Biochemical Control Of Disease Research Articles

Effect of Cabergoline on weight and glucose metabolism in patients with acromegaly.

Cabergoline (CAB) has shown to have benefic effects on the metabolism in different clinical settings but its metabolic role in acromegaly disease has not been studied yet. Aim of our study was to evaluate the impact of CAB on glucose metabolism and weight in patients with acromegaly. All patients with acromegaly undergoing continuous treatment with CAB for at least 6months were retrospectively screened. Exclusion criteria were discontinuation of CAB for more than one month, change of antidiabetic or other therapy for acromegaly, concomitant untreated hormonal deficiency, initiation of pregnancy and/or breastfeeding. All patients were evaluated in terms of biochemical disease control, glucose metabolism and weight at baseline (T0) and after the introduction of CAB therapy at 6 (T6) and 12months (T12). Twenty-six patients (15 females and 11 males) were evaluated at T0 and T6 and 19 patients (12 females and 7 males) were also evaluated at T12. Insulin-like growth factor I (IGF-I) and prolactin (PRL) levels were significantly lower at T6 and T12 compared to baseline (p < 0.001 for IGF-I, p < 0.05 for PRL) even if no further differences were observed between T12 and T6. Considering the entire cohort, no differences were appreciated regarding the metabolic parameters but a significant reduction in weight and body mass index (BMI) was observed at both T6 (p = 0.009 for weight, p = 0.021 for BMI) and T12 (p = 0.014 for weight, p = 0.017 for BMI) compared to baseline. Our results confirm the efficacy of CAB in providing a significant improvement in the biochemical disease control but do not demonstrate a marked benefit on glucose metabolism of acromegaly patients. In such patients, CAB appears to have a rapid effect on weight and BMI, with significant changes noticeable as early as 6months and persisting for at least 12months.

Long-Term Outcomes Associated with Different High-Dose-Rate Brachytherapy Dose Regimens for Favorable and Unfavorable Intermediate Risk Prostate Cancer.

To present long-term efficacy outcomes of prostate high-dose-rate (HDR) brachytherapy monotherapy using 38 Gy in 4 fractions, 24 Gy in 2 fractions, and 27 Gy in 2 fractions for men with favorable and unfavorable intermediate risk prostate cancer. Patients treated with HDR brachytherapy monotherapy for NCCN favorable (FIR) or unfavorable (UIR) intermediate risk prostate cancer from 1999-2020 were identified in a prospectively maintained, single institution database. Patients with less than two years of follow-up and those treated with single fraction HDR brachytherapy were excluded. Biochemical failure was determined using Phoenix criteria. 10-year biochemical control (BC), local control (LC), and distant metastasis (DM) rates were estimated using the Kaplan-Meier method. Two hundred sixty-seven patients were included. One hundred eighty-nine had FIR and 78 had UIR prostate cancer, with median follow-up of 9.6 years and 7.2 years, respectively. Of the 189 patients with FIR prostate cancer, 59 (31.2%) received 38 Gy in 4 fractions, 26 (13.7%) received 24 Gy in 2 fractions, and 104 (55.0%) received 27 Gy in 2 fractions. Of the 78 patients with UIR prostate cancer, 20 (25.6%) received 38 Gy in 4 fractions, 11 (14.1%) received 24 Gy in 2 fractions, and 47 (60.2%) received 27 Gy in 2 fractions. Date ranges of treatment for the respective fractionation schedules were 1999-2010, 2007-2016, and 2009-2020. Upfront androgen deprivation therapy (ADT) was given to 12 (6.3%) patients with FIR and 10 (12.8%) patients with UIR. 10-year rates of BC for FIR and UIR patients were 90.1% and 78.8% (p = 0.004), respectively. 10-year rates of LC were 92.4% and 85.0% (p = 0.06), respectively. 10-year rates of DM were 1.9% and 4.7% (p = 0.12), respectively. For FIR patients, 10-year BC rates were 96.2% for patients receiving 38 Gy in 4 fractions vs. 86.3% (p = 0.07) for those treated with the 2-fraction regimens, while 10-year LC rates were 97.9% and 89.0% (p = 0.049), respectively. Within the UIR subset, the 10-year BC rates for patients receiving 38 Gy in 4 fractions and patients receiving treatment in 2 fractions were 95.0% and 70.6% (p = 0.038). 10-year LC rates were 100% and 77.8% (p = 0.045), respectively. 10-year BC rates by treatment schedule are shown in the table below. HDR brachytherapy monotherapy results in excellent long-term local control for intermediate risk prostate cancer. Improvements in biochemical and local disease control for patients treated with 38 Gy in 4 fractions warrants consideration of prospective study of optimal treatment dosing regimens.

Adverse risk factors for salvage radiotherapy outcomes after radical prostatectomy in prostate cancer patients.

To investigate salvage treatment approaches and treatment outcomes in high-risk prostate cancer after radical prostatectomy (RP). In this retrospective, multicenter study, 272 patients who underwent salvage radiotherapy (RT) ± androgen deprivation therapy (ADT) for recurrent prostate cancer after RP between 2007 and 2021 were analysed. Univariate analyses of time to biochemical and clinical relapse after salvage therapies were conducted using Kaplan-Meier plots and log-rank tests. Multivariate analyses were performed using a Cox proportional hazards model to determine the risk factors for disease relapse. Median age was 65 (48-82) years. All patients underwent salvage prostate bed RT. Pelvic lymphatic RT was performed in 66 patients (24.3%) and ADT was included in 158 (58.1%) patients. The median PSA value before RT was 0.35ng/mL. The median follow-up time was 64 (12-180) months. 5-years bRFS, cRFS, and OS were 75.1%, 84.8%, and 94.9% respectively. In multivariate cox regression analysis; seminal vesicle invasion (HR 8.64, 95% CI 3.47-21.48, p < 0.001), pre-RT PSA higher than 0.14ng/mL (HR 3.79, 95% CI 1.47-9.78, p= 0.006), and ≥ 2 positive pelvic lymph nodes (HR 2.50, 95% CI 1.11-5.62, p= 0.027) were found to be unfavorable prognostic factors for bRFS. Salvage RT ± ADT provided 5-years biochemical disease control in 75.1% of patients. Seminal vesicle invasion, ≥ 2 positive pelvic nodes and delayed administration of salvage RT (PSA levels higher than 0.14ng/mL) were found to be adverse risk factors for relapse. Such factors should be taken into account during the decision process on salvage treatment.

Extreme hypofractionated stereotactic radiotherapy for elderly prostate cancer patients: side effects preliminary analysis of a phase II trial.

Aim of this study is to evaluate safety and efficacy of SBRT in elderly patients affected by localized prostate cancer (PC). Men aged 70years or older were enrolled and analyzed. The SBRT schedule was 35Gy in 5 fractions administered in 1-2weeks. According to risk group, androgen deprivation therapy (ADT) was prescribed. Urinary symptoms were evaluated at baseline using the International Prostate Symptom Score (IPSS). Genitourinary (GU) and gastrointestinal (GI) toxicities were assessed at the end of treatment, 2weeks after SBRT and during follow-up using the Common Terminology Criteria for Adverse Events (CTCAE). PSA values were recorded before treatment and during follow-up as biochemical response criteria. Between 07/2019 and 09/2021, 111 patients were enrolled. Median age was 77years. At the end of treatment, no acute GU/GI toxicities ≥ G2 were observed. At 2-3weeks after treatment, 3 patients reported G2 GU toxicity, while 14 patients referred G2 GI toxicity. During the last follow up, 26 and 2 patients reported, respectively, G1 and G2 GU toxicity, while 22 and 1 cases described, respectively, G1 and G2 GI toxicity. No late toxicities ≥ G3 were recorded. GU toxicity is related to absence of urethra sparing, increasing PTV volume, Dmax PTV and IPSS; GI toxicity is related to RT schedule (each other day is better than consecutive day), Dmax rectum and IPSS, At a median follow-up of 24months, excellent biochemical disease control was achieved in all cases with median PSA of 0.5ng/ml. SBRT in elderly patients affected by PC is feasible and well tolerated with excellent biochemical disease control. Longer follow-up is needed to assess late toxicity profile and long-term clinical outcome.

Biochemical disease control outcomes of stereotactic body radiation therapy (SBRT) or moderate hypo-fractionation (HFRT) for low- and intermediate-risk prostate cancer (PrCa): Retrospective analysis of 12 years of experience at two Canadian cancer centers.

363 Background: SBRT uses highly conformal radiotherapy to deliver high dose per fraction treatment. Advantages of SBRT include short treatment times, decreased costs and limited toxicity. Randomized trial outcomes of 7-fraction SBRT for low or intermediate PrCa were reported but results of studies that compared 5-fraction SBRT with conventional and HFRT are pending. Here, we reviewed the 12-year experience with SBRT and HFRT at the Juravinski and Walker Family Cancer Centers in Ontario. Methods: We reviewed patients with low or intermittent-risk PrCa treated with SBRT alone or HFRT alone in the period of July 2010 and February 2022. Database search criteria included treatments with SBRT 35-40Gy in 5 fractions and HFRT 60-62Gy in 20 fractions. Overall survival (OS), time to biochemical failure (per Phoenix criteria: i.e., 2ng/mL above PSA nadir) and biochemical failure-free survival (bFFS) were reviewed. Kaplan-Meier curves were used to assess OS and bFFS. Results: We identified 314 patients with low or intermediate-risk PrCa who were treated with SBRT and 258 patients who were treated with HFRT. Intermediate-risk category composed 86.0% and 95.7% of the SBRT and HFRT cohorts. ISUP Grade Group (GG) distributions for the SBRT and HFRT patients were: GG1: 19.4% and 9.3%, GG2: 72.9% and 74.0%, and GG3: 7.6% and 16.7%, respectively. OS rates at 5 years were 96.6% for SBRT vs. 95.8% for HFRT-treated patients. The 5-year bFFS rates for SBRT and HFRT were 92.3% and 90.1%, respectively. The 7-year bFFS rate for the SBRT cohort was 90.2%. Mean time to biochemical failure was 40.4 months after SBRT vs. 35.8 months after HFRT. Conclusions: SBRT is an effective treatment option for low to intermediate-risk PrCa with encouraging OS and bFFS rates comparable with HFRT. Pending randomized trial results will determine whether SBRT is the new standard of care for this population.

Metronomic Chemotherapy Based on Topotecan or Topotecan and Cyclophosphamide Combination (CyTo) in Advanced, Pretreated Ovarian Cancer.

Patients with advanced ovarian cancer (OC) have a detrimental prognosis. The options for systemic treatment of advanced OC in later lines of treatment are limited by the availability of active therapies and their applicability to often fragile, exhausted patients with poor performance status. Metronomic chemotherapy (MC) is a concept of a continuous administration of cytotoxic drugs, which is characterized by multidirectional activity (anti-proliferative, anti-angiogenic, and anti-immunosuppressive) and low toxicity. We have performed a retrospective analysis of consecutive, advanced, chemo-refractory OC patients treated with MC based on single-agent topotecan (1 mg p.o. q2d) or on a topotecan (1 mg q2d) and cyclophosphamide (50 mg p.o. qd) combination (CyTo). Metronomic chemotherapy demonstrated promising activity, with 72% and 86% of patients achieving biochemical or objective disease control and 18% and 27% of patients achieving a biochemical or objective response, respectively. The median PFS in the whole population was 3.65 months, but the median PFS in patients with a biochemical response to MC (18.2% of patients) reached 10.7 months. The study also suggested that overweight or obese patients had significantly better outcomes on MC than patients with BMI <25 kg/m2. This article is the first report in the literature on metronomic chemotherapy based on a topotecan + cyclophosphamide combination (CyTo). The CyTo regimen demonstrated safety, clinical activity, and potential broad clinical applicability in advanced OC patients and will be evaluated in a forthcoming clinical trial.

Inhibition of Tolaasin Cytotoxicity Causing Brown Blotch Disease in Cultivated Mushrooms Using Tolaasin Inhibitory Factors.

Tolaasin, a pore-forming bacterial peptide toxin secreted by Pseudomonas tolaasii, causes brown blotch disease in cultivated mushrooms by forming membrane pores and collapsing the membrane structures. Tolaasin is a lipodepsipeptide, MW 1985, and pore formation by tolaasin molecules is accomplished by hydrophobic interactions and multimerizations. Compounds that inhibit tolaasin toxicity have been isolated from various food additives. Food detergents, sucrose esters of fatty acids, and polyglycerol esters of fatty acids can effectively inhibit tolaasin cytotoxicity. These chemicals, named tolaasin-inhibitory factors (TIF), were effective at concentrations ranging from 10-4 to 10-5 M. The most effective compound, TIF 16, inhibited tolaasin-induced hemolysis independent of temperature and pH, while tolaasin toxicity increased at higher temperatures. When TIF 16 was added to tolaasin-pretreated erythrocytes, the cytotoxic activity of tolaasin immediately stopped, and no further hemolysis was observed. In the artificial lipid bilayer, the single-channel activity of the tolaasin channel was completely and irreversibly blocked by TIF 16. When TIF 16 was sprayed onto pathogen-treated oyster mushrooms growing on the shelves of cultivation houses, the development of disease was completely suppressed, and normal growth of oyster mushrooms was observed. Furthermore, the treatment with TIF 16 did not show any adverse effect on the growth of oyster mushrooms. These results indicate that TIF 16 is a good candidate for the biochemical control of brown blotch disease.

Associations between paraclinical parameters, symptoms and quality of life in patients with acromegaly: a cross sectional study

IntroductionAcromegaly is a rare chronic endocrine disorder that can lead to significant quality of life (QoL) impairment and persistent symptomatology in both biochemically uncontrolled as well as in cured or controlled patients. We aimed to conduct an observational cross-sectional study investigating the associations between biochemical disease control, associated comorbidities, and symptoms severity on QoL in a cohort of acromegalic patients.MethodsThirty-one patients with acromegaly were enrolled in our study. AcroQoL and PASQ (Pain assessed acromegaly symptoms questionnaire) questionnaires were applied to all patients. Information about disease status, associated comorbidities, and other relevant clinical and paraclinical data were gathered.ResultsPatients with uncontrolled acromegaly presented worse QoL and symptoms scores than controlled patients, but the difference was not statistically significant (AcroQoL 57.22 vs 64.04, p > 0.05; PASQ 12 vs 16.47, p > 0.05). Worse symptoms were significantly associated with impaired QoL (overall symptoms score on PASQ was negatively correlated with AcroQoL total score, r = − 0.61, p < 0.05). Cardiovascular complications were associated with lower QoL scores, but not with worse symptoms (AcroQoL total score in patients with- versus patients without cardiovascular complications: 54.89 vs 70.14, p < 0.05).ConclusionsAchieving biochemical control of acromegaly might not be enough to reverse the QoL impairment and improve symptomatology in acromegalic patients. While symptoms severity and the presence of cardiovascular complications seem to play an important role in reducing patients QoL, the roles of disease control, diabetes, and pituitary insufficiency are less clear.

Looking at the spine in controlled Acromegaly.

Skeletal fragility with high risk of vertebral fractures (VFs) is an emerging complication of growth hormone (GH) hypersecretion. VFs often coexist with spine arthropathy and both clinical conditions negatively impact on quality of life of acromegalic subjects. Management of spine osteopathy and arthropathy in acromegaly could be challenging since both complications can persist or even progress after biochemical control of disease. This article analyzes the latest evidence about possible pathophysiological links between VFs and spine arthropathy in active and controlled acromegaly, as well as the diagnostic and therapeutic aspects concerning the holistic management of acromegalic osteo-arthropathy.

Osilodrostat in Cushing’s disease: the management of its efficacy and the pitfalls of post-surgical results

Osilodrostat is a novel, orally administered cortisol synthesis inhibitor, approved in 2020 by the European Medicines Agency (EMA) for the treatment of Cushing's syndrome in adults. A significant amount of the studies currently available in the literature focus on treatment in patients with Cushing's disease. However, data collected from patients treated with osilodrostat in real-life settings still represents a small entity. For this reason, in this article, we will discuss two real-life cases of patients with Cushing's disease treated with this drug. The first report is about a 35-year-old woman with an adrenocorticotrophic hormone (ACTH)-secreting adenoma. After non-curative trans-nasal-sphenoidal (TNS) surgery, due to a small remnant of the adenoma, medical therapy with osilodrostat achieved fast and effective biochemical and clinical response. During treatment, progressive increase of ACTH levels and an enlargement of the pituitary remnant were documented, with planned radiosurgical treatment. The second case reports a 32-year-old man diagnosed with Cushing's disease in 2020, who, after surgery refusal, started osilodrostat at progressively up-titrated doses, according to 24 h urinary free cortisol levels, up to 5 mg twice a day. With osilodrostat, the patient reached biochemical and clinical control of disease until TNS surgery in October 2021, with complete remission. The first post-surgical biochemical assessment was equivocal in spite of a transient clinical hypoadrenalism, reverted after 2 months with the restoration of physiological hypothalamic-pituitary-adrenal axis (HPA) function. Osilodrostat is a potent oral drug viable for Cushing's disease as medical therapy when surgery is not feasible or remission cannot be reached. Osilodrostat proves to be a safe drug and its main adverse effect is hypoadrenalism, due to the adrenolytic action of the compound. Osilodrostat needs a very tailored approach in its clinical use because there is no correlation between the level of hypercortisolism pre-treatment and the dose required to reach disease control.

Toxicity and Patient Reported Quality of Life Outcomes Following Prostate SBRT with Focal Boost to MRI Identified Prostate Cancer Lesions: Results of a Phase II Trial

<h3>Purpose/Objective(s)</h3> A focused boost to MRI identified prostate cancer lesions treated with radiotherapy has been shown to improve biochemical disease control without increased toxicity in standard fractionated radiation treatment. Prostate cancer is known to be sensitive to higher radiation doses per fraction and thus stereotactic body radiotherapy (SBRT) has become an increasingly popular treatment method. In this prospective phase II trial, we investigated the toxicity and patient reported quality of life outcomes in patients treated with SBRT to the prostate gland and a simultaneous focal boost to MRI identified intraprostatic lesions while also de-escalating dose to the adjacent organs at risk. <h3>Materials/Methods</h3> Eligible patients included low- or intermediate- risk prostate cancer (Gleason score ≤ 7, PSA ≤20, T stage ≤2b). SBRT was prescribed to 40 Gy in 5 fractions delivered every other day to the prostate, with areas of high disease burden (MRI-identified PI-RADS 4 or 5 lesions) escalated to 42.5-45 Gy and areas overlapping organs at risk (within 2 mm of urethra, anterior rectal wall, and bladder base) constrained to 36.25 Gy (n=98). Patients without a pre-treatment MRI were treated to dose of 37.5 Gy with no focal boost (n=14). Acute and late toxicity were graded using RTOG modified toxicity scales. Patient-reported outcome and quality of life was assessed using the AUA-IPSS lower urinary tract symptom score, IIEF-5 erectile function, and EPIC-26 surveys. Statistical testing was performed in statistical software. <h3>Results</h3> From 2015 to 2022, a total of 112 patients were enrolled with a median follow-up of 36 months. No acute or late grade 3+ GI or GU toxicity was observed. Within the focal boost arm, acute grade 2 GU toxicity during treatment or at 6-week follow-up was seen in 26% of patients. Acute grade 2 GI toxicity was seen in 1 patient. Cumulative late grade 2 GU toxicity was 8%. Rate of alpha blocker medication use following treatment was 26%. Cumulative late grade 2 GI toxicity was 2.3%. Patient reported outcomes showed no significant changes from baseline IPSS lower urinary tract, IIEF erectile function, or EPIC-26 urinary incontinence, urinary irritative, gastrointestinal, or sexual domain quality of life scores following treatment (p >0.05 for all tests via RANOVA). Two patients have had a biochemical recurrence to date, at 42 months and 60 months post treatment. <h3>Conclusion</h3> SBRT to a dose of 40 Gy to the prostate gland with a focal boost up to 45 Gy is well tolerated with no observed grade 3 toxicity and similar rates of acute and late grade 2 GI and GU toxicity as seen in other SBRT regimens without intraprostatic dose boost. Moreover, no significant changes were seen in patient reported urinary, bowel, or sexual outcomes from pre-treatment baseline at any follow-up date. Biochemical control data continue to mature but few treatment failures have been observed to date.

Long Term Results of Elective Nodal Salvage Radiotherapy in Oligometastatic Prostate Cancer : A Mono-Institutional Series

Background The development of new metabolic diagnostic imaging PET is changing the history of metastatic prostate cancer (pCa), identifying situations of progression with a low disease burden; radiation treatment of metabolically active oligometastatic sites has been shown to be effective to prolong patient survival. In the scenario of oligometastatic disease to pelvic lymph nodes there is no uniform consensus on treatment volumes and radiotherapy doses to use. Methods We retrospectively assessed a series of 50 patients treated from 2015 to 2021 at our center who presented with recurrent pelvic lymph node pCa disease with 1-3 lymph-nodes lateralized to one side of the pelvis. Patients were treated with intensity modulated Rapid Arc radiotherapy (IMRT), limiting the treatment volume to the chain of the affected side only. During the follow-up, the patients who presented a biochemical recurrence of the disease were evaluated by PET. Results The biochemical progression-free survival and the metastatic progression-free survival were respectively 36% and 49% at 5 years. 22/50 patients presented a documented recurrence on PET. Only one patient presented a relapse within the irradiated volume and no patient presented a relapse on the contralateral pelvic lymph node chain. No patient had gastrointestinal toxicity &gt; grade 1 RTOG. Conclusion Treatment of patients with oligorecurrent (1-3 lesions) pelvic pCa, limiting the volume of irradiation to only one side of the affected lymph node chain, results in good biochemical disease control and presents a low risk of neoplastic contralateral progression.

The Russian Registry of Chronic Hypoparathyroidism.

IntroductionChronic hypoparathyroidism is a relatively rare disease associated with multicomponent medical therapy and various complications. The analysis of large databases of patients with chronic hypoparathyroidism is a necessary tool to enhance quality of medical care, as well as to determine the optimal clinical and therapeutic approaches, and prognostic markers of the disease.The Aimof this study is to estimate the clinical and biochemical profile, long-term complications, medical therapy and disease control of the patients with chronic postsurgical and non-surgical hypoparathyroidism.Materials and Methodsthe cross-sectional, observational, continuous study was based on the Russian Registry of patients with hypoparathyroidism. 544 patients from 63 regions of the Russian Federation were included in this study.ResultsThe majority of cases had postsurgical etiology (88.4%). Postsurgical hypoparathyroidism prevailed in females (р<0.001). About a half of patients had blood calcium and phosphorus targets, 56 and 52% respectively. Nephrolithiasis was confirmed in 32.5%, nephrocalcinosis - in 12.3% of cases. The risk of nephrocalcinosis/nephrolithiasis increased by 1.85 times with disease duration more than 4.5 years. The cataract was found in 9.4%. The cut-off point for the development of cataracts was 9.5 years, with a 6.96-fold increased risk. The longer duration of hypoparathyroidism of any etiology was associated with more frequent cataract (p=0.0018).We found brain calcification in 4%, arrhythmias in 7.2% and neuropsychiatric symptoms in 5.15% of cases. Generally, the BMD in the studied group corresponded to age values, and there was no evidence for the phenomenon of high bone density. TBS was consistent with normal bone microarchitectonics. In our study, the majority of patients (83.5%) was treated with standard therapy of calcium and vitamin D supplements. 5 patients with severe disease course were treated with rhPTH (1–34).ConclusionsAnalysis of the presented database indicates insufficient diagnosis of the complications associated with chronic hypoparathyroidism. Overall, hypoparathyroidism is associated with higher risks of renal stone formation, decreased GFR, cataract especially in patients with longer duration of disease.

177 Lu-PSMA-617 radioligand therapy of metastatic castration-resistant prostate cancer: Initial 254-patient results from a prospective registry (REALITY Study)

PurposePreliminary data from retrospective analyses and recent data from large randomized controlled trials suggest safety and efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC). Limited data on this modality have been published regarding large samples treated in everyday practice.MethodsWe analyzed prospectively collected registry data regarding lutetium-177 (177Lu)-PSMA-617 RLT of 254 consecutive men with mCRPC seen in everyday academic practice. Since 177Lu-PSMA-617 was experimental salvage treatment following failure of individually appropriate conventional therapies, patients were generally elderly and heavily pretreated (median age 70 years; prior taxanes 74.0%, 188/254), with late–end-stage disease (visceral metastasis in 32.7%, 83/254). Primary endpoints were response to RLT, defined by changes from baseline serum prostate-specific antigen (PSA) concentration, PSA progression-free survival (PSA-PFS), and overall survival (OS), estimated with Kaplan–Meier statistics, and caregiver-reported and patient-reported safety. Unless noted, median (minimum–maximum) values are given.ResultsPatients received 3 (1–13) 177Lu-PSMA-617 activities (6.5 [2.5–11.6] GBq/cycle) every 5.7 (3.0–11.0) weeks. Best response was ≥ 50% PSA reduction in 52.0% of patients (132/254). PSA-PFS was 5.5 (95% confidence interval [95%CI] 4.4–6.6) months and OS, 14.5 (95%CI 11.5–17.5) months. In multivariable Cox proportional-hazards modeling, response to the initial ≤ 2 RLT administrations was the strongest significant prognosticator related to OS (hazard ratio 3.7 [95%CI 2.5–5.5], p < 0.001). No RLT-related deaths or treatment discontinuations occurred; the most frequent RLT-related Grade 3/4 adverse events were anemia (18/254 patients, 7.1%), thrombocytopenia (11/254, 4.3%), and lymphopenia (7/254, 2.8%). RLT-related xerostomia, all grade 1/2, was noted in 53/254 (20.9%).ConclusionsIn a large, prospectively observed “real-world” cohort with late-stage/end-stage mCRPC and conventional treatment failure, 177Lu-PSMA-617 RLT was effective, safe, and well-tolerated. Early biochemical disease control by such therapy was associated with better OS. Prospective study earlier in the disease course may be warranted.

The Effect of 6 Months' Treatment With Pasireotide LAR on Glucose Metabolism in Patients With Resistant Acromegaly in Real-World Clinical Settings.

ObjectiveThe aim of the study was to evaluate glucose metabolism, as measured by glycated hemoglobin (HbA1c) levels and the need for antidiabetic medical treatment, in patients with acromegaly resistant to first-generation somatostatin receptors ligands (SRLs) treated with pasireotide long-acting release (LAR) in real-world clinical practice. Biochemical control of acromegaly, as measured by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, was also assessed.Study DesignTwo-center retrospective cohort of consecutive patients with acromegaly treated with first-generation SRLs at maximum doses, who had not achieved biochemical disease control. After SRLs were discontinued, patients were given pasireotide LAR 40 mg i.m. every 28 days. The dose was increased to 60 mg i.m. in patients for whom adequate control was not achieved after 3 months. Patients were given dietary and lifestyle advice, and antihyperglycemic treatment was modified as needed.Main Outcome MeasuresBiochemical disease control parameters (GH and IGF-1 concentration), as well as HbA1c level at baseline and after 6 months.ResultsIn total, 39 patients with acromegaly were enrolled. GH concentration decreased (Δme =-1.56 µg/L, range -21.38–3.62, p <0.001) during 6 months of pasireotide LAR treatment. A worsening of metabolic status was observed, with an increase of median HbA1c (Δme =0.40%, range -0.20%–2.30%, p <0.001), and antihyperglycemic treatment intensification in 23 (59.0%) patients. The median decline in IGF-1 concentration was: -283.0 µg/L, range -682.7–171.6, p <0.001. IGF-1 reached the age- and gender-specific upper level of normal in 23 (59%) patients.ConclusionsPasireotide LAR is an effective therapeutic option in patients with acromegaly refractory to first-generation SRLs. However, this therapy may result in pasireotide LAR-associated hyperglycemia, which requires early and aggressive antidiabetic medical therapy to prevent glucose homeostasis alterations.

Robotic Radiosurgery for Persistent Postoperative Acromegaly in Patients with Cavernous Sinus-Invading Pituitary Adenomas-A Multicenter Experience.

Simple SummaryGrowth hormone-secreting tumors of the pituitary gland which infiltrate surrounding tissue structures may not be fully resectable. This causes many patients to suffer from acromegaly after an unsuccessful surgery. To limit the considerable morbidity and mortality of such patients, effective and safe treatment options are needed. Fractionated radiotherapy and growth hormone-lowering medication are possible treatment options. Robotic radiosurgery (RRS) may be a suitable treatment modality as well. However, only sparse and heterogeneous data are available. This first retrospective multicenter study investigated the efficacy and safety of RRS for this patient group. Outcomes provide evidence that RRS may achieve biochemical disease control or remission in most of the patients. The hormone levels are decreasing after treatment, whereas favorable risk and safety profiles of RRS were shown. No new tumor growth was observed throughout the available follow-up. These findings may guide future care for this challenging patient population.Background: The rates of incomplete surgical resection for pituitary macroadenomas with cavernous sinus invasion are high. In growth hormone-producing adenomas, there is a considerable risk for persistent acromegaly. Thus, effective treatment options are needed to limit patient morbidity and mortality. This multicenter study assesses the efficacy and safety of robotic radiosurgery (RRS) for patients with cavernous sinus-invading adenomas with persistent acromegaly. Methods: Patients who underwent RRS with CyberKnife for postoperative acromegaly were eligible. Results: Fifty patients were included. At a median follow-up of 57 months, the local control was 100%. The pretreatment insulin-like growth factor 1 (IGF-1) levels and indexes were 381 ng/mL and 1.49, respectively. The median dose and prescription isodose were 18 Gy and 70%, respectively. Six months after RRS, and at the last follow-up, the IGF-1 levels and indexes were 277 ng/mL and 1.14, as well as 196 ng/mL and 0.83, respectively (p = 0.0001 and p = 0.0002). The IGF-1 index was a predictor for biochemical remission (p = 0.04). Nine patients achieved biochemical remission and 24 patients showed biochemical disease control. Three patients developed a new hypopituitarism. Conclusions: RRS is an effective treatment for this challenging patient population. IGF-1 levels are decreasing after treatment and most patients experience biochemical disease control or remission.

Updates in rare and not-so-rare complications of acromegaly: focus on respiratory function and quality of life in acromegaly.

Acromegaly is a complex disease with excessive growth hormone and insulin-like growth factor 1 (IGF-1) causing multisystem effects, particularly cardiovascular, respiratory, and metabolic. Psychological concerns and poor quality of life (QoL) are also major disease consequences. This review is intended for clinicians and focuses on the latest developments related to respiratory and QoL effects of long-term growth hormone excess. Along with biochemical disease control, patient treatment satisfaction and outcomes have become major treatment objectives; current knowledge and tools to evaluate and manage this aspect of the disease are described. Sleep apnea syndrome and other derangements of lung function and apparatus, from pathophysiology to treatment, and evaluation tools and determinants of QoL in patients with acromegaly are discussed.

Multivariable Prediction Model for Biochemical Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. Retrospective multicenter study. Eight participating European centers. We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72-0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98-0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19-1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43-4.29), P = .0013; insulin therapy OR = 2.65, (1.02-6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01-1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94-0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β = 0.002, SE = 0.001, P = .014, respectively). Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.

Implications of fluorodeoxyglucose uptake in low-intermediate grade metastatic neuroendocrine tumors from peptide receptor radionuclide therapy outcome viewpoint: A semi-quantitative standardized uptake value-based analysis.

Dual tracer positron emission tomography (PET) imaging approach (with 68Ga-DOTATATE PET-computed tomography (CT) for somatostatin receptor and 18-fluorodeoxyglucose (18FDG) PET-CT for glucose transporter receptor) plays a vital role in baseline differentiation, treatment decision-making, and prognostic assessment of neuroendocrine tumors (NETs). The aims of this study were to observe and compare the clinical behavior of low-/intermediate-grade NETs depending on their baseline FDG metabolism (calculated through pre-peptide receptor radionuclide therapy [PRRT] FDG standardized uptake value [SUV]) and to determine its prognostic importance in predicting extent of therapeutic response (post-PRRT) in terms of symptomatic, biochemical, and scan parameters along with the long-term impact on progression-free survival (PFS) and overall survival (OS). Fifty-nine patients with low (≤2%) and intermediate (3–20% Mib-1/Ki-67 index) grade metastatic NET were selected for this retrospective analysis and divided into three groups: Group 1 consisted of patients having low-grade FDG uptake at baseline, predefined as SUVmax< 5 (n = 13); Group 2 consisted of those having intermediate-grade FDG uptake at baseline, SUVmax5–10 (n = 34), and Group 3 consisted of patients having high-grade FDG uptake at baseline, defined as SUVmax>10 (n = 12). The trend of FDG avidity was studied from the baseline till the time of analysis and the overall outcomes were compared in terms of symptomatic response (Karnofsky and ECOG performance score), biochemical response, scan response (anatomical and metabolic, RECIST 1.1 and PERCIST 1.0), PFS and OS. Patients in Groups 1 and 2 showed highest proportion of symptomatic complete response, biochemical partial response, and stable disease on scan. These patients also demonstrated better PFS and OS and lowest hazard ratio compared to patients in the Group 3. An important finding was a substantial fraction of the complete metabolic responders (CMRs) across the groups, achieved CMR within first 2 cycles of PRRT (85% of Group 1, 51% of Group 2, and 47% of Group 3). In conclusion, most of the patients of low-/intermediate-grade NET having low-to-moderate baseline tumor FDG metabolism (SUVmax≤10) showed favorable symptomatic response with good biochemical and anatomical disease control and were associated with prolonged PFS and OS, compared to that of those having high-grade baseline tumor FDG metabolism (SUVmax>10).

Current perspectives on the impact of clinical disease and biochemical control on comorbidities and quality of life in acromegaly.

Acromegaly is a rare chronic, systemic disorder caused by excessive growth hormone (GH) secretion from a somatotroph pituitary adenoma. GH hypersecretion leads to overproduction of insulin-like growth factor-1 (IGF-1), which contributes to the somatic overgrowth, physical disfigurement, onset of multiple systemic comorbidities, reduced quality of life (QoL) and premature mortality of uncontrolled patients. Somatostatin receptor ligands, dopamine agonists and a GH receptor antagonist are currently available for medical therapy of acromegaly. The main aim of treatment is biochemical normalisation, defined as age-normalised serum IGF-1 values and random GH levels <1.0μg/L. However, there is an increasing evidence suggesting that achieving biochemical control does not always decrease the burden of disease-related comorbidities and/or improve patients' QoL. This lack of correlation between biochemical and clinical control can be due to both disease duration (late diagnosis) or to the peculiarity of a given comorbidity. Herein we conducted ad hoc literature searches in order to find the most recent and relevant reports on biochemical and clinical disease control during medical treatment of acromegaly. Particularly, we analyse and describe the relationship between biochemical, as well as clinical disease control in patients with acromegaly receiving medical therapy, with a focus on comorbidities and QoL. In conclusion, we found that current literature data seem to indicate that clinical disease control (besides biochemical control), encompassing clinical signs and symptoms, comorbidities and QoL, emerge as a primary focus of acromegaly patient management.