women. RESULTS: HPV genotypes were detected in 94% (16/17) patients in urine samples by real-time PCR while a 100% detection rate (15/15) was observed in the cervical swab samples. The results of the urine and cervical swab samples, tested by the TRUPCR ®HPV high-risk genotyping kit, are shown in Table 2. HPV genotype 68 was found in 82.3% urinary samples and 100% of self-collected vaginal swab samples. Out of 16 positive urine samples, 2 were positive for HPV genotype 16 and 5 were positive for HPV genotype 18, and in cervical swab testing out of 15 positive samples, 3 were positive for HPV genotype 16, and 5 were positive for HPV genotype 18. Diagnostic accuracy of urine was found to be 98.8% (95% CI 79.43% - 100.00%). CONCLUSION: This pilot study aims to assess the accuracy of urine samples in the screening of HPV infection among asymptomatic women and establish the distribution of prevalent HPV genotypes. This may further contribute to standardizing the urine and cervical swab testing methods for cervical cancer screening strategies.

Financial Toxicity Order Set: Implementing a Simple Intervention to Better Connect Patients With Resources.

PURPOSE: Financial toxicity of cancer treatment is well described in the literature, including characterizations of its risk factors, manifestations, and consequences. There is, however, limited research on interventions, particularly those at the hospital level, to address the issue. METHODS: From March 1, 2019, to February 28, 2022, a multidisciplinary team conducted a three-cycle Plan-Do-Study-Act (PDSA) process to develop, test, and implement an electronic medical record (EMR) order set to directly refer patients to a hospital-based financial assistance program. The cycles included an assessment of the efficacy of our current practice in connecting patients experiencing financial hardship with assistance, the development and piloting of the EMR referral order, and the broad implementation of the order set across our institution. RESULTS: In PDSA cycle 1, we found that approximately 25% of patients at our institution experienced some form of financial hardship, but most patients were not connected to available resources because of our referral mechanism. In PDSA cycle 2, the pilot referral order set was deemed feasible and received positive feedback. Over the 12-month study period (March 1, 2021-February 28, 2022) of PDSA cycle 3, 718 orders were placed for 670 unique patients across interdisciplinary providers from 55 treatment areas. These referrals resulted in at least $850,000 in US dollars (USD) in financial aid in 38 patients (mean = $22,368 USD). CONCLUSION: The findings from our three-cycle PDSA quality improvement project demonstrate the feasibility and efficacy of interdisciplinary efforts to develop a hospital-level financial toxicity intervention. A simple referral mechanism can empower providers to connect patients in need with available resources.

Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer.

Purpose: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs). Experimental design: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. Results: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment. Conclusions: Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy. Statement of translational relevance: Longitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.

Use of the V-sign in the diagnosis of bucket-handle meniscal tear of the knee.

OBJECTIVE: Bucket-handle tear is a displaced vertical longitudinal tear of the meniscus. Several signs of the tear have been described on MRI but none in the axial plane. We propose to describe such a sign named the V-sign that is seen at the junction of the displaced fragment and the meniscus, which is in place. MATERIALS AND METHODS: MRI imaging of 25 surgically proven bucket-handle tears was reviewed for presence of the V-sign. Two control groups, one with normal menisci (n = 75) and one with surgically proven non-bucket-handle tears (n = 25), were also evaluated. Comparisons for presence or absence of the V-sign were performed among the three groups, and also for other commonly associated signs such as double PCL sign, double delta sign, and presence of ACL tear. Also, sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: Among those with bucket-handle tear, 72% demonstrated the V-sign while no participant in either control group had the V-sign (P ≤ 0.001). The V-sign occurred in 38% of those with double PCL sign, 55.6% with ACL tear, and 66.7% with double delta sign. The V-sign had higher sensitivity and negative predictive values than other signs related to bucket-handle tear. CONCLUSION: The V-sign, when seen on an axial plane image, is highly suggestive of bucket-handle tear. Our data suggest the benefit of using the V-sign for detecting bucket-handle tears, perhaps even above other commonly used approaches.

Factors that Influence Reading Acquisition in L2 English for Students in Bangalore, India.

This study explores the possibility of adapting specific progress-monitoring tools developed in the US for use in English-medium private schools in Bangalore. In the US, many teachers adopt progress-monitoring tools like the Dynamic Indicators of Basic Early Literacy Skills (DIBELS) and Curriculum Based Measurement (easyCBM) to keep track of their students' reading abilities. We report on Phase 1 of a longitudinal study that included three phases of data collection. Participants included 1003 students in Grades 1, 3 and 5, and 50 teachers. Both quantitative and qualitative data were collected. Results indicated that students in low-cost schools struggled on all reading measures throughout elementary school; students in middle-cost schools had below average to average scores on reading measures; and students from high-cost schools had average to above average scores on all measures. Moreover, factors like oral language proficiency in English, socio-economic status, school and curriculum increased in their significance in predicting reading as students progressed through elementary grades. Teacher data suggested that the reading goals and instructional strategies varied considerably across schools. Implications for reading instruction and practice within the Indian context will be discussed.

Femoral condylar necrosis: treatment with hyperbaric oxygen therapy.

BACKGROUND: Osteonecrosis of the knee (ONK) is a form of aseptic necrosis resulting from ischemia to subchondral bone tissue. Typically, treatment is invasive. Hyperbaric oxygen therapy (HBOT) may provide a noninvasive alternative by improving oxygenation and reperfusion of ischemic areas. This study evaluates the efficacy of HBOT in a series of ONK patients. METHODS: This retrospective study evaluates 37 ONK patients (29 male, 8 female; mean age ± 1 standard deviation: 54 ± 14); 83.7% of patients presented with Aglietti stage I-II; 16.3% presented with Aglietti stage III. Patients were treated with HBOT once a day, 5 days a week, at 2.5 atmosphere absolute with 100% inspired oxygen by mask for an average of 67.9 ± 15 sessions. Magnetic resonance imaging was performed before HBOT, within 1 year after completion of HBOT, and in 14 patients, 7 years after treatment. Oxford Knee Scores (OKSs) were recorded before HBOT and at the end of each HBOT treatment cycle. RESULTS: After the 30 sessions of HBOT, 86% of patients experienced improvement in their OKS, 11% worsened, and 3% did not change. All patients improved in OKS after 50 sessions. Magnetic resonance imaging evaluation 1 year after HBOT completion showed that edema at the femoral condyle had resolved in all but 1 patient. CONCLUSIONS: HBOT is beneficial for treating ONK. Patients experienced improvements in pain and mobility as demonstrated by improvement in OKS. Radiographic improvements were also seen upon post-treatment follow-up. Aglietti staging for the entire sample saw an aggregate decrease (P < .01) from 1.7 ± 0.7 to 0.3 ± 0.6.

Online Training in Specific Meditation Practices Improves Gratitude, Well-Being, Self-Compassion, and Confidence in Providing Compassionate Care Among Health Professionals.

Mind-body practices that intentionally generate positive emotion could improve health professionals' well-being and compassion. However, the feasibility and impact of clinician training in these practices is unknown. Data were analyzed from 3 online modules offered to health professionals: ( a) Gratitude, ( b) Positive Word, and ( c) Loving-kindness/Compassion meditation. Paired t tests were used to assess pre- to posttraining changes in gratitude (Gratitude Questionnaire), well-being (World Health Organization Well-Being Index), self-compassion (Neff's Self-Compassion Scale), and confidence in providing compassionate care (Confidence in Providing Calm, Compassionate Care Scale). The 177 enrollees included diverse practitioners (nurses, physicians, social workers, and others). Training was associated with statistically significant improvements in gratitude (38.3 ± 4.6 to 39.5 ± 3.3), well-being (16.4 ± 4.0 to 17.9 ± 4.2), self-compassion (39.5 ± 8.1 to 43.1 ± 7.6), and confidence in providing compassionate care (73.3 ± 16.4 to 80.9 ± 13.8; P < .001 for all comparisons). Brief, online training appeals to diverse health professionals and improves their gratitude, well-being, self-compassion, and confidence in providing compassionate care.