Time toxicity associated with early phase clinical trial participation.

BACKGROUND: Early phase cancer clinical trials (EPCTs) involve experimental drugs being used for the first time in humans. These studies are designed for dose determination and safety, and represent the most time intensive of all clinical trials for both clinicians and patients. We sought to quantify the amount of patient time consumed through EPCT participation. PATIENTS AND METHODS: A retrospective audit of patients treated in the EPCT unit at Liverpool Hospital, Sydney was carried out from 2013 to 2023. We defined 'time toxicity' (TT) as a composite measure where time-toxic days were considered days with any health care system contact, including clinic visits, infusions, procedures or blood work. RESULTS: A total of 219 patients across 36 EPCTs were included. The median age was 65 years (range 31-81 years). Patients spent a median of 29% (range 4%-100%) of their days in direct contact with the health care system during their study. Protocol-specified visits accounted for the greatest contribution to total TT in 101 (46%) patients. In 7% (n = 16) of patients, unscheduled visits due to either adverse events or cancer-related symptoms accounted for the greatest TT. TT reduced as patients completed additional cycles of treatment. Patients who completed >10 cycles spent 14% of their days interacting with health care systems compared with 35% for those who completed ≤2 cycles. No statistically significant difference in TT was noted between dose-expansion and dose-escalation studies or trials focusing on immune-oncology versus targeted therapy. CONCLUSIONS: Our study is the first to report TT in EPCTs with an extended follow-up. Clinicians should be aware of TT when discussing risks and benefits. TT also may not be the appropriate term when describing the time patients invest during EPCTs. Toxicity implies a negative impact, but for many patients, trial participation would be seen as positive. There should be efforts to streamline health care visits to limit TT in EPCTs.

Differentiation of follicular carcinomas from adenomas using histogram obtained from diffusion-weighted MRI.

AIM: To evaluate the role of histogram analysis of apparent diffusion coefficient (ADC) maps from diffusion-weighted imaging (DWI) in the differentiation of follicular thyroid carcinoma (FTC) from follicular adenoma (FA) in nodules indeterminate on ultrasound-guided core needle biopsy (USCNB). MATERIALS AND METHODS: This study was performed with institutional review board approval. Seventeen patients who were planned to undergo diagnostic lobectomy for an indeterminate thyroid nodule (atypical of unknown significance/follicular lesion of undetermined significance [AUS/FLUS] or suspicious for follicular neoplasm/follicular neoplasm [SFN]) on USCNB were enrolled prospectively. All patients underwent DWI on the day before surgery. Histogram parameters were derived from ADC values obtained from the whole extent of the tumours. The parameters were compared with the final diagnosis based on histopathological examination after surgery. The accuracy of the parameters in differentiating FTC from FA was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Twelve patients were confirmed as having FA and five patients as having FTC. Histogram parameters including the 10th (ADC10), 25th (ADC25), and 50th (ADC50) percentiles of the ADC values were significantly lower in FA than in FTC (p < 0.05, all). ROC curve analysis revealed that ADC25 resulted in the highest AUC (0.867; confidence interval, 0.616-0.980), with a cut-off value of 0.352×10-3 mm2/s. CONCLUSION: Histogram parameters from ADC maps could differentiate FTC from FA effectively in indeterminate nodules on USCNB, with ADC25 being the most promising parameter.

Efficacy of HVT-IBD vector vaccine compared to attenuated live vaccine using in-ovo vaccination against a Korean very virulent IBDV in commercial broiler chickens.

The production performance, efficacy, and safety of two types of vaccines for infectious bursal disease virus (IBDV) were compared with in-ovo vaccination of Cobb 500 broiler chickens for gross and microscopic examination of the bursa of Fabricius, bursa/body weight (b/B) ratio, flow cytometry, and serologic response to Newcastle disease virus (NDV) vaccination. One vaccine was a recombinant HVT-IBD vector vaccine (HVT as for herpesvirus of turkeys) and the other was an intermediate plus live IBDV vaccine. A significant difference was detected at 21 d. Eight of 10 chickens that received the IBDV live vaccine had severe bursal lesions and a relatively low b/B ratio of 0.95, and an inhibited NDV vaccine response. On the other hand, the HVT-IBD vector vaccine resulted in mild bursal lesions and a b/B ratio of 1.89. Therefore, the live vaccine had lower safety than that of the HVT-IBD vector vaccine. To determine the protective efficacy, chickens were intraocularly challenged at 24 d. Eight of 10 chickens in the IBDV live vaccination group showed gross and histological lesions characterized by hemorrhage, cyst formation, lymphocytic depletion, and a decreased b/B ratio. In contrast, the HVT-IBD vector vaccinated chickens showed mild gross and histological lesions in three of 10 chickens with a b/B ratio of 1.36, which was similar to that of the unchallenged controls. Vaccinated chickens showed a significant increase in IBDV antibody titers, regardless of the type of vaccine used. In addition, significantly better broiler flock performance was observed with the HVT-IBD vector vaccine compared to that of the live vaccine. Our results revealed that the HVT-IBD vector vaccine could be used as an alternative vaccine to increase efficacy, and to have an improved safety profile compared with the IBDV live vaccine using in-ovo vaccination against the Korean very virulent IBDV in commercial broiler chickens.

Comparison of fine-needle aspiration and core needle biopsy under ultrasonographic guidance for detecting malignancy and for the tissue-specific diagnosis of salivary gland tumors.

BACKGROUND AND PURPOSE: Diagnostic test accuracy studies for ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy have shown inconclusive results due to their heterogenous study designs. Our aim was to compare the diagnostic accuracy of ultrasonography-guided fine-needle aspiration versus ultrasonography-guided core needle biopsy for detecting malignant tumors of the salivary gland and for the tissue-specific diagnosis of salivary gland tumors in a single tertiary hospital. MATERIALS AND METHODS: This retrospective study was approved by our institutional review board and informed consent was waived. Four hundred twelve patients who underwent ultrasonography-guided fine-needle aspiration (n = 155) or ultrasonography-guided core needle biopsy (n = 257) with subsequent surgical confirmation or clinical follow-up were enrolled. We compared the diagnostic accuracy of ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy regarding malignant salivary gland tumors and the correct tissue-specific diagnosis of benign and malignant tumors. We also tested the difference between these procedures according to the operator's experience and lesion characteristics. RESULTS: The inconclusive rates of ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy were 19% and 4%, respectively (P < .001). The overall accuracy of ultrasonography-guided core needle biopsy for diagnosing malignant tumors was significantly higher than that of ultrasonography-guided fine-needle aspiration (P = .024). The correct tissue-specific diagnosis rates of ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy were 95% versus 97% for benign tumors (P = .648) and 67% versus 80% for malignant tumors (P = .310). Trainees showed significantly lower accuracy with ultrasonography-guided fine-needle aspiration than with ultrasonography-guided core needle biopsy for diagnosing malignant tumors (P = .021). There was no difference between the diagnostic accuracy of ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy according to the internal composition of the lesions. There were no complications requiring intervention or hospitalization in our patients. CONCLUSIONS: Ultrasonography-guided core needle biopsy is superior to ultrasonography-guided fine-needle aspiration in detecting and characterizing malignant tumors of the salivary gland and could emerge as the diagnostic method of choice for patients presenting with a salivary gland mass.

Clinical significance of an increased cochlear 3D fluid-attenuated inversion recovery signal intensity on an MR imaging examination in patients with acoustic neuroma.

BACKGROUND AND PURPOSE: The increased cochlear signal on FLAIR images in patients with acoustic neuroma is explained by an increased concentration of protein in the perilymphatic space. However, there is still debate whether there is a correlation between the increased cochlear FLAIR signal and the degree of hearing disturbance in patients with acoustic neuroma. Our aim was to investigate the clinical significance of an increased cochlear 3D FLAIR signal in patients with acoustic neuroma according to acoustic neuroma extent in a large patient cohort. MATERIALS AND METHODS: This retrospective study enrolled 102 patients with acoustic neuroma, who were divided into 2 groups based on tumor location; 22 tumors were confined to the internal auditory canal and 80 extended to the cerebellopontine angle cistern. Pure tone audiometry results and hearing symptoms were obtained from medical records. The relative signal intensity of the entire cochlea to the corresponding brain stem was calculated by placing regions of interest on 3D FLAIR images. Statistical analysis was performed to compare the cochlear relative signal intensity between the internal auditory canal acoustic neuroma and the cerebellopontine angle acoustic neuroma. The correlation between the cochlear relative signal intensity and the presence of hearing symptoms or the pure tone audiometry results was investigated. RESULTS: The internal auditory canal acoustic neuroma cochlea had a significantly lower relative signal intensity than the cerebellopontine angle acoustic neuroma cochlea (0.42±0.15 versus 0.60±0.17, P<.001). The relative signal intensity correlated with the audiometric findings in patients with internal auditory canal acoustic neuroma (r=0.471, P=.027) but not in patients with cerebellopontine angle acoustic neuroma (P=.427). Neither internal auditory canal acoustic neuroma nor cerebellopontine angle acoustic neuroma showed significant relative signal intensity differences, regardless of the presence of hearing symptoms (P>.5). CONCLUSIONS: The cochlear signal on FLAIR images may be an additional parameter to use when monitoring the degree of functional impairment during follow-up of patients with small acoustic neuromas confined to the internal auditory canals.

Long-term bisphosphonate usage and subtrochanteric insufficiency fractures: a cause for concern?

For over a decade, bisphosphonate administration has evolved and become the cornerstone of the prevention and treatment of fragility fractures. Millions of post-menopausal women have relied on, and continue to depend on, the long-acting, bone density-maintaining pharmaceutical drug to prevent low-energy fractures. In return, we have seen the number of fragility fractures decrease, along with associated costs and emotional benefits. However, with any drug, there are often concerns with side effects and complications, and this unique drug class is seeing one such complication in atypical subtrochanteric femoral fracture, counterproductive to that which it was designed to prevent. This has created concern over long-term bisphosphonate administration and its potential link to these atypical fractures. There is controversial evidence surrounding such a definitive link, and no protocol for managing these fractures. This review offers the latest information regarding this rare but increasingly controversial adverse effect and its potential connection to one of the most successful forms of treatment that is available for the management of fragility fractures.

Developmental dental defects linked with chemoradiotherapy: a case report.

Developmental orofacial dentoalveolar complications associated with chemoradiotherapy in an 8 year old child with a history of rhabdomyosarcoma are reported. This report details, clinically and radiographically, these effects in a child diagnosed at 3 years of age with a lesion primary to the left buccinator. Early evaluation is vital to determine potential dentoalveolar complications and long-term consequences.

High-dose nevirapine in previously untreated human immunodeficiency virus type 1-infected persons does not result in sustained suppression of viral replication.

High-dose nevirapine treatment has been reported to confer sustained antiretroviral effects, despite a rapid development of resistance. The use of this strategy was evaluated in 20 previously untreated human immunodeficiency virus type 1 (HIV-1) p24 antigenemic persons with CD4 cell counts between 100 and 500/mm3. Treatment consisted of 400 mg of nevirapine, after a 2-week lead-in dose of 200 mg. Rash was the most frequently reported adverse event, occurring in 25%. While sustained declines in p24 antigen levels were observed in the majority, serum HIV-1 RNA load and CD4 cell counts returned to baseline values within 12 weeks in virtually all subjects. The resistance-conferring tyrosine-to-cysteine substitution at reverse transcriptase position 181 was detected after 4 weeks in most subjects. These observations suggest that plasma drug levels attained with high-dose nevirapine were not sufficient to inhibit nevirapine-resistant virus, although they were approximately 2-fold higher than reported IC50 values of resistant virus.