Quantifying Chemotherapy Delivery in Older and Younger Women With Early-Stage Breast Cancer Using Longitudinal Cumulative Dose.

BACKGROUND: Delivery of cancer treatments, such as chemotherapy, requires a complex set of decisions that can change over time. Traditional measures of chemotherapy delivery, such as relative dose intensity, measure the amount of chemotherapy received by the end of treatment but mask the timing of dose reductions, delays, and discontinuation. These events may be important for delivering timely interventions to support adherence and lower the risk of recurrence. MATERIALS AND METHODS: We used an institutional database to identify women diagnosed with stage I-III breast cancer receiving adjuvant chemotherapy with a standard 4-cycle regimen of docetaxel + cyclophosphamide (TC, every 21 days) from April 2014 to December 2019. LCD was calculated as the amount of a given chemotherapy agent delivered at a specified time, t, divided by the total planned standard chemotherapy dose at time t. We visualized LCD curves for each chemotherapy agent and reported the median LCD and interquartile range (IQR) at the end of the regimen, overall and by age group (<65 years vs. 65+ years). RESULTS: The study population included 80 women. At the end of treatment, overall median LCDs for both cyclophosphamide and docetaxel were 100% (IQR: 99.6%, 100%), suggesting that TC was well tolerated. However, the lower quartile LCD for cyclophosphamide was 98.7% in older women treated with TC compared with 99.7% in younger women. CONCLUSION: Within our cohort, adjuvant TC was well tolerated with LCD curves showing largely on-time and full-dose administration. Subgroup analyses showed only slight decreases in adjuvant TC LCD for patients aged 65+ versus <65 years.

Prospective Assessment of Glucocorticoid Toxicity in Rheumatology Practice: A Focus on the Glucocorticoid Toxicity Index.

OBJECTIVE: The glucocorticoid toxicity index (GTI) is developed to measure glucocorticoid (GC)-related morbidity over time. This study aimed to assess GC-toxicity in patients at a rheumatology outpatient clinic by using the GTI and to identify the factors that interfere with the GTI. METHODS: This prospective study included patients with inflammatory arthritis (IA), connective tissue disease, and vasculitis who were newly prescribed GC-treatment (GC-naive) or have been still on GC-treatment for ≤2 years (GC-experienced). Patient demographics and disease characteristics, aggregate improvement score (GTI-AIS), cumulative worsening score (GTI-CWS), and cumulative GC-doses were recorded at baseline, 3rd month, and 6th month. Generalized estimating equations (GEE) were used to evaluate the GTI scores and associated factors including cumulative GC-doses. RESULTS: The study included 156 (48.7% GC-naive) patients with a mean age of 49.1 ± 17.1 years. More than half of the patients in both groups had a diagnosis of vasculitis. A higher cumulative GC-dose was found to be associated with higher GTI-scores in both groups (p< 0.001). In the GC-naive group, patients with vasculitis showed higher GTI-scores than IA patients (p< 0.001); there was also a significant increase in the GTI-CWS at the 6th month compared with the 3rd month. In the GC-experienced group, GTI-AIS and GTI-CWS were significantly different at 3rd and 6th month (p< 0.05). CONCLUSION: It was shown that GTI scores were associated with cumulative GC-doses and vasculitis patients in the GC-naive patients had higher GTI scores than inflammatory arthritis. The GTI allows individualized assessment and management of adverse effects experienced by patients as a result of GC treatment.

Cumulative Dose from Recurrent CT Scans: Exploring the DNA Damage Response in Human Non-Transformed Cells.

Recurrent computed tomography (CT) examination has become a common diagnostic procedure for several diseases and injuries. Though each singular CT scan exposes individuals at low doses of low linear energy transfer (LET) radiation, the cumulative dose received from recurrent CT scans poses an increasing concern for potential health risks. Here, we evaluated the biological effects of recurrent CT scans on the DNA damage response (DDR) in human fibroblasts and retinal pigment epithelial cells maintained in culture for five months and subjected to four CT scans, one every four weeks. DDR kinetics and eventual accumulation of persistent-radiation-induced foci (P-RIF) were assessed by combined immunofluorescence for γH2AX and 53BP1, i.e., γH2AX/53BP1 foci. We found that CT scan repetitions significantly increased both the number and size of γH2AX/53BP1 foci. In particular, after the third CT scan, we observed the appearance of giant foci that might result from the overlapping of individual small foci and that do not associate with irreversible growth arrest, as shown by DNA replication in the foci-carrying cells. Whether these giant foci represent coalescence of unrepaired DNA damage as reported following single exposition to high doses of high LET radiation is still unclear. However, morphologically, these giant foci resemble the recently described compartmentalization of damaged DNA that should facilitate the repair of DNA double-strand breaks but also increase the risk of chromosomal translocations. Overall, these results indicate that for a correct evaluation of the damage following recurrent CT examinations, it is necessary to consider the size and composition of the foci in addition to their number.

A Clinical Response-Adjusted Steroid Treatment Protocol for Children With Newly Diagnosed Idiopathic Nephrotic Syndrome.

RATIONALE & OBJECTIVE: Prednisone protocols for children with idiopathic nephrotic syndrome (INS) are generally similar in dose and duration, despite wide variations in time to response. We assessed the feasibility of a novel clinical treatment protocol characterized by a shorter duration and lower cumulative dose for children with early clinical response. STUDY DESIGN: Nonrandomized pilot clinical trial. SETTING & PARTICIPANTS: The study population included 59 children with newly diagnosed INS treated between 2014 and 2019 who responded to treatment within 8 days. INTERVENTION: The intervention group (n = 27) was treated with a response-adjusted protocol during which responders received an 8-week course of tapering doses of prednisone. The usual care group (n =32) was treated with the standard protocol (prednisone, 60 mg/m2/24 hours for 6 weeks, followed by 40 mg/m2/48 hours for 4 weeks, followed by a slow taper for a total of 24 weeks). OUTCOME: Consent rate, cumulative prednisone dose, the development of frequently relapsing or steroid-dependent nephrotic syndrome (FRNS or SDNS, respectively), relapses per year, treatment with steroid-sparing therapies, and adverse effects of steroid therapy over 3 years of follow-up observation. RESULTS: The consent rate was 88%. The mean cumulative steroid dose for the initial treatment was 70 mg/kg and 141 mg/kg (P < 0.001) in the intervention and usual care groups, respectively. None of the patients in the intervention group relapsed while on faster steroid taper down. The occurrence of FRNS and SDNS in the intervention group was not statistically different than in the usual care group, hazard ratios were 0.80 (95% CI, 0.37-1.73) and 0.61 (95% CI, 0.30-1.27), respectively. The proportions of relapse-free patients were similar (P = 0.5), and adverse steroid events did not differ between the groups. LIMITATIONS: Lack of randomization and small sample size. CONCLUSIONS: These findings demonstrate the feasibility of a shortened duration of steroid dosing for INS when patients demonstrate an initial clinical response to treatment. A larger study is needed to characterize the relative efficacy and toxicity of this novel treatment regimen. FUNDING: This study received no funding. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCTO2649413.

Impact of relative dose intensity of oxaliplatin in adjuvant therapy among stage III colon cancer patients on early recurrence: a retrospective cohort study.

BACKGROUND: Oxaliplatin-based therapy with FOLFOX-4 or CAPOX administered over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients. METHODS: The study included 365 patients treated at five oncology centers in Poland between 2000 and 2014. Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the α level of 0.05 was employed. RESULTS: The median follow-up was 51.8 months (range 8.2-115.1). Early recurrence < 36 months after surgery occurred in 130 patients (37.8%). In this group 51 (39.2%) and 87 (66.9%) of patients were low and high-risk, respectively. Receipt < 60% of RDI-O was associated with early recurrence within 18 months after surgery (OR = 2.05; 95%CI: 1.18-3.51; p = 0.010), especially in low-risk group (HR = 1.56 (95%CI: 0.96-2.53), p = 0.07). In the multivariate analysis early recurrence was correlated with grade (OR = 2.47; 95% CI: 1.25-4.8; p = 0.008), pN (OR = 2.63; 95% CI: 1.55-4.54; p < 0.001), the number of lymph nodes harvested (OR = 0.51; 95% CI: 0.29-0.86; p = 0.013) and RDI-O (OR = 1.91; 95%CI: 1.06-3.39; p = 0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR = 22.9 (95%CI: 13.9-37.6; p < 0.001). CONCLUSIONS: RDI-O < 60% in adjuvant therapy among stage III CC (especially in low-risk group) increases the risk of early recurrence within 18 months of surgery. Patients with early recurrence showed worse overall survival regardless of the RDI-O.

Efficacy and tolerability of VCD chemotherapy in a UK real-world dataset of elderly transplant-ineligible newly diagnosed myeloma patients.

OBJECTIVE: There are limited data on the efficacy and tolerability of VCD chemotherapy in transplant-non-eligible (TNE) newly diagnosed myeloma (NDMM) patients. In this retrospective study, we set out to evaluate this triplet combination in this setting across Thames Valley Cancer Network (UK). METHODS: The primary end point was overall response rate (ORR). Secondary outcomes included event-free survival (EFS), overall survival (OS) and adverse events (AEs). RESULTS: In a total cohort of 158 patients, ORR for total cohort was 72.1%. Median EFS was 10.5 months, and for subgroups by age (<75:11.7 vs ≥75:10.3 months, P = .124), by Charlson Co-morbidity Index (CCI) (<5:11.1 vs ≥5:8.2 months, P = .345). The 4-month landmark analysis showed the following median EFS results: by cumulative bortezomib dose (≥26 mg/m2 : 9.0 months vs <26 mg/m2 : 6.4, P = .13), by cumulative cyclophosphamide dose (≥7000 mg: 9.2 vs <7000 mg: 7.0 months, P = .02) and by cumulative dexamethasone dose (>600 mg: 7.8 vs ≤600 mg: 8.3 months, P = .665). Median OS was 46.9 months. The incidence rate of AE was as follows: any grade (76.8%), ≥G3 (27.1%), ≥G3 haematological AEs (7.9%), any grade infections (31.1%) and ≥G3 infections (11.9%). CONCLUSION: This study demonstrated a good ORR achieved from fixed duration VCD, which was reasonably well tolerated. This was followed by modest median EFS. We envisage that the latter may be improved in this patient group with the use of a higher cumulative bortezomib dose (≥26 mg/m2 ) which showed a trend for improved EFS although without statistical significance (P = .13), and with the use of a higher cumulative cyclophosphamide doses (≥7000 mg, P = .02), subject to tolerability and close monitoring.

Differences in phototherapy among skin diseases and genders in real-life conditions-A retrospective analysis of the cumulative doses, numbers of sessions, side effects and costs in 561 patients.

BACKGROUND: Phototherapy has been a mainstay therapy for dermatological diseases since more than a century. Although phototherapy is still extensively used and some recommendations exist, only scarce data are available addressing disease-specific differences in cumulative doses, treatment durations and costs. Knowledge of such differences could help to avoid over-/undertreatment, predict treatment duration and costs. Therefore, we sought to determine differences in cumulative doses, numbers of sessions, side effects and costs among different skin diseases and genders in real-life conditions. METHODS: In this single-centre, retrospective study, patients treated with phototherapy between March 2014 and April 2019 were classified into seven diagnostic groups and analysed according to the study goals. RESULTS: Out of 561 patients (age 53.9 ± 20.3 yrs; 52.9% females), 83.7% percent were treated with cabin NB-UVB (mean cumulative dose 17.79 ± 17.11 J/cm2 ). Patients with vitiligo and psoriasis were treated with significantly higher cumulative NB-UVB doses (cabin, local) in comparison with the five other diagnostic groups as were males in comparison with females. Consequently, significantly higher UV-related costs resulted in patients with vitiligo, psoriasis and males. Patients with atopic dermatitis and pruritus were treated with significantly higher cumulative UVA1 doses compared to patients with non-atopic eczema. The complication rate (pooled from all UV modalities) in our population was 3.8% (erythema 3.4%, aggravated itch 0.4% and worsening of symptoms 0.2%). CONCLUSIONS: Our results demonstrate that cumulative doses and phototherapy-related costs vary strongly among skin diseases-a fact not adequately considered in recommendations. A more disease-specific stratification of phototherapy could not only help to optimize outcomes, but also to facilitate comparability of clinical trials using phototherapy.

Is methotrexate hepatotoxicity associated with cumulative dose? A systematic review and meta-analysis.

BACKGROUND/OBJECTIVE: Methotrexate (MTX) is widely used in various medical specialties. However, hepatotoxicity is an ongoing concern and this is thought to be directly associated with cumulative dose. We sought to synthesise the published literature to evaluate the association between methotrexate hepatotoxicity and cumulative dose. METHODS: A systematic review of Medline (PubMed) EMBASE, CINAHL and The Cochrane Library was performed. Full texts of articles were examined, and excluded articles were recorded with reasons for exclusion. A meta-analysis of correlation coefficients was performed using Fisher's z-transformation and a random effects model. Cochran's Q-test and the I2 statistic were calculated to assess heterogeneity. RESULTS: A total of 35 studies met inclusion criteria. Measures of hepatotoxicity were highly varied and included liver biopsy, elastography, FibroTest, biochemical tests and scoring systems (Fib-4, APRI, AST:ALT). Some studies analysed for the association with MTX cumulative dose using more than one modality. Overall, 38 analyses found no significant association between MTX cumulative dose and hepatoxicity vs eight that identified a significant association. The pooled correlation coefficient from five studies which utilised elastography was 0.18 (95% CI, -0.09 to 0.42), with significant heterogeneity between studies (P < 0.0001), I2  = 92%). CONCLUSIONS: Our synthesis of a large volume of studies in this review found no significant association between MTX cumulative dose and hepatotoxicity, both in terms of vote counting and with regard to the meta-analysis of correlation coefficients from studies that utilised elastography. This challenges the long-held belief that liver injury is a direct result of drug accumulation.

Factors affecting high cumulative radiation exposure from paediatric computed tomography.

PURPOSE: To estimate occurrence rate of high cumulative radiation exposure from paediatric computed tomography (CT), and to determine influential factors on high-dose inclination. MATERIAL AND METHODS: Patients below 18 years old receiving at least 50 mSv of a cumulative dose during a 5-year period in a tertiary care centre were retrospectively enrolled. Individual patient characteristics, diagnoses, frequency of exa-minations, scanner sites, designated scans, and effective doses were recorded. Collective doses were compared among groups of the diagnoses and scanner sites, and regression analyses were applied. RESULTS: Of 2771 patients, 3.2% received individual cumulative doses between 50 and 303 mSv (median, 74 mSv). Frequency of examinations ranged from 1 to 13 times (median, 4 times) per patient. About 70% of the patients had oncological illness. Radiation was predominantly high in a CT simulator that could contribute the percentage of collective dose to twice that of examinations owing to higher scanning parts and CT dose index. Some scanner sites used higher acquisition phases. Regression analysis showed that the number of scanning parts and phases significantly influenced the cumulative dose inclination (p < 0.05) while frequent examinations did not. CONCLUSIONS: There was a low occurrence of paediatrics with high dose accumulation. Significant factors affecting potentially high exposure were customized CT protocols in the specific scanners.

Role of upper abdominal reirradiation for gastrointestinal malignancies: a systematic review of cumulative dose, toxicity, and outcomes on behalf of the Re-Irradiation Working Group of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

PURPOSE: Abdominal recurrences of gastrointestinal malignancies are common. Evidence in clinical studies has shown that re-irradiation (Re-I) is tolerable and efficient in different tumor locations. In contrast, little clinical data are available on normal long-term Re­I tolerance doses. A systematic review of upper abdominal Re­I was performed with the aim of exploring the cumulative dose, toxicity, and outcomes. METHODS: A computerized search was undertaken in MEDLINE, EMBASE, OVID, and the Cochrane database. Only studies reporting toxicity and/or outcomes were taken into consideration. To improve the comparability of the different Re­I regimens and assess the relationship between Radiotherapy (RT) dose and toxicity, the equivalent dose in 2­Gy fractions was calculated according to the linear quadratic model. RESULTS: Sixteen studies met the inclusion criteria, with the total patients numbering 408. Median follow-up Re­I ranged from 5.9 to 45 months. The median time elapsed since previous RT treatment was 15 months (2-162 months). Re­I prescription doses were variable (22.5 Gy in 3 fractions to 126.5 Gy with 125I). Cumulative doses calculated for acute- and late-responding tissues ranged from 67.25 to 136 Gy and 30.3 to 188.38 Gy, respectively. Comprehensively, the pooled ≥G3 toxicity was 12% (95%CI: 7.6-19%). The overall 1­year survival and local recurrence-free survival rates were 53.7% (95%CI: 45.6-63.2%) and 66.5% (95% CI: 58.7-75.4%), respectively. Pain improvement was reported in 66.9% of patients. CONCLUSION: Due to limited evidence as a result of the retrospective design of the majority of the studies, our review suggests that upper abdominal Re­I is effective in terms of local control and palliation, with a moderate rate of severe toxicities.

Age-dependent hemato- and nephrotoxicity in patients with head and neck cancer receiving chemoradiotherapy with weekly cisplatin.

BACKGROUND AND PURPOSE: In cases of simultaneous chemoradiotherapy (CRT), early recognition of toxic side effects is important, as drug discontinuation may prevent further injury. It appears favorable to undertake further steps to investigate whether patient subgroups behave differently depending on their toxicity profile. METHODS: We retrospectively analyzed 125 consecutive patients with non-metastasized carcinoma of the head and neck who were treated with CRT (cisplatin 40 mg/m2 weekly) in 2013/2014. Patients were planned to receive six cycles of cisplatin. Statistical analyses were performed using the chi2 test, t-test, Kaplan-Meier method, and the log-rank test, as appropriate. RESULTS: Eighty-six patients did not reach the intended sixth cycle (68.8%; 60.0% of whom were ≥60 years, p < 0.05). Acute kidney injury (glomerular filtration rate <60 mL/min/1.73m2) was the most common reason for drug discontinuation (26.7%; 82.6% of whom were ≥60 years; p < 0.01), followed by leukopenia <3/nL (23.3%; 75% of whom were <60 years; p < 0.01) and infection (11.6%). Patients who underwent ≥5 cycles were associated with prolonged overall survival and metastasis-free survival after CRT (p < 0.02; median follow-up 24 months), especially patients <60 years. CONCLUSION: Acute kidney injury was the most common side effect in patients ≥60 years, whereas leukopenia characteristically occurred significantly more often in younger patients. Discontinuing cisplatin during CRT was associated with a worse outcome, especially in patients <60 years.

Optimal cumulative dose of cisplatin for concurrent chemoradiotherapy among patients with non-metastatic nasopharyngeal carcinoma: a multicenter analysis in Thailand.

BACKGROUND: Chemoradiotherapy (CRT) with high cumulative doses (CDs) of cisplatin has been considered the standard of care for non-metastatic nasopharyngeal carcinoma (NPC). However, given most patients' inability to tolerate high CDs due to cisplatin-related toxicities, the optimal CD of cisplatin during CRT remains undetermined. METHODS: Patients with non-metastatic NPC who received CRT with cisplatin between 2007 and 2017 were identified through the Thai head and neck cancer multicenter database and then categorized according to cisplatin CD (mg/m2) received. All complications and cisplatin-related toxicities during CRT were recorded. RESULTS: We identified 779 non-metastatic NPC patients receiving low (≤150; n = 97), intermediate (151-250; n = 411), and high (> 250; n = 271) CDs of cisplatin. Low CD patients had significantly lower mean actual radiation dose (p < 0.001) and more radiotherapy delay (p = 0.010), while intermediate CD patients had the least hospitalization (p < 0.001). Overall, 39.3% of the patients experienced cisplatin-related toxicity, which was associated with poor overall survival (OS) (p = 0.001). Acute kidney injury was observed in 7% in all patients, which was highest among low CD patients (15.5%; p = 0.002). Intermediate CD patients had significantly longer median OS than the low and high groups (64 vs. 49.8 vs. 53.2, respectively; p = 0.015). Univariate, but not multivariate, analysis showed that CD of cisplatin was significantly associated with OS. CONCLUSION: CD of cisplatin during CRT was not an independent prognostic factor for OS. An intermediate CD induced minimal toxicity without compromising survival and should be considered the optimal CD. Nonetheless, a randomized phase 3 study evaluating the optimal CD of cisplatin is warranted.

High cumulative doxorubicin dose for advanced soft tissue sarcoma.

BACKGROUND: The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients. However, the treatment and prognosis of STS and breast cancer are quite different, and reference to breast cancer data alone may not reflect the efficacy of doxorubicin treatment in STS. This study, thus, aimed to review and analyze clinical data of STS patients treated with a high cumulative doxorubicin dose, to provide a reference for treatment selection and clinical trial design. METHODS: We retrospectively collected and analyzed clinical data of patients with advanced STS who received doxorubicin-based chemotherapy from January 2016 to January 2020. The patients were divided into a standard-dose group (who received ≤6 cycles of doxorubicin after the initial diagnosis) and an over-dose group (who were re-administered doxorubicin [doxorubicin-rechallenge] after receiving 6 cycles of doxorubicin therapy discontinuously). Patient characteristics, cumulative doxorubicin dose, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), cardiotoxicity incidence, and treatment effectiveness were evaluated in both groups. RESULTS: A total of 170 patients with advanced STS were recruited (146 in the standard-dose group and 24 in the over-dose group). The average cumulative doxorubicin dose was 364.04 ± 63.81 mg/m2 in the standard-dose group and 714.38 ± 210.09 mg/m2 in the over-dose group. The ORR, DCR, and median PFS were 15.07, 58.9%, and 6 (95% confidence interval [CI]: 5.8-6.5) months in the standard-dose group and 16.67, 66.67%, and 4 (95%CI: 2.0-5.8) months in the over-dose group, respectively. Symptomatic heart failure occurred in five patients (3.42%) of the standard-dose group and in one patient (4.17%) of the over-dose group. In these patients with cardiotoxicity, doxorubicin was discontinued, and all of them died of uncontrolled tumor growth. No drug-related deaths occurred. CONCLUSIONS: The continuation of or rechallenge with doxorubicin beyond the recommended cumulative dose could be a promising therapeutic option in the treatment of chemotherapy-sensitive advanced sarcomas. Further evaluation is necessary in prospective trials.

Higher daily doses of caffeine lowered the incidence of moderate to severe neurodevelopmental disabilities in very low birth weight infants.

AIM: We determined the influence of cumulative dosing of caffeine citrate on the neurodevelopmental outcomes of low birth weight (VLBW) infants at 18-22 months of postmenstrual age. METHODS: This retrospective chart analysis was conducted at Detroit Medical Center, Michigan, USA. The 181 infants we included were born between January 2006 and December 2016, were less than 32 weeks of gestational age and weighed less than 1500 grams. Data on their perinatal and postnatal characteristics were retrieved from their medical records and they were assessed using the Bayley Scales of Infant Development - Third Edition. RESULTS: The 64 infants with no neurodevelopmental disability or a mild disability received a significantly higher average daily dose (mg/kg/day) of caffeine citrate with a median of 7.58 (range 2.7-12.2) mg/kg/day, than the 79 infants with a moderate to severe disability, who received a median of 6.47 (range 3.1-12.5, p = 0.01). The total cumulative dose had no effect on bronchopulmonary dysplasia or neurodevelopmental outcomes. CONCLUSION: A higher average daily dose of caffeine citrate was associated with better neurodevelopmental outcomes of VLBW infants. However, the cumulative dose did not have an impact on their short-term or long-term outcomes. Further research is needed to confirm our findings.

Effect of Cumulative Intravenous Voriconazole Dose on Renal Function in Hematological Patients.

Intravenous voriconazole (VRC) is formulated by the incorporation of sulfobutylether-ß-cyclodextrin (SBECD), which may accumulate to adversely affect renal function. However, the effect of long-term use of intravenous VRC on renal function is unclear. Our retrospective analysis of data confirmed that worsening of renal function was significantly associated with a cumulative dose of intravenous VRC (≥400 mg/kg), suggesting that a higher cumulative dose of intravenous VRC is a risk factor for renal dysfunction.

Randomized controlled trials define shape of dose response for Pollinex Quattro Birch allergoid immunotherapy.

BACKGROUND: The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose. METHODS: The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED50 ), a measure of potency. RESULTS: Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. CONCLUSION: Increasing the cumulative dose of PQBirch 5.5-fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.

The severity of lung injury and metabolic disorders induced by ambient PM2.5 exposure is associated with cumulative dose.

Lots of epidemiological and experimental studies have found that ambient fine particulate matter (PM2.5) exposure is associated with the development of cardiopulmonary diseases, obesity and diabetes. This study focused on the effects of cumulative PM2.5 exposure on pulmonary and systemic inflammation and insulin resistance. Thirty-two 6-week-old male Balb/c mice were randomly divided into four groups (FA, PM, WEEK and DAY groups) and were continuously or intermittently exposed to concentrated PM2.5 or filtered air (FA) for four weeks using Shanghai Meteorological and Environmental Animal Exposure System ("Shanghai-METAS"). The levels of IL-6 and TNF-α in serum, bronchoalveolar lavage fluid (BALF), lung tissues and white adipose tissue (WAT) were measured. Meanwhile, the expression of NF-κB and phosphor-NF-κB in lung tissue was detected by Western blot. Glucose tolerance and insulin resistance were also determined at the end of exposure. The results found that the mice in PM group displayed moderate inflammatory cell infiltration in lung, whereas the mice in WEEK and DAY groups displayed slight inflammatory cell infiltration in lung. Compared with the mice in FA group, the mRNA expressions of IL-6 and TNF-α in lung tissue and WAT significantly increased in the mice of PM group. Importantly, IL-6 and TNF-α mRNA expressions in PM group were higher than those in WEEK and DAY groups. The protein expression of phospho-NF-κB in lung tissue showed that PM group showed the activation of NF-κB, which was higher than that in the WEEK and DAY groups. Meanwhile, the mice in PM group showed more severe glucose tolerance and insulin resistance than that in the WEEK and DAY groups. The results suggested that the reduction of PM2.5 cumulative exposure may alleviate pulmonary and adipose inflammation, insulin resistance and glucose tolerance impairment. The results provided a clue that the interruption of ambient PM2.5 exposures by systems such as indoor air purification could be of benefit to people's health.

Is there any cumulative dose for trastuzumab?

Trastuzumab is one of the most important agents that target human epidermal growth factor receptor 2, but its cardiotoxic effect limits to use it. The mechanism of cardiac dysfunction-related trastuzumab is still unclear. In literature, there is no definite information about the cumulative dose of trastuzumab for cardiotoxicity. In presented case, we reported a breast cancer patient who has been receiving long-term trastuzumab. We have not found any cardiac problems for duration of over four years. According to our case and literature review, we may say that trastuzumab is safely used with periodically echocardiographic control in patients with breast cancer.

Early effect of hydroxychloroquine therapy: relationship between cumulative dose and retinal thickness.

BACKGROUND: Hydroxychloroquine (HCQ) is widely used for long-term treatment of autoimmune diseases such as rheumatoid arthritis. However, its long-term use is known to be associated with visual changes due to retinal damage. Retinal damage associated with long-term HCQ therapy is preventable if the drug is discontinued early when the patients are still asymptomatic. In view of contrasting reports from previous studies, we investigated the association of prolonged HCQ therapy with retinal thickness in macular area. METHODS: This study included 48 patients on long-term HCQ therapy and 38 healthy controls. All subjects underwent examination for corrected visual acuity, fundus photography, visual fields and SD-OCT for retinal thickness. RESULTS: Visual acuity, visual fields, fundus photography and SD-OCT did not reveal changes consistent with diagnosis of established HCQ retinopathy in any of the subjects from HCQ group. Retinal thickness in central, parafoveal and perifoveal areas did not show significant differences between HCQ and control groups. However, we observed negative correlation between cumulative dose and retinal thickness in the parafoveal (p = 0.003) and perifoveal areas (p = 0.019) but not in the central area. CONCLUSIONS: Correlation of cumulative dose with retinal thickness in parafoveal and perifoveal areas and not the central area is in accordance with the late appearance of HCQ-induced bull's eye retinopathy. Hence screening of asymptomatic patients using OCT seems to be of great importance for early detection of retinal changes.

Canadian Association of Radiologists Radiation Protection Working Group: Automated Patient-Specific Dose Registries­What Are They and What Are They Good for?

Medical radiation should be used appropriately and with a dose as low as reasonably achievable. Dose monitoring technologies have been developed that automatically accumulate patient dose indicators, providing effective dose estimates and patient-specific dose histories. Deleterious radiation related events have prompted increased public interest in the safe use of medical radiation. Some view individualized patient dose histories as a tool to help manage the patient dose. However, it is imperative that dose monitoring technologies be evaluated on the outcomes of dose reduction and effective patient management. Patient dose management needs to be consistent with the widely accepted linear no-threshold model of stochastic radiation effects. This essay reviews the attributes and limitations of dose monitoring technologies to provoke discussion regarding resource allocation in the current fiscally constrained health care system.