Implications For Treatment Guidelines Research Articles

What is cancer? A focus on Grade Group 1 prostate cancer.

Since the widespread adoption of prostate-specific antigen-based screening for prostate cancer, the prevalence of Grade Group 1 (GG1) prostate cancer has risen. Historically, these patients were subjected to overtreatment of this otherwise indolent disease process, leading to significant quality-of-life detriments. Active surveillance as a primary management strategy has allowed for a focus on early detection while minimising morbidity from unnecessary intervention. Here we provide a comprehensive overview of the characteristics of GG1 prostatic adenocarcinoma, including its histological features, genomic differentiators, clinical progression, and implications for treatment guidelines, all supporting the movement to reclassify GG1 disease as a non-cancerous entity.

Adverse Histological Features of Differentiated Thyroid Cancer Are Commonly Found in Autopsy Studies: Implications for Treatment Guidelines.

Background: While the popularity of lobectomy for differentiated thyroid cancer (DTC) has increased since the 2015 ATA (American Thyroid Association) guidelines, recent studies reported that adverse histological features (minimal extrathyroidal extension [mETE], multifocality, vascular invasion, and lymph node [LN] metastases) may be found in 30-60% of lobectomy specimens, questioning the validity of this approach. Aim: To assess the prevalence adverse histological features in occult DTC detected in autopsy studies. Methods: Meta-analysis of autopsy studies of the thyroid in subjects without known history of thyroid cancer. Results: Twenty-nine studies including 8750 subjects fulfilled the inclusion criteria, with incidentally discovered DTC in 740 autopsies (8.5%). Age was reported in 17 studies, with a median age of 61 years (range 41-68 years). Multifocality was reported in 27 studies with a calculated event rate of 28.2% ([CI 23.1-33.8], I2 = 46.3%), with bilateral involvement in 18% [CI 12.6-25.1]. mETE was reported in 5 studies, with an event rate of 24.5% ([CI 9.3-50.7], I2 = 88.5%), and the presence of LN metastases were reported in 13 studies with an event rate of 11% ([CI 6.1-19.1], I2 = 69.5%). Vascular invasion was reported in seven studies with an event rate of 16% ([CI 4-47], I2 = 86.8%). Of 25 studies with whole body autopsies (722 subjects), 3 cases of distant metastases were reported, of which 2 had fatal metastatic disease (where thyroid origin was not diagnosed before death), and 1 had occult disease. Conclusions: Adverse histological features including mETE, LN metastases, multifocality, and vascular invasion are common in occult DTC. When minimal in size, these adverse histological features do not seem to be markers of aggressive disease and may not be an indication for completion thyroidectomy or radioiodine therapy.

Levels of Mycoplasma genitalium Antimicrobial Resistance Differ by Both Region and Gender in the State of Queensland, Australia: Implications for Treatment Guidelines.

Mycoplasma genitalium is frequently associated with urogenital and rectal infections, with the number of cases of macrolide-resistant and quinolone-resistant M. genitalium infection continuing to increase. In this study, we examined the levels of resistance to these two common antibiotic treatments in geographically distinct locations in Queensland, Australia. Samples were screened for macrolide resistance-associated mutations using a commercially available kit (ResistancePlus MG; SpeeDx), and quinolone resistance-associated mutations were identified by PCR and DNA sequencing. Comparisons between antibiotic resistance mutations and location/gender were performed. The levels of M. genitalium macrolide resistance were high across both locations (62%). Quinolone resistance mutations were found in ∼10% of all samples, with a number of samples harboring mutations conferring resistance to both macrolides and quinolones. Quinolone resistance was higher in southeast Queensland than in north Queensland, and this was consistent in both males and females (P = 0.007). The M. genitalium isolates in rectal swab samples from males harbored high levels of macrolide (75.9%) and quinolone (19%) resistance, with 15.5% harboring resistance to both classes of antibiotics. Overall, the lowest observed level of resistance was to quinolones in females from north Queensland (1.6%). These data highlight the high levels of antibiotic resistance in M. genitalium isolates within Queensland and the challenges faced by sexually transmitted infection clinicians in managing these infections. The data do, however, show that the levels of antibiotic resistance may differ between populations within the same state, which has implications for clinical management and treatment guidelines. These findings also support the need for ongoing antibiotic resistance surveillance and tailored treatment.

Protease inhibitors and preterm delivery: another piece in the puzzle.

Questions remain regarding preterm delivery (PTD) risk in HIV-infected women on antiretroviral therapy (ART), including the role of ritonavir (RTV)-boosted protease inhibitors, timing of ART initiation and immune status. We examined data from the UK/Ireland National Study of HIV in Pregnancy and Childhood on women with HIV delivering a singleton live infant in 2007-2015, including those pregnancies receiving RTV-boosted protease inhibitor-based (n = 4184) or nonnucleoside reverse transcriptase inhibitors-based regimens (n = 1889). We conducted logistic regression analysis adjusted for risk factors associated with PTD and stratified by ART at conception and CD4 cell count to minimize bias by indication for treatment and to assess whether PTD risk differs by ART class and specific drug combinations. Among women conceiving on ART, lopinavir/RTV was associated with increased PTD risk in those with CD4 cell count 350 cells/μl or less [odds ratio 1.99 (1.02, 3.85)] and with CD4 cell count more than 350 cells/μl [odds ratio 1.61 (1.07, 2.43)] vs. women on nonnucleoside reverse transcriptase inhibitors-based (mainly efavirenz and nevirapine) regimens in the same CD4 subgroup. Associations between other protease inhibitor-based regimens (mainly atazanavir and darunavir) and PTD risk were complex. Overall, PTD risk was higher in women who conceived on ART, had low CD4 cell count and were older. No trend of association of PTD with tenofovir or any specific drug combinations was observed. Our data support a link between the initiation of RTV-boosted/lopinavir-based ART preconception and PTD in subsequent pregnancies, with implications for treatment guidelines. Continued monitoring of PTD risk is needed as increasing numbers of pregnancies are conceived on new drugs.

A journey through the ‘rational mind’ and the ‘paradoxical logic of the unconscious’: Implications for treatment guidelines

Current political and economic trends in psychology push for an evidence-based practice whereby interventions are chosen on the basis of relevant research findings. Although valuable and effective, the efficacy and the ecological validity of evidence-based interventions has often been questioned, as it can be argued that human beings are too complex presentations to be captured by the restraints of clinical trials only. In addition, the dangers of pressurising psychology services to strictly adhere to manualised guidelines means that specialist’s skills might be obscured. This paper and the case-study presented in it position itself in the midst of this debate by highlighting how clinical intuition and idiosyncratic formulations can be integrated and enrich research based practice. In addition, this paper also highlights how these fluid specialist skills are crucial to the vitality of the field and to the identity of counselling psychologists. This urge for a wider definition of what constitutes ‘evidence base’ when working with such complex presentations as human beings.

Do scores on the Beck Depression Inventory-II predict outcome in cognitive processing therapy?

Current treatment guidelines for posttraumatic stress disorder (PTSD) recognize that severe depression may limit the effectiveness of trauma-focused interventions, making it necessary to address depression symptomatology first. However, there is a paucity of research providing specific treatment recommendations using a common depression measure like the Beck Depression Inventory-II (BDI-II). Accordingly, we examined the utility of using BDI-II cutoff scores for predicting response to cognitive processing therapy (CPT). Our sample was 757 military veterans receiving outpatient therapy at a Department of Veterans Affairs specialty clinic. At baseline, the majority of participants (58.9%) reported BDI-II scores suggestive of severe depression, and 459 (60.7%) met DSM-IV diagnostic criteria for major depressive disorder (MDD). Despite this high level of depression severity, most participants who completed therapy experienced a clinically significant reduction in symptoms (75.1%). No differences were observed across BDI-II groups on rates of clinically significant change in PTSD symptoms or on rates of treatment completion. Taken together, results suggest that CPT is an effective treatment, even in cases of severe co-occurring depression. Limitations and implications for treatment guidelines are discussed.

Protein binding of lopinavir and ritonavir during 4 phases of pregnancy: implications for treatment guidelines.

To investigate the intraindividual pharmacokinetics (PKs) of total (protein bound plus unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100 mg/25 mg) can overcome any pregnancy-associated changes. Prospective longitudinal PK study. HIV-infected pregnant antiretroviral therapy-naive and experienced women receiving LPV/RTV 400 mg/100 mg tablets twice daily. Intensive PK evaluations were performed at 20-24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100 mg/25 mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4). Twelve women completed prespecified PK evaluations. Median (range) age was 28 (18-35) years and baseline BMI was 32 (19-41) kg/m. During pregnancy, total area under the time concentration (AUC0-12h) for LPV was significantly lower than postpartum (PK1, PK2, or PK3 vs. PK4, P = 0.005). Protein-unbound LPV AUC0-12h remained unchanged during pregnancy [PK1: 1.6 (1.3-1.9) vs. PK2: 1.6 (1.3-1.9) μg·h/mL, P = 0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3-2.1) μg·h/mL, P = 0.5]. Protein-unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08-0.15) vs. PK3: 0.12 (0.10-0.15) μg/mL, P = 0.09]. Albumin and LPV AUC0-12h fraction unbound were correlated (rs = 0.3, P = 0.03). Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women.

The airflow resistance sensing threshold during tidal breathing rises in old age in patients with asthma

in a previous study, we showed that the ability to detect a rise in airflow resistance at rest was reduced in some non-asthmatic subjects in old age. to determine whether airflow resistance detection is attenuated in elderly subjects with asthma. we studied 60 adult subjects with stable asthma (age range 20-88). Progressive external airflow resistance loading was used to measure the inspiratory load detection threshold (LDT) during tidal breathing at rest. the mean inspiratory LDT was 5.57 (4.33 SD) kPa.s/l in the 20-64 age group (n=32) and 15.6 (10.1 SD) kPa.s/l in those aged 65 and above (n=28) (P<0.0001). The inspiratory LDT was significantly correlated with age (r=0.5246, P<0.00008), mainly due to the effect of higher LDTs in about half of the subjects above the age of 65 years. Expiratory LDT values and correlations were very similar to inspiratory values. the threshold for detecting external resistive loads during tidal breathing rises in old age in some, but not all, asthmatic patients as was observed in non-asthmatic subjects. The finding has implications for treatment guidelines because some elderly subjects are likely to have reduced awareness of worsening airflow obstruction, and consequently delay their use of rescue treatments.

Pandemic (H1N1) 2009 influenza in Canadian pediatric cancer and hematopoietic stem cell transplant patients

The impact of pandemic H1N1 influenza (pH1N1) virus in pediatric cancer is uncertain. The objectives of this study were to characterize the clinical course of pH1N1 and identify factors associated with severe outcomes. We conducted a Canadian multicenter retrospective review of children with cancer and stem cell transplant (SCT) recipients who were diagnosed with laboratory-confirmed pH1N1 infection between May 1, 2009 and January 31, 2010. We identified 100 (19 in wave 1 and 81 in wave 2) cases of pH1N1 infection. Median age was 8.7 years. 71% had a hematologic malignancy, and 20% received SCT. Median duration of fever and illness was 2 and 12.5 days, respectively. 51 (51.5%) were hospitalized for a median of 5 days, with no deaths and only 1 requiring admission to the intensive care unit. Radiologically confirmed pneumonia was diagnosed in 10 (10%). Interruption of chemotherapy or conditioning occurred in 43 patients. In multivariable analyses, age <5 years (relative to ≥ 10 years) and neutropenia were associated with hospitalization while neutropenia was associated with pneumonia. Despite oseltamivir use in 89%, viral shedding was prolonged (median, 46 days) and often persisted after symptom resolution. However, an extended treatment course (>5 days) correlated with shortened duration of viral shedding (P=0.041). pH1N1 infection in pediatric cancer and SCT patients infrequently caused complications but commonly interrupted cancer treatment. Persistent shedding of virus after illness resolution was common. Further research is needed to verify this finding as it could have implications for treatment guidelines and infection control practices.

Gonococcal resistance: evolving from penicillin, tetracycline to the quinolones in South Africa – implications for treatment guidelines

Resistant Neisseria gonorrhoeae has been evolving. This study assessed the antimicrobial susceptibility profile of isolates in the Pretoria region, South Africa. Isolates of N. gonorrhoeae from men with urethritis were tested for susceptibility to eight antimicrobial agents by disc diffusion, Etest and agar dilution methods. Chromosomal resistance to penicillin was found in 16% of isolates, 16% showed plasmid-mediated resistance and decreased susceptibility was seen in 73% of isolates. For the first time, there is evidence of high-level tetracycline resistance (36%). Ciprofloxacin resistance emerged at 7%. All isolates remained susceptible to ceftriaxone. In view of these findings of the emergence of quinolone-resistant N. gonorrhoeae, national treatment guidelines for syndromic management of sexually transmitted infections need to be urgently reviewed. The injectable preparation, ceftriaxone has to be considered as a first-line agent for the management of gonococcal infections. Overall, the gonococcal isolates in the Pretoria region remain susceptible to ceftriaxone, cefoxitin, cefpodoxime and spectinomycin.

Clinical Trial Results of New Therapies for HBV: Implications for Treatment Guidelines

Currently approved treatments for chronic infection with hepatitis B virus (HBV) are limited by low rates of sustained response, side effects, and in some cases, the emergence of drug resistance. Thus, new treatments, characterized by more potent antiviral effects less toxicity, and minimal or no risk of resistance, are needed. During the last few years, several agents have been developed that have increased potency and reduced potential for resistance--among them, entecavir and pegylated interferons. In addition, several novel anti-HBV agents recently evaluated in phase II clinical trials, such as tenofovir, clevudine, telbivudine, pradefovir, and valtorcitabine, appear to be promising agents for the treatment of chronic hepatitis B. This article describes the clinical experience with new antiviral agents and the implications of the trial results for practice guidelines.