Long-Term Outcomes of Patients with Acromegaly - A Report from the Swedish Pituitary Register

Objective: To describe treatment and long-term outcomes of patients with acromegaly from all health-care regions in Sweden. Design and Methods: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991-2011. The latest clinical follow-up date was December, 2012, while mortality data were collected for 28.5 years until June, 2019. Results: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy and 39% medical treatment. At the 5- and 10-year follow-ups, IGF-I levels were within the reference range in 69% and 78% of patients, respectively. In linear regression the proportion of patients with biochemical control including adjuvant therapy at 10 year follow-up increased over time with 1.23 % per year. The SMR (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed 1991-2000, SMR 1.06 (0.85-1.33) or 2001-2011, SMR 0.87 (0.61-1.24). In contrast, non- controlled patients at the latest follow up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively. Conclusions: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.

Results of salvage radiotherapy for prostate cancer after radical prostatectomy

The aim of the study. To evaluate the results of radiation therapy for recurrent prostate cancer after radical prostatectomy.Methods. The analysis of medical records data of 60 patients with recurrent prostate cancer after radical prostatectomy (RP) was performed.Results. Biochemical control was achieved in 55 (92.0%) patients, PSA progression – in 3 (5.0%) and generalization – in 2 (3.0%) patients. Grade I–II cystitis developed in 25 patients (42.0%), grade I–II rectitis – in 7 (11.0%), late hemorrhagic cystitis was noted in 4 (7.0%) patients, late hemorrhagic rectitis – in 2 (3.3%) ones.Сonclusions. Salvage radiation therapy for recurrent prostate cancer after radical prostatectomy is an important treatment method that allows to achieve biochemical control with acceptable toxicity.

Salvage hypofractionated accelerated versus standard radiotherapy for the treatment of biochemical recurrence after radical prostatectomy (SHARE): the protocol of a prospective, randomized, open-label, superiority, multi-institutional trial

Background While several phase III trials have investigated the role of hypofractionated radiotherapy in the definitive treatment of localized prostate cancer, prospective data reporting the outcomes of hypofractionated radiotherapy in the postoperative treatment setting are sparse. Therefore, this study is designed to assess the efficacy and treatment-related toxicity of hypofractionated salvage radiotherapy for the treatment of biochemical recurrence in men who underwent radical prostatectomy. The primary objective of this trial is to investigate whether hypofractionated radiotherapy improves biochemical control compared with conventionally fractionated radiotherapy. In addition, treatment-related toxicity, quality of life, and survival will be evaluated as secondary endpoints. Methods In this prospective, randomized, multi-institutional trial (the SHARE study), patients with intermediate- or high-risk prostate cancer will be randomized to receive either hypofractionated radiotherapy (65 Gy in 2.5-Gy fractions) or conventionally fractionated radiotherapy (66 Gy in 2-Gy fractions). Prostate bed irradiation or elective pelvic nodal irradiation including the prostate bed will be performed using intensity-modulated radiotherapy and daily image guidance. Treatment efficacy will be assessed using the serum tumor marker prostate-specific antigen, and toxicity will be evaluated through both physician- and patient-reported outcomes. Quality of life will also be investigated. Discussion This study is designed to demonstrate whether hypofractionated radiotherapy is beneficial in terms of biochemical control and toxicity compared with standard salvage radiotherapy. If hypofractionated radiotherapy is shown to be superior to conventionally fractionated radiotherapy, it will mean that improved biochemical control can be achieved, accompanied by greater patient convenience and more efficient use of medical resources. Trial registration ClinicalTrials.gov NCT03920033. Registered on 18 April 2019

The future of somatostatin receptor ligands in acromegaly

Currently, first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot and nasal octreotide, may improve patients’ adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788 and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.

gsp Mutation Is Not a Molecular Biomarker of Long-Term Response to First-Generation Somatostatin Receptor Ligands in Acromegaly

Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.

Orchestration of Force Generation and Nuclear Collapse in Apoptotic Cells

Apoptosis, or programmed cell death, is a form of cell suicide that is extremely important for ridding the body of cells that are no longer required, to protect the body against hazardous cells, such as cancerous ones, and to promote tissue morphogenesis during animal development. Upon reception of a death stimulus, the doomed cell activates biochemical pathways that eventually converge on the activation of dedicated enzymes, caspases. Numerous pieces of information on the biochemical control of the process have been gathered, from the successive events of caspase activation to the identification of their targets, such as lamins, which constitute the nuclear skeleton. Yet, evidence from multiple systems now shows that apoptosis is also a mechanical process, which may even ultimately impinge on the morphogenesis of the surrounding tissues. This mechanical role relies on dramatic actomyosin cytoskeleton remodelling, and on its coupling with the nucleus before nucleus fragmentation. Here, we provide an overview of apoptosis before describing how apoptotic forces could combine with selective caspase-dependent proteolysis to orchestrate nucleus destruction.

Tolerability and Efficacy of Long-term Medical Therapy in Primary Aldosteronism

Introduction Patients with primary aldosteronism (PA) have increased cardiovascular risk, and some studies find medical therapy less effective than surgery. This may be due to side effects and limited efficacy of medications at tolerable doses. Methods We conducted a retrospective study on 201 patients with PA treated with medical therapy (spironolactone, eplerenone or amiloride) for PA from 2000-2020 at two tertiary centres. Patients were assessed for efficacy to achieve clinical and biochemical control, and for side effects. Results Amongst 155 patients on long-term medications, 57.4% achieved blood pressure &lt;140/90mmHg, 90.1% achieved normokalemia(48.0% achieved potassium≥4.3mmol/L), and 63.2% achieved renin&gt;1ng/ml/hr. Concordance of biochemical control using potassium and renin levels was 49.1%. 52.3% of patients experienced side effects, with 10.3% switching to another medication, 22.6% decreasing dose, and 11.0% stopping medications. Risk factors for side effects were spironolactone use, dose≥50mg, treatment duration ≥1year, male gender and unilateral PA. Patients with unilateral PA, compared to bilateral PA, used higher spironolactone doses, 57mg vs 50mg, P&lt;0.001, and had more side effects, 63.2% versus 41.8%, P=0.008. Amongst 46 patients with unilateral PA who underwent surgery after initial medical therapy, surgery further improved systolic and diastolic BP, from 141 to 135mmHg, P=0.045, and from 85 to 79mmHg, P=0.002, respectively. Conclusion Dose-dependent side effects limit the efficacy of medical therapy in PA. Future prospective studies should assess the best monitoring strategy for biochemical control during long-term medical therapy. For unilateral PA, surgery remains preferable to medications, as surgery leads to better control with less long-term side-effects.

Getting around the gut: a unique management challenge of thyroid storm precipitated by amphetamine-associated duodenal ischaemia leading to compromised enteric absorption

Thyroid storm is a rare, life-threatening endocrine emergency with a high mortality rate of up to 30%. We present a unique management challenge of a critically ill patient who developed thyroid storm in the setting of a duodenal perforation from amphetamine-associated non-occlusive mesenteric ischaemia. The diagnosis of ‘thyroid storm’ was made based on clinical criteria and a Burch-Wartofsky score of 100. During emergent exploratory laparotomy, a 1 cm duodenal perforation with surrounding friable tissue was found and repaired. Intraoperatively, a nasogastric tube was guided distal to the area of perforation to allow for enteric administration of medications, which was critical in the setting of thyroid storm. Therapeutic plasma exchange achieved biochemical control of our patient’s thyroid storm but ultimately did not prevent in-hospital mortality.