Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T‐cell therapy for diffuse large B‐cell lymphoma (DLBCL). We present a ...retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T‐cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post‐CAR T‐cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T‐cell therapy may lead to an increase in severity of CRS without decreasing infection rates.
What's new
Chimeric antigen receptor (CAR) T‐cell therapy in patients with relapsed/refractory diffuse large B‐cell lymphoma is limited by associated cytokine release syndrome, neurotoxicity, and cytopenias. Little is known about the benefits and risks of myeloid growth factor administration in CAR T‐cell therapy. This retrospective analysis reveals a significant increase in the severity but not the incidence of cytokine release syndrome in those patients that received filgrastim. There was no association of filgrastim use with the severity or incidence of neurotoxicity and infection rates. The findings call for caution in the use of myeloid growth factors in patients undergoing CAR T‐cell therapy.
Background The 7th edition of the AJCC Cancer Staging Manual (AJCC-7) includes substantial changes for colon cancer (CC), which are particularly complex in patients with stage II and III disease. We ...used a national cancer database to determine if these changes improved prediction of survival. Study Design The database of the Surveillance, Epidemiology and End Results Program was queried to identify patients with pathologically confirmed stage I to III CC diagnosed between 1988 and 2008. Colon cancer was staged by the 6th edition of the AJCC Cancer Staging Manual (AJCC-6) and then restaged by AJCC-7. Five-year disease-specific survival and overall survival were compared. Results After all exclusion criteria were applied, AJCC-6 and AJCC-7 staging was possible in 157,588 patients (68.9%). Bowker's test of symmetry showed that the number of patients per substage was different for AJCC-6 and AJCC-7 (p < 0.001). The Akaike information criteria comparison showed superior fit with the AJCC-7 model (p < 0.001). However, although AJCC-7 staging yielded a progressive decrease in disease-specific survival and overall survival of patients with stage IIA (86.3% and 72.4%, respectively), IIB (79.4% and 63.2%, respectively), and IIC (64.9% and 54.6%, respectively) CC, disease-specific survival and overall survival of patients with stage IIIA disease increased (89% and 79%, respectively). Subset analysis of patients with >12 lymph nodes examined did not affect this observation. Conclusions The AJCC-7 staging of CC does not address all survival discrepancies, regardless of the number of lymph nodes examined. Consideration of other prognostic factors is critical for decisions about therapy, particularly for patients with stage II CC.
Abstract
Objective
To evaluate the feasibility, acceptability, and preliminary efficacy of a mind–body intervention for moderate to severe primary dysmenorrhea (PD).
Design
Open trial (single arm).
...Setting
Academic medical school.
Subjects
A total of 20 young adult women with moderate to severe primary dysmenorrhea were included across four separate intervention groups.
Methods
All participants received five 90-minute sessions of a mind–body intervention and completed self-report measures of menstrual pain, depression, anxiety, somatization, and pain catastrophizing at baseline, post-treatment, and at one-, two-, three-, and 12-month follow-up. Self-report of medication use and use of skills learned during the intervention were also collected at all follow-up points.
Results
Participants reported significantly lower menstrual pain over time compared with baseline. No changes in anxiety, depression, or somatization were observed, although pain catastrophizing improved over time. Changes in menstrual pain were not associated with changes in medication use or reported use of skills.
Conclusions
A mind–body intervention is a promising nondrug intervention for primary dysmenorrhea, and future research should focus on testing the intervention further as part of a randomized clinical trial.
To elucidate molecular pathways contributing to metastatic cancer progression and poor clinical outcome in serous ovarian cancer.
Poor survival signatures from three different serous ovarian cancer ...datasets were compared and a common set of genes was identified. The predictive value of this gene signature was validated in independent datasets. The expression of the signature genes was evaluated in primary, metastatic, and/or recurrent cancers using quantitative PCR and in situ hybridization. Alterations in gene expression by TGF-β1 and functional consequences of loss of COL11A1 were evaluated using pharmacologic and knockdown approaches, respectively.
We identified and validated a 10-gene signature (AEBP1, COL11A1, COL5A1, COL6A2, LOX, POSTN, SNAI2, THBS2, TIMP3, and VCAN) that is associated with poor overall survival (OS) in patients with high-grade serous ovarian cancer. The signature genes encode extracellular matrix proteins involved in collagen remodeling. Expression of the signature genes is regulated by TGF-β1 signaling and is enriched in metastases in comparison with primary ovarian tumors. We demonstrate that levels of COL11A1, one of the signature genes, continuously increase during ovarian cancer disease progression, with the highest expression in recurrent metastases. Knockdown of COL11A1 decreases in vitro cell migration, invasion, and tumor progression in mice.
Our findings suggest that collagen-remodeling genes regulated by TGF-β1 signaling promote metastasis and contribute to poor OS in patients with serous ovarian cancer. Our 10-gene signature has both predictive value and biologic relevance and thus may be useful as a therapeutic target.
Background
There has been an increasing trend toward contralateral prophylactic mastectomy (CPM) in the management of breast cancer (BCa). This study’s objective was to compare clinicopathologic ...characteristics of BCa patients who elected CPM to those who elected unilateral total mastectomy (UTM) and to determine whether CPM improved survival.
Methods
Comparison was performed on 355 patients with stage 0–III BCa matched by age and stage who underwent mastectomy from 1995 to 2008: 177 patients had CPM; 178 patients had UTM. Clinicopathological characteristics and survival outcomes were analyzed.
Results
Women who underwent preoperative MRI were twice as likely to have CPM (40.9 vs. 19.7%,
P
< 0.001). MRI identified additional suspicious foci in 45% CPM and 19% UTM. Patients with history of previous breast biopsies, family history, or BRCA mutation were more likely to choose CPM than UTM (40.1 vs. 24%,
P
= 0.001; 64.3 vs. 41.4%,
P
< 0.001; 20.3 vs. 6.5%,
P
= 0.04, respectively). CPM patients elected nipple preservation (26 vs. 5.2%,
P
< 0.001) and immediate reconstruction more often (92.2 vs. 73.5%,
P
< 0.001); UTM patients were more likely to have attempted breast conservation prior to mastectomy (52.8 vs. 39.5%,
P
= 0.01). CPM identified occult BCa in 11 patients (6.6%), and three UTM patients (1.7%) developed contralateral BCa. With median follow-up of 61 months, by univariable/multivariable analyses, CPM did not improve overall, disease-free, or distant metastases-free survival.
Conclusion
Factors that may influence choice of CPM included preoperative MRI, history of prior breast biopsies, immediate reconstruction, nipple preservation, family history, and BRCA status. Those who chose CPM did not have improved survival.
Abstract
Placenta accreta spectrum (PAS) is a high-risk obstetrical condition associated with significant morbidity and mortality. Current clinical screening modalities for PAS are not always ...conclusive. Here, we report a nanostructure-embedded microchip that efficiently enriches both single and clustered circulating trophoblasts (cTBs) from maternal blood for detecting PAS. We discover a uniquely high prevalence of cTB-clusters in PAS and subsequently optimize the device to preserve the intactness of these clusters. Our feasibility study on the enumeration of cTBs and cTB-clusters from 168 pregnant women demonstrates excellent diagnostic performance for distinguishing PAS from non-PAS. A logistic regression model is constructed using a training cohort and then cross-validated and tested using an independent cohort. The combined cTB assay achieves an Area Under ROC Curve of 0.942 (throughout gestation) and 0.924 (early gestation) for distinguishing PAS from non-PAS. Our assay holds the potential to improve current diagnostic modalities for the early detection of PAS.
IMPORTANCE Nonanatomic factors, such as histologic grade and biomarkers, can guide breast cancer management
but are not included in the current TNM staging system. OBJECTIVE To use as an example the ...triple-negative phenotype (TNP) defined by the absence of estrogen
receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) to examine
whether such inclusion improves the prognostic accuracy of TNM staging for breast cancer. DESIGN, SETTING, AND PARTICIPANTS Women diagnosed with primary invasive ductal breast cancer from January 1, 1991, through December
31, 2008, were identified from a prospective institutional database. Excluded were patients who
received neoadjuvant therapy, those whose staging information was incomplete, or those whose tumor
lacked ER, PR, and HER2 data. Breast cancers were categorized by TNM stage and by the presence or
absence of TNP. MAIN OUTCOMES AND MEASURES Overall survival at 5 years. RESULTS Database review identified 1842 consecutive eligible patients with breast cancer. When patients
were stratified by TNM stage, overall survival curves for those with TNP breast cancer matched those
for patients whose non-TNP breast cancer was 1 TNM stage higher. Multivariable analysis showed that
TNP status was a powerful prognostic variable, and the likelihood ratio test revealed that the
prognostic accuracy of the TNM staging system that incorporated TNP was superior to the current TNM
staging system (P < .001). A TNM staging system that incorporated
TNP reduced early-stage compression by 15%. CONCLUSIONS AND RELEVANCE The internationally recognized and easily reproducible examination of ER, PR, and HER2 status
exemplifies how nonanatomic factors can improve the prognostic accuracy of breast cancer
staging.
Debate exists surrounding the morphological evolution of the submandibular gland (SMG) with aging, and due to the inconclusive influence of patient demographics, there remains hesitancy to ...incorporate targeted interventions of the SMG into clinical practice.
To determine whether SMG ptosis, hypertrophy, or both is the primary etiology behind increased submandibular volume as one ages.
MRI segmentation was used to calculate the total and inframandibular (IM) volume and height of the SMG. Adult subjects with prior MRIs of the head and neck were used for analysis. Those with pathology or artifact compromising the SMG were excluded. Subjects were divided into four age-defined cohorts, for clinical applicability.
The study included 129 patients (Females n=65; Male n=64) with a mean age of 52.3 (range 20-85). No significant change in total SMG volume was observed between the reference group and all cohorts. IM-SMG volume of the reference cohort was 5.77 cm 3. All 3 cohorts had a greater IM-SMG volume compared to the reference group. The 45-54 cohort had a mean volume of 6.7 cm 3 (p=.4), the 55-64 cohort, 7.5 cm 3 (p=.01), and the 55-64 cohort, 7.2 cm 3 (p=.01). Male sex and overweight or obese BMI were associated with significantly larger total and IM-SMG volumes.
The novel finding of a significantly larger IM-SMG volume with no change in total volume provides evidence for SMG ptosis rather than hypertrophy as a significant contributor to age-related submandibular fullness. Given no significant difference in total volume or height with aging emphasizes glandular descent.
Hypermethylation of the promoter region of tumor-related genes (TRGs) has been shown to silence gene expression during melanoma progression, whereas microRNA-29(miR-29) has been found to downregulate ...DNA methyltransferases DNMT3A and DNMT3B which were shown as essential to the methylation of TRGs. We hypothesized that the expression level of miR-29 is associated to TRG methylation status and may have prognostic utility in melanoma. AJCC stage I-IV cutaneous melanoma paraffin-embedded archival tissue (PEAT) specimens (n=149) were assessed. Expression of miR-29 isoforms a, b, and c were analyzed by reverse-transcription quantitative real-time polymerase chain reaction(RT-qPCR). Expression of DNMT3A and DNMT3B was assessed by immunohistochemistry(IHC) on defined clinically annotated tissue microarrays (TMA) of AJCC stage III melanoma lymph node metastases. Promoter region CpG island methylation status of RASSF1A, TFPI-2, RAR-β, SOCS, GATA4 and genomic repeat sequence MINT17 and MINT31 were previously evaluated in melanoma tissues. Only miR-29c isoform expression was correlated to advancing AJCC stages in melanoma. miR-29c expression was significantly downregulated in AJCC stage IV melanoma tumors compared to primary melanomas. Hypermethylation status of TRGs and non-coding MINT loci in different stages of melanoma showed an inverse association with miR-29c expression. Overall, an increase in miR-29c expression inversely correlated to both DNMT3A and DNMT3B protein expression in melanomas. Expression of DNMT3B and miR-29c were significantly (p=0.004 and p=0.002, respectively) associated with overall survival(OS) in AJCC stage III melanoma patients by multivariate analysis. The studies demonstrated that both miR-29c and DNMT3B have significant roles in melanoma progression, and may be useful epigenetic biomarkers for disease outcome.
Fluid restriction and diuretic management are mainstays in the postoperative management of cardiac patients, at risk of volume overload and its deleterious effects on primary cardiac function and ...multi-organ systems. The importance of fluid homeostasis is further emphasized among orthotopic heart transplant recipients (OHT). We sought to investigate the relationship between postoperative volume overload, mortality, and allograft dysfunction among pediatric OHT recipients within 1-year of transplantation. This is a retrospective cohort study from a single pediatric OHT center. Children under 21 years undergoing cardiac transplantation between 2010 and 2018 were included. Cumulative fluid overload (cFO) was assessed as percent fluid accumulation adjusted for preoperative body weight. Greater than 10% cFO defined those with postoperative cFO and a comparison of postoperative cFO vs. no postoperative cFO (< 5%) is reported. 102 pediatric OHT recipients were included. Early cFO at 72 h post-OHT occurred in 14% and overall cFO at 1-week post-OHT occurred in 23% of patients. Risk factors for cFO included younger age, lower weight, and postoperative ECMO. Early cFO was associated with postoperative mortality at 1-year, OR 8.6 (95% CI 1.4, 51.6),
p
= 0.04, independent of age and weight. There was no significant relationship between cFO and allograft dysfunction, measured by rates of clinical rejection and cardiopulmonary filling pressures within 1-year of transplant. Early postoperative volume overload is prevalent and associated with increased risk of death at 1-year among pediatric OHT recipients. It may be an important postoperative marker of transplant survival, and this relationship warrants further clinical investigation.
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