Somatostatin Analogs in Acromegaly

Somatostatin Analogs in Acromegaly

In vitro, native somatostatin retains its inhibitory effect on GH secretion in many GH-secreting tumors, and this led to the development of analogs of somatostatin for clinical use in the treatment of acromegaly 1).

The two analogs of somatostatin available for clinical use are the cyclic octapeptides octreotide (Dphe-cys-phe-Dtrp-lys-thr-cys-thr-ol) and lanreotide (Dnal-cys-tyr-Dtrp-lys-val-cys-thr) (1, 5–7). Octreotide is the only analog currently available for clinical use in the treatment of acromegaly in the United States.


Clinically available somatostatin analogs control GH or IGF-I excess in about 50–60% of patients whether used as primary or secondary therapy. Signs and symptoms of the disease improve in most patients. Tumor shrinkage occurs with somatostatin analogs used as adjunctive therapy in about 30% of patients and with their use as primary therapy in about 48% of patients. The shrinkage in most patients is greater than 20%, but less than 50% of tumor size 2).


Current data suggest that response to these drugs is better analyzed by taking together biochemical and tumoral effects because only the absence of both responses might be considered as a poor response or resistance. This latter evidence seems to occur in 25% of treated patients after 12 months of currently available long-acting SA 3).


Somatostatin analogues may be used when complete recovery cannot be achieved by surgical excision of GH-secreting pituitary adenomas or the patient declines surgery. This position statement is established based on the consensus of opinion among experts and evidence from published data regarding the use of somatostatin analogs in patients with acromegaly. However, this position statement cannot be considered as complete, given the clinical characteristics of acromegaly and the absence of large-scale clinical data in Korea; at this time, the clinical judgment of the physician should take precedence over this statement. This position statement will be revised as needed when additional data for Korean patients become available 4).


Shao et al. retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After Somatostatin Analogs treatment, both GH and IGF-1 significantly decreased (p<0.001). Triglyceride (TG), total to high-density lipoprotein cholesterol (HDL-C) ratio, and lipoprotein (a) [Lp(a)] levels were significantly decreased, while HDL-C levels were increased (p<0.05). The reduction of mean serum GH (GHm) was positively associated with the decrease of TG (r=0.305, p=0.001) and Lp(a) (r=0.257, p=0.005), as well as the increase of HDL-C (r=-0.355, p<0.001). The changes of lipid profiles were observed only in OCT group, but not in LAN group. In addition, systolic blood pressure (SBP) had significantly declined after SSAs treatment, with an average reduction of 4.4 mmHg (126.7±1.28 vs. 122.3±1.44 mmHg, p=0.003), while no change was observed regarding diastolic blood pressure (DBP) (p>0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, the study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly 5).

Lanreotide for Acromegaly.

Octreotide for Acromegaly.


1)

Lamberts SW. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev. 1988 Nov;9(4):417-36. doi: 10.1210/edrv-9-4-417. PMID: 2905987.
2)

Freda PU. Somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2002 Jul;87(7):3013-8. doi: 10.1210/jcem.87.7.8665. PMID: 12107192.
3)

Colao A, Auriemma RS, Lombardi G, Pivonello R. Resistance to somatostatin analogs in acromegaly. Endocr Rev. 2011 Apr;32(2):247-71. doi: 10.1210/er.2010-0002. Epub 2010 Dec 1. PMID: 21123741.
4)

Chin SO, Ku CR, Kim BJ, Kim SW, Park KH, Song KH, Oh S, Yoon HK, Lee EJ, Lee JM, Lim JS, Kim JH, Kim KJ, Jin HY, Kim DJ, Lee KA, Moon SS, Lim DJ, Shin DY, Kim SH, Kwon MJ, Kim HY, Kim JH, Kim DS, Kim CH. Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement. Endocrinol Metab (Seoul). 2019 Mar;34(1):53-62. doi: 10.3803/EnM.2019.34.1.53. PMID: 30912339; PMCID: PMC6435847.
5)

Shao XQ, Chen ZY, Wang M, Yang YP, Yu YF, Liu WJ, Wang Y, Zeng FF, Gong W, Ye HY, Wang YF, Zhao Y, Zhang L, Zhang ZY, He M, Li YM. Effects of Long-Acting Somatostatin Analogues on Lipid Metabolism in Patients with Newly Diagnosed Acromegaly: A Retrospective Study of 120 Cases. Horm Metab Res. 2022 Jan;54(1):25-32. doi: 10.1055/a-1717-9332. Epub 2022 Jan 5. PMID: 34986497.

Rhino orbital cerebral mucormycosis

Rhino orbital cerebral mucormycosis

Rhino orbital cerebral mucormycosis rapidly became an epidemic following the COVID-19 pandemic 1)

Gutiérrez-Delgado et al searched PubMed database from 1964 to 2014 for all available articles in the English language related to rhino-orbital-cerebral chronic infections caused by fungi of the order Mucorales and found 22 cases 2).

Rhino-orbital-cerebral mucormycosis is usually associated with a poor prognosis and is almost exclusively seen in immunocompromised patients

2015

A unique case of isolated intracranial mucormycosis of a slowly progressive nature in a healthy immunocompetent child. A 4-year-old girl with a clear medical and surgical history presented with complaints of right side facial asymmetry and unsteady gait for a period of 10 months. Clinical and radiographic investigations revealed right-sided lower motor neuron facial palsy caused by an infiltrative lesion on the right cerebellopontine angle. Initial surgical debulking was performed, a biopsy was sent for histopathological examination, and a course of prophylactic antibiotic and antifungal drugs was prescribed. The pathological report confirmed the mucormycosis fungal infection, and intravenous amphotericin B was administered for 3 weeks. One month after admission, the patient left the hospital with complete recovery. Follow-ups after 4, 8 and 12 weeks revealed no sensory or motor neurological deficits. In conclusion, this is a unique case of mucormycosis with regard to the nature and location of the infection, along with the host being a healthy child. Initial surgical exploration is a very critical step in the early diagnosis and treatment of such rare conditions 3).

2014

A 42-year-old man who developed a cerebellar mucor abscess after undergoing hematopoietic stem cell transplant for the treatment of myelodysplastic syndrome. In the post-operative period he was admitted to the neurocritical care unit and received liposomal amphotericin B intravenously and through an external ventricular drain. This patient demonstrates that utilization of an external ventricular drain for intrathecal antifungal therapy in the post-operative period may warrant further study in patients with difficult to treat intracranial fungal abscesses 4).

2013

A case of mucormycosis presenting with extensive necrosis of the maxilla with extension into the retrobulbar and infrabulbar region in an otherwise healthy patient. He underwent extensive debriding surgery followed by amphotericin B first and then oral antifungal therapy, but unfortunately, even after extensive surgery and medical treatment, he did not survive 5).

2010

Yoon et al describe a case of Rhino-orbital-cerebral (ROC) mucormycosis with pericranial abscess occurring in a female patient with uncontrolled diabetes mellitus. The infection initially developed in the right-sided nasal sinus and later progressed through the paranasal sinuses with the invasion of the peri-orbital and frontotemporal region, due to the delayed diagnosis and treatment. Numerous non-septate hyphae of the zygomycetes were identified by a punch biopsy from the nasal cavity and by an open biopsy of the involved dura. The patient was treated successfully with extensive debridement of her necrotic skull and surrounding tissues, drainage of her pericranial abscess and antifungal therapy, including intravenous amphotericin B for 61 days and oral posaconazole for the following 26 days. She returned to a normal life and has had no recurrence since the end of her treatment 15 months ago 6).

2000

A 59-year-old immunocompetent white man sustained a high-pressure water jet injury to the right inner canthus while cleaning an air conditioner filter. He later had “orbital cellulitis” develop that did not respond to antibiotics and progressed to orbital infarction. Imaging studies and biopsy results led to a diagnosis of mucormycosis. Tissue culture grew Apophysomyces elegans, a new genus of the family Mucoraceae first isolated in 1979. Orbital exenteration and radical debridement of involved adjacent structures, combined with intravenous liposomal amphotericin, resulted in patient survival.

After orbital exenteration and debridement of involved adjacent structures along with intravenous liposomal amphotericin, our patient has remained free from relapse with long-term follow-up.

The agent causing this case of rhino-orbital-cerebral mucormycosis (Apophysomyces elegans) contrasts with the three genera most commonly responsible for mucormycosis (Rhizopus, Mucor, and Absidia) in that infections with this agent tend to occur in warm climates, by means of traumatic inoculation, and in immunocompetent patients. Rhino-orbital-cerebral mucormycosis should be considered in all patients with orbital inflammation associated with multiple cranial nerve palsies and retinal or orbital infarction, regardless of their immunologic status. A team approach to management is recommended for early, appropriate surgery and systemic antifungal agents 7).


1)

Soni K, Das A, Sharma V, Goyal A, Choudhury B, Chugh A, Kumar D, Yadav T, Jain V, Agarwal A, Garg M, Bhatnagar K, Elhence P, Bhatia PK, Garg MK, Misra S. Surgical & medical management of ROCM (Rhino-orbito-cerebral mucormycosis) epidemic in COVID-19 era and its outcomes – a tertiary care center experience. J Mycol Med. 2021 Dec 25;32(2):101238. doi: 10.1016/j.mycmed.2021.101238. Epub ahead of print. PMID: 34979299.
2)

Gutiérrez-Delgado EM, Treviño-González JL, Montemayor-Alatorre A, Ceceñas-Falcón LA, Ruiz-Holguín E, Andrade-Vázquez CJ, Lara-Medrano R, Ramos-Jiménez J. Chronic rhino-orbito-cerebral mucormycosis: A case report and review of the literature. Ann Med Surg (Lond). 2016 Feb 6;6:87-91. doi: 10.1016/j.amsu.2016.02.003. eCollection 2016 Mar. PubMed PMID: 26981237; PubMed Central PMCID: PMC4776268.
3)

Al Barbarawi MM, Allouh MZ. Successful Management of a Unique Condition of Isolated Intracranial Mucormycosis in an Immunocompetent Child. Pediatr Neurosurg. 2015;50(3):165-7. doi: 10.1159/000381750. Epub 2015 May 7. PubMed PMID: 25967858.
4)

Grannan BL, Yanamadala V, Venteicher AS, Walcott BP, Barr JC. Use of external ventriculostomy and intrathecal anti-fungal treatment in cerebral mucormycotic abscess. J Clin Neurosci. 2014 Oct;21(10):1819-21. doi: 10.1016/j.jocn.2014.01.008. Epub 2014 May 19. Review. PubMed PMID: 24852901.
5)

Rahman A, Akter K, Hossain S, Rashid HU. Rhino-orbital mucourmycosis in a non-immunocompromised patient. BMJ Case Rep. 2013 Feb 6;2013. pii: bcr2012007863. doi: 10.1136/bcr-2012-007863. PubMed PMID: 23391952; PubMed Central PMCID: PMC3604437.
6)

Yoon YK, Kim MJ, Chung YG, Shin IY. Successful treatment of a case with rhino-orbital-cerebral mucormycosis by the combination of neurosurgical intervention and the sequential use of amphotericin B and posaconazole. J Korean Neurosurg Soc. 2010 Jan;47(1):74-7. doi: 10.3340/jkns.2010.47.1.74. Epub 2010 Jan 31. PubMed PMID: 20157385; PubMed Central PMCID: PMC2817523.
7)

Fairley C, Sullivan TJ, Bartley P, Allworth T, Lewandowski R. Survival after rhino-orbital-cerebral mucormycosis in an immunocompetent patient. Ophthalmology. 2000 Mar;107(3):555-8. PubMed PMID: 10711895.

Vestibular schwannoma natural history

Vestibular schwannoma natural history

see also Vestibular schwannoma conservative treatment.

Spontaneous involution of acoustic tumors does occur. Long-term follow-up is necessary to determine this potential 1).

Three-dimensional volumetric assessment of VS provides a more sensitive measure of tumor growth when compared with linear diameter assessment. Through volumetric analysis, a study revealed that a significant proportion of VSs demonstrate growth during observation 2).

An extensive MEDLINE search was performed to cull studies on VS growth according to sequential imaging. The percentages of growing and regressing tumors and lesions requiring treatment during follow-up periods were calculated. Factors associated with differences among studies were identified. Twenty-six studies including 1340 patients met all inclusion criteria. The overall frequency of VS growth during a mean follow-up period of 38 months was 46% (95% confidence interval [CI] 43-48%) and that of regression was 8% (95% CI 6-10%). The mean annual tumor growth rate was 1.2 mm/year. Furthermore, the percentage of cases requiring treatment during follow up was 18% (95% CI 16-21%). According to results of a sensitivity analysis, evaluation by serial MR imaging (39%, 95% CI 35-43%) and a prospective study design (29%, 95% CI 21-37%) were associated with less frequent reported tumor growth.

Conclusions: Although their applicability may be limited to relatively elderly patients with small tumors, data revealing a limited frequency of VS enlargement and an infrequent necessity for eventual therapy should assist decision-making in the treatment of small VSs causing minimal symptoms 3)


Volumetric tumor measurements from 3,505 serial MRI studies were analyzed from unselected consecutive patients undergoing wait-and-scan management at three tertiary referral centers between 1998 and 2018. Volumetric tumor growth was defined as a change in volume ≥20%.

Among 952 patients undergoing observation, 622 experienced tumor growth with initial growth-free survival rates (95% CI) at 1, 3, and 5 years following diagnosis of 66% (63-69), 30% (27-34), and 20% (17-24). Among 405 patients who continued to be observed despite demonstrating initial growth, 210 experienced subsequent tumor growth with subsequent growth-free survival rates at 1, 3, and 5 years following initial growth of 77% (72-81), 37% (31-43), and 24% (18-31). Larger tumor volume at initial growth (HR 1.13, p=0.02) and increasing tumor growth rate (HR 1.31; p<0.001) were significantly associated with an increased likelihood of subsequent growth, whereas a longer duration of time between diagnosis and detection of initial growth was protective (HR 0.69; p<0.001).

While most vestibular schwannomas exhibit an overall propensity for volumetric growth following diagnosis, prior tumor growth does not perfectly predict future growth. Tumors can subsequently grow faster, slower, or demonstrate quiescence and stability. Larger tumor size and increasing tumor growth rate portend a higher likelihood of continued growth. These findings can inform timing of intervention: whether upfront at initial diagnosis, after detection of initial growth, or only after continued growth is observed 4).


Of the 1,818 consecutive patients, diagnosed with VS during the period from 1975 to 2005, 729 patients were allocated to observation by repetitive magnetic resonance imaging. At least two scans had been performed in 552 patients at the time of data analysis. Two hundred thirty patients had a tumor confined to the internal acoustic meatus, whereas 322 patients had a tumor with an extrameatal extension. Growth to extrameatal extension was the definition for growth in intrameatal tumors, whereas a largest diameter change of more than 2 mm was the criteria for growth/shrinkage of extrameatal tumors. The mean observation time was 3.6 years (range, 1-15 yr).

Seventeen percent of the intrameatal tumors grew, whereas significantly more of the extrameatal tumors displayed growth during the period (28.9%). Growth occurred within the first 5 years after diagnosis. No correlation could be demonstrated between tumor growth rate, sex, or age.

VS growth occurs within the first 5 years after diagnosis in a limited number of tumors, primarily in tumors with an extrameatal extension. They found no relation between tumor growth and sex or age. These findings justify primary observation of small tumors. A treatment strategy is proposed for this disease, focusing on the patient group allocated to observation 5).


The natural history of Vestibular Schwannomas (VS) is yet not totally known, but most of them have the tendency to slow growth, sometimes without any kind of symptoms during the individuals entire time. About 69% of diagnosed VS do not grow at all and 16% of these can even regress. Considering tumors that grow, about 70% have grown less than 2mm an year. Advanced radiological diagnosis, especially magnetic resonance imaging with gadolinium helps us diagnose small and less symptomatic tumors. Treatment of choice still is complete tumor resection. Surgical approaches have improved considerably and have helped preserve facial nerve function and hearing. Considering VSs natural history, there is a possibility for conservative treatment for these tumors, because their growth in the first year after diagnosis predicts tumor growth behavior in the next years. Surgery should be done in cases of tumor growth, patients desire or symptoms worsening. Moreover, in terms of postoperative sequelae, there is no difference between patients who underwent surgery immediately after diagnosis and those who underwent initial conservative treatment for these tumors 6).


1)

Luetje CM. Spontaneous involution of acoustic tumors. Am J Otol. 2000 May;21(3):393-8. PubMed PMID: 10821554.
2)

Lees KA, Tombers NM, Link MJ, Driscoll CL, Neff BA, Van Gompel JJ, Lane JI, Lohse CM, Carlson ML. Natural History of Sporadic Vestibular Schwannoma: A Volumetric Study of Tumor Growth. Otolaryngol Head Neck Surg. 2018 Sep;159(3):535-542. doi: 10.1177/0194599818770413. Epub 2018 Apr 24. PMID: 29685084.
3)

Yoshimoto Y. Systematic review of the natural history of vestibular schwannoma. J Neurosurg. 2005 Jul;103(1):59-63. doi: 10.3171/jns.2005.103.1.0059. PMID: 16121974.
4)

Marinelli JP, Schnurman Z, Killeen DE, Nassiri AM, Hunter JB, Lees KA, Lohse CM, Roland JT, Golfinos JG, Kondziolka D, Link MJ, Carlson ML. Long-term Natural History and Patterns of Sporadic Vestibular Schwannoma Growth: A Multi-institutional Volumetric Analysis of 952 Patients. Neuro Oncol. 2021 Dec 29:noab303. doi: 10.1093/neuonc/noab303. Epub ahead of print. PMID: 34964894.
5)

Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. The natural history of vestibular schwannoma. Otol Neurotol. 2006 Jun;27(4):547-52. doi: 10.1097/01.mao.0000217356.73463.e7. PMID: 16791048.
6)

Oliveira Penido N, Tangerina RP, Macoto Kosugi E, Cesário de Abreu CE, Brandão Vasco M. Vestibular Schwannoma: spontaneous tumor involution. Braz J Otorhinolaryngol. 2007 Nov-Dec;73(6):867-871. doi: 10.1016/S1808-8694(15)31189-7. PubMed PMID: 18278239.
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