Treatment-related Risk Factors Research Articles

Risk Factors Related to Acute Radiation Dermatitis in Breast Cancer Patients After Radiotherapy: A Systematic Review and Meta-Analysis

BackgroundAcute radiation dermatitis (ARD) is the most common acute response after adjuvant radiotherapy in breast cancer patients and negatively affects patients’ quality of life. Some studies have reported several risk factors that can predict breast cancer patients who are at a high risk of ARD. This study aimed to identify patient- and treatment-related risk factors associated with ARD.MethodsPubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and WanFang literature databases were searched for studies exploring the risk factors in breast cancer patients. The pooled effect sizes, relative risks (RRs), and 95% CIs were calculated using the random-effects model. Potential heterogeneity and sensitivity analyses by study design, ARD evaluation scale, and regions were also performed.ResultsA total of 38 studies composed of 15,623 breast cancer patients were included in the analysis. Of the seven available patient-related risk factors, four factors were significantly associated with ARD: body mass index (BMI) ≥25 kg/m2 (RR = 1.11, 95% CI = 1.06–1.16, I 2 = 57.1%), large breast volume (RR = 1.02, 95% CI = 1.01–1.03, I 2 = 93.2%), smoking habits (RR = 1.70, 95% CI = 1.24–2.34, I 2 = 50.7%), and diabetes (RR = 2.24, 95% CI = 1.53–3.27, I 2 = 0%). Of the seven treatment-related risk factors, we found that hypofractionated radiotherapy reduced the risk of ARD in patients with breast cancer compared with that in conventional fractionated radiotherapy (RR = 0.28, 95% CI = 0.19–0.43, I 2 = 84.5%). Sequential boost and bolus use was significantly associated with ARD (boost, RR = 1.91, 95% CI = 1.34–2.72, I 2 = 92.5%; bolus, RR = 1.94, 95% CI = 1.82–4.76, I 2 = 23.8%). However, chemotherapy regimen (RR = 1.17, 95% CI = 0.95–1.45, I 2 = 57.2%), hormone therapy (RR = 1.35, 95% CI = 0.94–1.93, I 2 = 77.1%), trastuzumab therapy (RR = 1.56, 95% CI = 0.18–1.76, I 2 = 91.9%), and nodal irradiation (RR = 1.57, 95% CI = 0.98–2.53, I 2 = 72.5%) were not correlated with ARD. Sensitivity analysis results showed that BMI was consistently associated with ARD, while smoking, breast volume, and boost administration were associated with ARD depending on study design, country of study, and toxicity evaluation scale used. Hypofractionation was consistently shown as protective. The differences between study design, toxicity evaluation scale, and regions might explain a little of the sources of heterogeneity.ConclusionThe results of this systematic review and meta-analysis indicated that BMI ≥ 25 kg/m2 was a significant predictor of ARD and that hypofractionation was consistently protective. Depending on country of study, study design, and toxicity scale used, breast volume, smoking habit, diabetes, and sequential boost and bolus use were also predictive of ARD.

Risk Factors for Late Persistent Fatigue After Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer: An Analysis From the EMBRACE-I Study

This study aimed to evaluate patient- and treatment-related risk factors for late persistent fatigue within the prospective, multicenter EMBRACE-I study. Fatigue was prospectively assessed (Common Terminology Criteria for Adverse Events, version 3) at baseline and during regular follow up in 993 patients with locally advanced cervical cancer after treatment with chemoradiotherapy and magnetic resonance imaging-guided brachytherapy. Risk factors for baseline and late persistent fatigue were evaluated with multivariable logistic regression. Late persistent fatigue was defined when either grade ≥1 or ≥2 was scored in at least half of the follow ups. The median follow-up time was 57 months. Baseline fatigue grade ≥1/≥2 (35.8%/6.3%, respectively) was associated with preexisting comorbidities, World Health Organization performance status, being underweight, severe pain, and tumor volume. Late persistent grade ≥1/≥2 fatigue (36.3%/5.8%, respectively) was associated with patient-related factors (baseline fatigue, younger age, obesity) along with the size of irradiated volumes and the level of radiation doses from external beam radiation therapy (EBRT) and brachytherapy (EBRT: V43Gy, V57Gy; EBRT+brachytherapy: V60Gy equivalent dose in 2-Gy fractions). Large-volume lymph node (LN) boost increased the risk for late persistent fatigue grade ≥2 by 18% and 5% in patients with and without baseline fatigue, respectively, compared with no LN boost. The risk for late persistent fatigue grade ≥1 increased by 7% and 4% with V43Gy <2000 cm³ versus >3000 cm³ in patients with and without baseline fatigue, respectively. Late persistent grade ≥1 fatigue occurred in 13% of patients without late persistent organ-related symptoms (gastrointestinal, genitourinary, and vaginal) versus 34% to 43%, 50% to 58%, and 73% in patients suffering from persistent symptoms involving 1, 2, or 3 organs, respectively. Late persistent fatigue occurs in a considerable number of patients after chemoradiotherapy, and is associated with patient-related factors, the size of volumes irradiated to intermediate and high EBRT and brachytherapy doses, and other persistent organ-related morbidity. These findings support the importance of ongoing efforts to better tailor the target dose and reduce irradiation of healthy tissue without compromising target coverage, using highly conformal EBRT and brachytherapy techniques.

Urinary Beta-2-Microglobulin and Late Nephrotoxicity in Childhood Cancer Survivors.

The objectives of this study were to evaluate urinary beta-2-microglobulin (β2M) levels in long-term childhood cancer survivors and to establish its association with anticancer drug-induced nephrotoxicity. The study consisted of 165 childhood cancer survivors (CCS) who were in continuous complete remission. We reported that CCS had a significantly higher level of β2M (p < 0.001) and β2M/Cr. ratio (p < 0.05) than healthy peers. Among all participants, 24 (14.5%) had decreased eGFR (<90 mL/min/1.73 m2). A significant positive correlation between β2M/Cr. ratio and body mass index (coef. 14.48, p = 0.046) was found. Furthermore, higher levels of urinary β2M were detected among CCS with a longer follow-up time (over 5 years) after treatment. Subjects with decreased eGFR showed statistically higher urinary β2M levels (20.06 ± 21.56 ng/mL vs. 8.55 ± 3.65 ng/mL, p = 0.007) compared with the healthy peers. Twelve survivors (7.2%) presented hyperfiltration and they had higher urinary β2M levels than CCS with normal glomerular filtration (46.33 ± 93.11 vs. 8.55 ± 3.65 ng/mL, p = 0.029). This study did not reveal an association between potential treatment-related risk factors such as chemotherapy, surgery, radiotherapy, and the urinary β2M level. The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed (p < 0.05). We demonstrated that urinary beta-2-microglobulin may play a role in the subtle kidney injury in childhood cancer survivors; however, the treatment-related factors affecting the β2M level remain unknown. Further prospective studies with a longer follow-up time are needed to confirm the utility of urinary β2M and its role as a non-invasive biomarker of renal dysfunction.

Predictors of Acute Transfer and Mortality Within 6 Months From Admission to an Inpatient Rehabilitation Facility for Patients With Brain Tumors

ObjectiveTo obtain useful information for clinicians in evaluating patients with brain tumors for transfer to and subsequent care in inpatient rehabilitation facilities (IRFs). DesignRetrospective chart review. SettingInpatient rehabilitation facility. ParticipantsA total of 208 adults with either initial or recurrent brain tumors who were admitted to an IRF between January 2017 and December 2018 after an acute hospitalization. InterventionsNone Main Outcome MeasuresTransfer from an IRF to an acute care hospital and mortality within 6 months from admission to an IRF. ResultsOf the 208 patients who met inclusion criteria, 20.2% were transferred to an acute care hospital during the IRF stay, which was associated with prior chemotherapy, steroid use, and laterality of tumor. In total, 36.9% of patients with brain tumors died within 6 months of an IRF admission that was associated with recurrent tumor diagnosis, prior chemotherapy, prior neurosurgical intervention, prior neurostimulant use, use of steroids, isocitrate dehydrogenase and O6-methyl-guanyl-methyl-transferase biomarkers, and laterality and location of tumor. ConclusionsPatients with brain tumors have a notable potential for acute hospital transfer and mortality within 6 months of IRF stay, with several tumor- and treatment-related risk factors. This information can help identify functional goals, identify high risk patients, enable closer clinical monitoring, and facilitate focused care discussions at IRFs.

Bleeding Risk in Patients with Multiple Myeloma Treated for Venous Thromboembolism

▪Introduction:Multiple myeloma diagnosis is associated with a 10-15% absolute risk of venous thromboembolism (VTE) due to disease-related (i.e., vascular inflammation, hyperviscosity) and treatment-related risk factors (i.e., immunomodulatory drugs [IMiDs], high-dose dexamethasone). This has led to ongoing clinical trials to determine the best thromboprophylaxis strategy. In contrast, the risk of major bleeding following incident VTE events in patients with MM is not well described. We conducted a real-world analysis of bleeding complications in MM following anticoagulation treatment for VTE.Methods:The IBM MarketScan Commercial Claims Database was used to identify adults with MM diagnosis and an incident VTE event between 2011 and 2019. MM and VTE were defined as 1 inpatient or 2 outpatient claims based on International Classification of Diseases (ICD) 9th and 10 th Revision codes, and at least 1 prescription for anticoagulation within 31 days of first VTE claim. IMiD-related VTE was defined in subjects with an IMiD prescription prior to the VTE event. Major bleeding was defined as bleeding requiring hospitalization using inpatient ICD codes as previously validated (Cunningham algorithm). Patients were followed from index VTE and initiation of anticoagulation to first major bleeding event, disenrollment (due to death or other reasons) or December 31, 2019. Descriptive statistics were used to calculate the rate of major bleeding. Cox regression was used to determine risk factors associated with major bleeding.Results:Our population included 1,605 patients with a diagnosis of multiple myeloma and an incident VTE event requiring treatment. Anticoagulant agent of choice was warfarin in 45.7% (734), low-molecular weight heparin (LMWH) in 29% (466), and direct oral anticoagulants (DOAC) in 25.3% (405). There were no significant differences in age/sex distribution, comorbidity burden, history of significant bleeding, or use of IMiD across the different types of anticoagulation (Table 1). Hospitalized bleeding occurred in 63 (3.9%) patients during an average follow-up of 1.6 years, yielding an overall incidence rate of major bleeding in multiple myeloma patients starting anticoagulation for a new VTE event of 24.1 per 1,000 person-years. Adjusting for age and sex, risk factors significantly associated with risk of major bleeding included Charlson comorbidy index [CCI] (per standard deviation [SD] increment, HR 1.29, 95%CI 1.03 - 1.62), diabetes (HR 1.71, 95%CI 1.06 - 2.92), and liver disease (HR 1.96, 95%CI 1.04 - 3.68). The use of IMiDs was not associated with increased risk of major bleeding (Table 2). The cumulative incidence of major bleeding by VTE anticoagulation strategy in multiple myeloma was 4.8% in warfarin group and 3.2% in the LMWH and DOAC groups, though the difference was not statistically significant after adjusting for age and sex. The estimated incidence rate of bleeding was 25.7, 20.1, and 25.2 per 1,000 person-years for patients treated with warfarin, LMWH, and DOACs, respectively. In an adjusted model for age, sex, CCI, diabetes and liver disease, patients treated with LMWH and DOACs had HR for major bleeding of 0.91 and 0.82, respectively, compared to anticoagulation with warfarin, though this was not statistically significant.Discussion:In a real-world analysis of commercial claims data, the rate of major bleeding in patients with multiple myeloma receiving anticoagulation for VTE appears to be comparable to those reported in other subsets of cancer associated VTE. Surprisingly, almost half of identified patients were treated with warfarin, a non-preferred option in this setting. The point estimate of major bleeding was lower in patients treated with LMWH or DOACs compared to warfarin, though the association was not statistically significant and larger studies are needed. Higher CCI, diabetes and liver disease were clinical factors associated with higher risk of major bleeding and may be included in risk assessment models to help clinicians assess individual bleeding risk in patients with multiple myeloma treated for VTE. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Overweight in the Dutch National Cohort of Long-Term Survivors of Childhood Cancer

BACKGROUNDOverweight is a common problem in the general population, but occurs more frequently among childhood cancer survivors (CCS) and is regarded as a late adverse effect. However, risk factors are not fully elucidated and it is often disguised in CCS because they can have normal weight but high fat percentage (fat%) on dual-energy X-ray absorptiometry (DXA, gold standard). We aimed to assess overweight prevalence in a nationwide survivor cohort, to clarify risk factors and to identify which measurement method captures overweight best.METHODSThe prevalence of overweight and obesity (body mass index (BMI) ≥25 and ≥30 kg/m 2) was assessed in the Dutch nationwide cohort of adult CCS treated between 1963 and 2002. Risk factors for overweight were analyzed using multivariable logistic regression models. In addition, overweight prevalence was calculated according to fat%, waist circumference (WC), waist/hip ratio (WHR) and waist/height ratio (WHtR). The validity of BMI, WC, WHR and WHtR for characterizing obesity, compared to fat% (expressed as false-negative percentage and in logistic regression models to identify treatment-related risk factors for disguised overweight) was studied.RESULTSA total of 2,338 (51.2% male) survivors (54.7% hematologic malignancies) participated, with mean age 35.5 (±9.3) years and 28.3 (±8.4) years follow-up. In men and women respectively, overweight prevalence was 45.9% and 43.8%, for obesity this was 11.2% and 15.5%.Risk factors for overweight included overweight at cancer diagnosis (adjusted odds ratio (aOR) 3.43, p<0.001), cranial radiotherapy (CRT, aOR 3.27, p<0.001) and growth hormone deficiency (GHD) (unadjusted OR 2.28, p<0.001, after adjustment the effect partially disappeared, aOR 1.60, p=0.072). Previous treatment with corticosteroids was not associated with overweight.Using BMI, WC, WHR and WHtR, similar overweight prevalence was observed. However, this was 58.4% in men and even 83.7% in women when measured with DXA. Disguised overweight was more frequent after treatment with abdominal radiotherapy, high dose anthracyclines and stem cell transplantation (SCT) (aOR up to 3.37).CONCLUSIONSOverweight occurs in almost half of all long-term CCS, and risk factors include overweight at cancer diagnosis, CRT and potentially GHD. DXA identified overweight in an additional 25% of survivors. In CCS treated with abdominal irradiation, anthracyclines and SCT, overweight is more often missed with conventional methods. Hence, in these risk groups DXA needs serious consideration in surveillance, to enable early intervention and prevent complications of overweight including diabetes and atherosclerotic disease. DisclosuresNo relevant conflicts of interest to declare.

Quantifying Risk of Ipsilateral Arm Lymphedema Causing Functional Impairment in Breast Cancer Patients: Results From a Prospective, Multi-Centre International Study of Treatment Toxicity

Breast cancer related lymphedema (BCRL) of the ipsilateral arm remains a highly morbid long-term side effect of breast cancer treatment, one which can lead to functional impairment. We sought to independently examine clinical and treatment related risk factors for the development of lymphedema-associated functional impairment.The REQUITE Consortium is a multi-center cohort study of patients with breast cancer treated at 26 hospitals in 8 countries from 2014-2017 who were prospectively evaluated for treatment toxicity. All patients received lumpectomy and adjuvant radiotherapy (RT) with or without chemotherapy at the discretion of their treating physician, and were enrolled prior to beginning RT. Arm circumference measurements and patient reported outcome (PRO) toxicity assessments were obtained before RT and annually after RT for a minimum of two years. Lymphedema-associated functional impairment was determined by PRO lymphedema that constrains activity and self-care. Grade 2+ BCRL was defined as ≥10% discrepancy in ipsilateral arm circumference compared to the contralateral arm. Cumulative incidence curves were stratified by the extent of axillary surgery and RT. Multivariable Cox models adjusted for axillary surgery, radiation, body mass index, and chemotherapy.The cohort included 1921 patients followed for a median of 27 months: 1345 received sentinel node biopsy (SLNBx) alone, 90 received SLNBx and regional lymph node RT (RLNR), 136 received axillary node dissection (ALND) alone, 200 received ALND+RLNR, and 150 received no axillary treatment. Invasive breast cancer was present in 1678 (87%) patients, while 591 (30.7%) received chemotherapy. Among the whole cohort, four times as many patients reported functional impairment than Grade 2+ BCRL (4.6% vs 1.1%). On multivariable analysis, taxane-based chemotherapy resulted in a significantly higher risk of functional impairment (hazard ratio [HR] 1.90, P = 0.01), as did ALND (HR 11.92, P = 0.02) and higher BMI (HR 1.06, P < 0.001). Although RLNR and SLNBx did not confer significantly higher risk on multivariable analysis when evaluated individually, the SLNBx+RLNR treatment group demonstrated a trend towards significantly higher risk of functional impairment compared to no axillary treatment (HR 8.21, P = 0.05). The risk of functional impairment was highest in those receiving ALND+RLNR (HR 15.52, P = 0.008) and ALND alone (HR 14.58, P = 0.01), with a 3-year cumulative incidence rate of 21% in both groups.Patients treated with taxane-based chemotherapy and those receiving more extensive axillary surgery are at significantly higher risk of developing ipsilateral arm lymphedema causing functional impairment. Additional variation in this toxicity may be due to genetic predisposition, which is under investigation in REQUITE. Lymphedema-associated functional impairment occurred substantially more often than Grade 2+ BCRL, highlighting the importance of capturing PROs.

Severity and Persistency of Late Gastrointestinal Morbidity in Locally Advanced Cervical Cancer: Lessons Learned From EMBRACE-I and Implications for the Future

The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer. Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups. The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms tovarying degrees. Among treatment-related factors, rectum D2cm3 and the International Commission on Radiation Units and Measurements recto-vaginal reference point (ICRU RV-RP) correlated with G ≥3 anus/rectum events and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps, and difficulty in bowel control. Bowel D2cm3 correlated with G ≥3 sigmoid and colon/small bowel events and moderate/persistent diarrhea and flatulence. For external beam radiation therapy (EBRT), prescription dose correlated with G ≥3 anus/rectum, diarrhea, and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G ≥3 sigmoid events, moderate/persistent diarrhea, proctitis, and cramps. The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D2cm3, ICRU RV-RP , and bowel D2cm3 are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45 Gy than 50 Gy and increased with larger V57Gy.

Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors’ late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy’s long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines’ possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect’s vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

Late Kidney Effects of Childhood Cancer and Cancer Therapies.

Childhood cancer therapy carries a high risk of treatment-related toxicities and complications that can impact kidney function. Although many of these adverse effects in the acute setting are well described, less is known about the latent effects of childhood cancer treatments on long-term kidney health. With decades of advancements in treatment protocols for many pediatric malignancies, more children than ever before are surviving into adulthood after being cured of their disease and with lower long-term morbidity. Although there is decreased prevalence of many chronic health conditions in cancer survivors, including gastrointestinal, endocrine, and musculoskeletal disorders, the long-term risk of kidney dysfunction has increased. In this review, we summarize the epidemiology of kidney disease in survivors of childhood cancer and describe the treatment-related risk factors associated with long-term impairment of kidney health. We organize this review by specific kidney disease-related outcomes of interest (chronic electrolyte abnormalities, CKD, proteinuria, and hypertension) to highlight what specific aspects of cancer treatment have been associated with these outcomes. Finally, we conclude by comparing different clinical practice guidelines that exist for long-term kidney function monitoring and include recommendations for when a childhood cancer survivor would benefit from long-term nephrology care.

Healing the Index Tibial Nonunion: Risk Factors for Development of a Recalcitrant Nonunion in 222 Patients.

To compare and stratify the healing rates after our index nonunion surgery using contemporary methods of fixation, report the prevalence of recalcitrant non-union, and identify specific demographic, injury, and treatment-related risk factors for the development of a recalcitrant nonunion. Retrospective analysis of a prospectively collected database. Academic Level 1 Trauma Center. Two hundred twenty-two tibial nonunions treated with internal fixation by a single surgeon. Bivariate and multivariate regression analysis were performed to compare healing rates by the type of fixation and graft augmentation and to identify specific demographic, injury, and treatment-related risk factors for the development of a recalcitrant nonunion. Of the 222 patients, 162 (73%) healed as intended and 51 (23%) required 1 or more subsequent interventions to achieve union (96%). Nine fractures (4%) failed to unite. The 60 fractures (27%) that required a subsequent intervention(s) or failed to consolidate were defined as recalcitrant nonunions. There were no statistically significant differences in the recalcitrant rate when we compared plates versus nails or types of bone graft. Risk factors for developing a recalcitrant nonunion were multifactorial and included grade III open fractures, compartment syndrome, deep infection, and 2 or more prior surgical procedures. Internal fixation remains a successful method of treatment for most tibial nonunions. However, 27% of patients required a subsequent intervention because of failure to heal our index nonunion procedure. Factors that are associated with recalcitrant nonunions were a grade III open fracture, compartment syndrome, deep infection, and 2 or more or more prior surgical procedures. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Pulmonary Toxicity After Total Body Irradiation - Critical Review of the Literature and Recommendations for Toxicity Reporting.

IntroductionTotal body irradiation is an effective conditioning regimen for allogeneic stem cell transplantation in pediatric and adult patients with high risk or relapsed/refractory leukemia. The most common adverse effect is pulmonary toxicity including idiopathic pneumonia syndrome (IPS). As centers adopt more advanced treatment planning techniques for TBI, total marrow irradiation (TMI), or total marrow and lymphoid irradiation (TMLI) there is a greater need to understand treatment-related risks for IPS for patients treated with conventional TBI. However, definitions of IPS as well as risk factors for IPS remain poorly characterized. In this study, we perform a critical review to further evaluate the literature describing pulmonary outcomes after TBI.Materials and MethodsA search of publications from 1960-2020 was undertaken in PubMed, Embase, and Cochrane Library. Search terms included “total body irradiation”, “whole body radiation”, “radiation pneumonias”, “interstitial pneumonia”, and “bone marrow transplantation”. Demographic and treatment-related data was abstracted and evidence quality supporting risk factors for pulmonary toxicity was evaluated.ResultsOf an initial 119,686 publications, 118 met inclusion criteria. Forty-six (39%) studies included a definition for pulmonary toxicity. A grading scale was provided in 20 studies (17%). In 42% of studies the lungs were shielded to a set mean dose of 800cGy. Fourteen (12%) reported toxicity outcomes by patient age. Reported pulmonary toxicity ranged from 0-71% of patients treated with TBI, and IPS ranged from 1-60%. The most common risk factors for IPS were receipt of a TBI containing regimen, increasing dose rate, and lack of pulmonary shielding. Four studies found an increasing risk of pulmonary toxicity with increasing age.ConclusionsDefinitions of IPS as well as demographic and treatment-related risk factors remain poorly characterized in the literature. We recommend routine adoption of the diagnostic workup and the definition of IPS proposed by the American Thoracic Society. Additional study is required to determine differences in clinical and treatment-related risk between pediatric and adult patients. Further study using 3D treatment planning is warranted to enhance dosimetric precision and correlation of dose volume histograms with toxicities.

Intraoperative fluorescence angiography as an independent factor of anastomotic leakage and a nomogram for predicting leak for colorectal anastomoses.

Colorectal anastomotic leakage (AL) is a life-threatening complication, which increases morbidity, hospital stay and cost of treatment. The aim of this study is to identify risk factors, including intraoperative indocyanine green fluorescence angiography (ICG FA), associated with the leak of stapled colorectal anastomosis. Four hundred twenty-nine consecutive patients underwent surgery between 2017 and 2019 for benign (n=10, 2.3%) or malignant (n=419, 97.7%) and rectal (n=349, 81.4%) or distal sigmoid (n=80, 18.6%) lesions with double-stapling technique reconstruction were included into retrospective study. Univariate analysis and multivariate logistic regression of the tumor-, patient- and treatment-related risk factors of AL was performed. An AL developed in 52 patients (12.1%). In multivariate analysis following variables were independently associated with AL; male sex (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.9-7.7; P<0.01), anastomosis at ≤6.5 cm from anal verge (OR, 3.1; 95% CI, 1.3-7.5; P=0.01), and age of ≤62.5 years (OR, 2.1; 95% CI, 1.1-4.1; P=0.03). ICG FA was found as independent factor reducing colorectal AL rate (OR, 0.4; 95% CI, 0.2-0.8; P=0.02). A nomogram with high discriminative ability (concordance index, 0.81) was created. ICG FA is a modifiable surgery-related risk factor associated with a decrease of colorectal AL rate. A suggested nomogram, which takes into consideration ICG FA, might be helpful to identify the individual risk of AL.

Pediatric Invasive Fungal Risk Score in Cancer and Hematopoietic Stem Cell Transplantation Patients With Febrile Neutropenia.

Invasive fungal diseases (IFDs) are opportunistic infections that result in significant morbidity and mortality in pediatric oncology patients. Predictive risk tools for IFD in pediatric cancer are not available. We conducted a 7-year retrospective study of pediatric oncology patients with a diagnosis of febrile neutropenia at UCM Comer Children's Hospitals. Fourteen clinical, laboratory, and treatment-related risk factors for IFD were analyzed. Stepwise variable selection for multiple logistic regression was used to develop a risk prediction model for IFD. Two comparative analyses have been conducted: (i) all suspected IFD cases and (ii) all proven and probable IFD cases. A total of 667 febrile neutropenia episodes were identified in 265 patients. IFD was diagnosed in 62 episodes: 13 proven, 27 probable, and 22 possible. In the final multiple logistic regression models, 5 variables were independently significant for both analyses: fever days, neutropenia days, hypotension, and absolute lymphocyte count <250 at the time of diagnosis. The odds ratio and a relative weight for each factor were then calculated and summed to calculate a predictive score. A risk score of ≤4 and ≤5 (10/11 maximum) for each model signifies low risk, respectively (<1.2% incidence). Model discrimination was evaluated by the area under the receiver operator characteristics curve with an area under the curve of 0.95/0.94 for each model. Our prediction IFD risk models perform well, are easy-to-use, and are based on readily available clinical data. Profound lymphopenia absolute lymphocyte count <250 mm3 could serve as a new important prognostic marker for the development of IFD in pediatric cancer and hematopoietic stem cell transplant patients.

Cancer-Related Venous Thromboembolism: From Pathogenesis to Risk Assessment.

Cancer-related venous thromboembolism (VTE) remains a major health problem, accounting for at least 18% of all cases of VTE. Cancer patients with VTE have worse prognosis than those without VTE. Prophylaxis reduces VTE risk, but it is not feasible for all outpatients with cancer due to an increased bleeding risk. The factors involved in the pathogenesis of cancer-related VTE are direct coagulation activation, platelet activation, induction of inflammatory responses, and inhibition of fibrinolysis. Direct coagulation activation can be due to cancer procoagulant (a cysteine protease), microvesicles, or other prothrombotic abnormalities. Risk factors for developing VTE in cancer patients can be divided into four groups: tumor-related risk factors, patient-related risk factors, treatment-related risk factors, and biomarkers. Cancers of the pancreas, kidney, ovary, lung, and stomach have the highest rates of VTE. Patient-related risk factors such as age, obesity, or the presence of medical comorbidities can contribute to VTE. Platinum-based chemotherapies and antiangiogenesis treatments have also been associated with VTE. Biomarkers identified as risk factors include high platelet count, high leukocyte count, P-selectin, prothrombin fragments, D-dimer, and C-reactive protein. Based on the known risk factors, risk assessment models were developed to stratify patients who would benefit from thromboprophylaxis. The Khorana model was the first and is still the most widely used model. Because of its low sensitivity for certain tumor types, four new models have been developed in recent years. In this review, we describe the current knowledge about the pathogenesis and risk factors for cancer-related VTE, hoping to contribute to further research on the still many obscure aspects of this topic.

External apical root resorption after orthodontic treatment: Incidence, severity and risk factors.

Background. This study aimed to evaluate the incidence and severity of orthodontically induced inflammatory external apical root resorption (OIIEARR) and the relationship between OIIEARR and possible risk factors such as orthodontic treatment type, treatment duration, gender, and age of the patients. A further aim was to determine the prevalence of OIIEARR in different tooth groups. Methods. The study sample consisted of 1356 orthodontically treated patients (857 females and 498 males; mean age: 14.4±2.8 years). OIIEARR was evaluated using pre- and post-treatment panoramic radiographs for all the tooth groups. Teeth with severe resorption were also assessed. Patient- and treatment-related risk factors for OIIEARR were assessed statistically using Pearson’s chi-squared test, independent-samples t test, and one-way ANOVA. Results. The incidence of severe root resorption following orthodontic treatment was 14.8%. Males exhibited a higher incidence of root resorption compared to females. Orthodontic treatment duration and treatment with extractions were positively correlated with OIIEARR (P < 0.05). OIIEARR was observed most frequently in maxillary incisors, followed by mandibular incisors. Conclusion. Orthodontic treatment with extraction, prolonged treatment duration, and large movements of the incisors should especially be taken into consideration for OIIEARR risk. Routine radiographic follow-up during orthodontic treatment is recommended.

The Impact of Psychopathy on Treatment for Patients With Serious Mental Illness: Attitudes, Behavior, and Risk

Psychopathy is related to poor treatment retention. Understanding which features of psychopathy impact treatment is important to help develop strategies for disruptive patients, especially for patients with serious mental illness (SMI). The present study aimed to assess the relations between psychopathy and treatment-related attitudes, behaviors, and risk factors that may be important for developing treatment retention strategies for patients with SMI.

Vincristine-Induced Peripheral Neuropathy (VIPN) in Pediatric Tumors: Mechanisms, Risk Factors, Strategies of Prevention and Treatment.

Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug–drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer.

Risk factors for catheter related thrombosis during outpatient parenteral antimicrobial therapy

Outpatient parenteral antimicrobial therapy (OPAT) delivery using peripherally inserted central catheters is associated with a risk of catheter related thrombosis (CRT). Individualised preventative interventions may reduce this occurrence, however patient selection is hampered by a lack of understanding of risk factors. We aimed to identify patient, infection or treatment related risk factors for CRT in the OPAT setting. Retrospective case control study (1:3 matching) within OPAT services at two tertiary hospitals within Australia. Over a 2 year period, encompassing OPAT delivery to 1803 patients, there were 19 cases of CRT, giving a prevalence of 1.1% and incidence of 0.58/1000 catheter days. Amongst the cases of CRT, there were nine (47%) unplanned readmissions and two (11%) pulmonary emboli. Compared to controls, cases had a higher frequency of malposition of the catheter tip (4/19 (21%) vs 0/57 (0%), p = 0.003) and complicated catheter insertion (3/19 (16%) vs 1/57 (2%), p = 0.046). Although CRTs during OPAT are infrequent, they often have clinically significant sequelae. Identification of modifiable vascular access related predictors of CRT should assist with patient risk stratification and guide risk reduction strategies.

Variability in Emergency Management of Pediatric Diabetic Ketoacidosis

ObjectivesOur aim in this study was to identify pediatric patients presenting in diabetic ketoacidosis (DKA) who received initial treatment inconsistent with current guidelines and then to track associated complications. MethodsThis retrospective chart review examined 47 pediatric patients admitted to our institution with DKA, including those transferred from community hospitals. Primary outcome measures were exposure to treatment-related risk factors for cerebral edema (CE), including administration of an intravenous (IV) insulin bolus, IV bicarbonate, insulin within 1 hour of IV fluid start and non-NPO (nil per os) status. ResultsSeventy-five percent of patients were exposed to at least one management practice that deviated from guidelines. Thirty-four percent of patients were exposed to a treatment-related risk factor for CE, with a significantly higher prevalence in those presenting to community centres (52% vs 19%; p=0.02). There were no radiologically confirmed cases of CE. ConclusionsDespite the presence of multiple evidence-based guidelines, a significant proportion of children---and especially those who present to community centres---are exposed to practices that increase CE risk.