Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers

PURPOSE In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. METHODS Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant ( H-K-NRAS), BRAF-mutant ( BRAF p.V600E), and RET/ NTRK fusion ( RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. RESULTS Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/ NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. CONCLUSION Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/ NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

A personalized approach to preclinical diagnosis and initial therapy of primary glaucoma based on a comprehensive structural and functional examination. A clinical case

The principles of personalized approach to early diagnosis and monitoring of primary glaucoma are shown by a clinical example. We analyzed the potentials of contemporary electrophysiological tests for preclinically diagnosing glaucoma optic neuropathy and monitoring drug treatment. For the first time, we demonstrated the experience of using a new fixed combination of brinzolamide + brimonidine by a clinical case from our practice. The test results confirm the hypotensive effect of the medication (IOP reduction by 36.2 %) so that it can be recommended for the treatment of patients with glaucomatous optic neuropathy and that combined with vascular pathology.

Evaluation of the effectiveness of drug treatment in patients with arterial hypertension and insomnia

Objective: chronic sleep disturbance is a comorbid condition with arterial hypertension, often combined with affective disorders, anxiety, depression. Forced sleep deprivation in patients with hypertension indicates a high activity of the renin‑angiotensin‑aldosterone system (RAAS) and desynchronosis of biological rhythms caused by a probable deficit in melatonin secretion during the night. Timely elimination of any pathological process associated with insomnia and arterial hypertension (AH) in the early stages of its development is a prerequisite for the effectiveness of therapy. Therefore, initial therapy should help neutralize the adverse effects of RAAS and improve the 24‑hour blood pressure (BP) profile. The aim of this study was to determine the therapeutic effect of monotherapy with an angiotensin converting enzyme (ACE) inhibitor, As well as in combination with a synthetic analogue of melatonin, on the course of hypertension and parameters of systemic hemodynamics in patients with first degree hypertension with insomnia at the onset of the disease. Combined therapy with an ACE inhibitor and a synthetic analogue of MT in patients with hypertension and insomnia was accompanied by an improvement in the clinical state, achievement of the target blood pressure level in most patients, positive dynamics of central blood pressure parameters and indicators reflecting the rigidity of peripheral arteries.

Sustained HIV viral suppression with dolutegravir, tenofovir, and emtricitabine as initial therapy despite high-level transmitted multi-class resistance

Multi-class high-level transmitted HIV drug resistance is uncommon, and the selection of the optimal initial antiretroviral drug regimen may be challenging. We report a case of extensive transmitted multi-class resistance successfully treated with dolutegravir, tenofovir, and emtricitabine even though the baseline genotype demonstrated full susceptibility to only one drug class, the integrase strand transfer inhibitors. Our case highlights both the high resistance barrier of dolutegravir and the residual antiviral activity of nucleoside reverse transcriptase inhibitors despite extensive resistance on genotype.

Therapeutic Management of Breast Cancer Related Upper Limb Lymphedema

Lymphedema represents a chronic condition with impaired lymphatic transport, having primary and secondary etiologies. The most common type of secondary lymphedema in western countries is represented by breast cancer related upper limb lymphedema. This condition, once installed, determines limb structure changes, progressive functional impairment, specific complications, consequently impacting the quality of patient’s life. An accurate diagnosis is mandatory, using both clinical and imagistic methods with clear definition disease extent as per standardized staging systems, in order to further provide an adequate therapeutic strategy. The main therapeutic goal in patients with lymphedema is represented by limb volume reduction with subsequent symptoms relief, improving quality of life and avoiding complications such as recurrent infections. Through this paper, we aim to present a comprehensive overview of current therapeutic options of breast cancer upper limb related lymphedema. Therapeutic approach comprises of non-surgical (conservative) therapy, which is mandatory as initial therapy and surgical procedures for selected cases. Most patients with lymphedema benefit from conservative treatment alone. In non-responsive cases, in patients with progressive disease, in late stage complicated lymphedema, and also recently added as prophylactic strategy, surgical treatment, trough recent developed techniques, offer very good results in long-term control of disease. Surgical options are classified firstly in physiologic procedures that aim to create new lymphatic channels, promote physiologic drainage of the lymph and should be considered early in the course of the disease, and secondly ablative procedures that reduce through liposuction or various excision techniques the volume of the affected limb. Both types of techniques can be combined to ensure the best functional outcome of the patient.

DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing): A phase III trial—ECOG-ACRIN EA6134.

356154 Background: Combinations of immune checkpoint inhibitors (CPI) blocking PD-1 and CTLA-4 or BRAF/MEK inhibitors have both shown significant antitumor efficacy and overall survival (OS) benefit in patients (pts) with BRAFV600-mutant metastatic melanoma (MM), leading to broad regulatory approval. Little prospective data exists to guide the choice of one over the other as initial therapy or the preferred treatment sequence in this population. The DREAMseq Trial was designed to compare the efficacy and toxicity of the sequence of nivolumab/ipilimumab (N/I) followed by dabrafenib/trametinib (D/T) to the converse sequence. Methods: Eligible pts with treatment-naive BRAFV600-mutant MM were stratified by ECOG Performance Status (PS) 0 or 1 and LDH level and randomized 1:1 to receive Step 1 with either N/I (Arm A) or D/T (Arm B) and at disease progression (PD) were enrolled in Step 2 receiving the alternate therapy, D/T (Arm C) or N/I (Arm D), respectively. Pts received N (1mg/kg)/I (3 mg/kg) q3 wks x 4 doses followed by N 240 IV q2 wks for up to 72 wks (Arms A and D) or D 150 mg po BID and T 2 mg po qD until PD (Arms B and C). In 2019, investigators were given the option to use alternate induction dosing of N (3mg/kg)/I (1 mg/kg) q3 wks x 4 doses for Arms A and D. Cycles were every 6 wks and imaging was obtained at baseline and q12 wks on each arm. Primary endpoint was 2-year OS. At the 4th Interim Analysis with 59% of pts being 2 yrs from enrollment, the DSMC and NCI CTEP recommended halting accrual and releasing the data. Results: Beginning 7/2015, 265 out of a proposed 300 pts were enrolled (133 Arm A and 132 Arm B). Median age was 61 (25-85) and 63% were male. Demographics for Arm A and B were balanced with 67% PS 0 and 60% with normal LDH. As of 7/16/21, at a median follow-up of 27.7 mos, 27 pts had switched to Arm C and 46 to Arm D. Overall Grade 3+ toxicity was 60% in Arm A and 52% in Arm B. Grade 5 treatment-related AEs included 2 on Arm A and 1 on Arm C. ORR to date is: Arm A 46% (52/113), Arm B 43% (49/114), Arm C 48% (11/23) and Arm D 30% (8/27). 37/42 assessed pts in Arm A and 19/37 in Arm B remain in response. Median DOR: Arm A- Not reached; Arm B-12.7 mos (95% CI: 8.2, -) (p <0.001). There were 100 deaths (Arm A to C- 38/Arm B to D- 62). 2-yr OS rate for those starting with Arm A was 72% (95% CI: 62-81%) and for Arm B 52% (95% CI: 42-62%) (log-rank p= 0.0095). PFS showed a trend in favor of Arm A (log-rank p=0.054). Both the PFS and OS curves show a biphasic pattern with Arm B being above Arm A until 6 and 10 mos, respectively. For the 115 pts with documented progression on Step 1 (Arm A-44/Arm B-71), 60 (52%) had registered for Step 2. The principal reason for not enrolling on Step 2 was death from PD within 6 mos (Arm A:15/23; Arm B: 25/32). Conclusions: For pts with advanced BRAFV600-mutant MM, the treatment sequence beginning with the CPI combination of N/I resulted in superior OS, which became evident at 10 mos, with longer Step 1 DOR and more ongoing responses than the treatment sequence beginning with D/T. Clinical trial information: NCT02224781.

Efficacy of fluoroquinolones as substitutes for ethambutol or rifampin in the treatment of Mycobacterium avium complex pulmonary disease according to radiologic types

Objective: During the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD), ethambutol or rifampin is often discontinued because of adverse events. This study investigated the treatment outcomes when later-generation fluoroquinolones substitute ethambutol or rifampin in MAC-PD treatment based on the radiologic type. Methods: Between 2006 and 2019, patients who initiated standard treatment and whose treatment duration was ≥1 year were retrospectively identified at a tertiary referral center in South Korea, including 178 patients with cavitary disease (fibrocavitary and cavitary nodular bronchiectatic types) and 256 patients with noncavitary nodular bronchiectatic (NC-NB) type. We compared the microbiologic cure at 1 year between the patients who maintained the initial regimen and those who replaced ethambutol or rifampin with fluoroquinolones (moxifloxacin or levofloxacin). Results: The overall microbiologic cure rate of the 178 patients with cavitary disease was 71.3%. Among these, the microbiologic cure rates of the 16 patients who substituted fluoroquinolones for ethambutol were lower than those of the 156 patients who maintained three-drug oral antibiotics with aminoglycoside (37.5% vs. 74.4%, respectively; P = 0.007), which was statistically significant in multivariate analysis. The outcomes of the six patients receiving fluoroquinolones as an alternative to rifampin were similar to that of those continuing the initial regimen. The microbiologic cure rate of the patients with the NC-NB type receiving daily or intermittent oral three-drug therapy was similar regardless of maintaining the initial therapy or replacing ethambutol or rifampin with fluoroquinolones. Conclusions: In cavitary MAC-PD, substituting ethambutol with fluoroquinolones resulted in inferior patient outcomes.