Efficacy and Safety of CyberKnife Stereotactic Radiosurgery in Acromegaly

Abstract Aims Objective: Active acromegaly is associated with increased mortality. While surgery is the mainstay of treatment, it is not always curative. In selected cases, CyberKnife stereotactic radiosurgery (CK SRS) can be used as adjuvant treatment in patients with persistent disease. Method Methodology: Biochemical response was measured using serum IGF-1 levels, calculated as a percentage of the upper limit of normal (% ULN). Levels were recorded prior to treatment, at 6-12 months post-treatment and at the most recent follow-up. Anterior pituitary hormone deficits were assessed before and after treatment. Tumour size was followed-up using MRI. Results 10 patients (7 male, mean age 36 yrs [+/- 12.6, SD]) with acromegaly were treated with CK SRS. 9 were treated following failure to attain biochemical remission with TSS. 1 had primary CK SRS. 2 had previous conventional fractionated external beam radiotherapy. Median tumour diameter was 6 mm (IQR 5.2-10.5 mm), with cavernous sinus invasion in 2 cases. The dose was 20-24Gy/1#. 4 patients were on dopamine agonist, 4 on somatostatin analogue and 2 on pegvisomant. Mean follow-up 31.6 months (+/- 13.5 months, SD). Median IGF-1 % ULN was 146% pre-treatment (IQR 126.5-208.5), 109% at 6-12 months (IQR 76.5-131%) and 71% (IQR 59-91%) at last follow-up. Mean radiological follow-up 16.6 months (+/- 15.9 months, SD). No cases showed tumour enlargement. One patient developed secondary hypothyroidism. Side-effects: headache (7 patients), blurred vision (1 patient), fatigue/nausea (1 patient). No new visual fields defects, cranial nerve palsies, cerebrovascular events or secondary tumours. Conclusion Conclusions: CK SRS appears safe and effective in selected patients with acromegaly, when there is failure to attain biochemical cure with surgery and in patients intolerant or resistant to medical treatment.

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Adrenocorticotropic Hormone-producing Pituitary Tumors: 12- to 22-year Follow-up after Treatment with Stereotactic Radiosurgery

Neurosurgery ◽

10.1097/00006123-200108000-00008 ◽

2001 ◽

Vol 49 (2) ◽

pp. 284-292 ◽

Cited By ~ 20

Author(s):

Charlotte Höybye ◽

Eva Grenbäck ◽

Tiit Rähn ◽

Marie Degerblad ◽

Marja Thorén ◽

...

Keyword(s):

Stereotactic Radiosurgery ◽

Adrenocorticotropic Hormone ◽

Visual Fields ◽

Pituitary Tumors ◽

Pituitary Hormone ◽

Pituitary Insufficiency ◽

Primary Therapy ◽

Radiation Induced ◽

Effect Of Treatment

Abstract OBJECTIVE To study retrospectively long-term outcomes of patients with adrenocorticotropic hormone-producing pituitary tumors that were treated with stereotactic Leksell gamma knife unit radiosurgery. METHODS Eighty-nine patients aged 5 to 67 years were treated between 1976 and 1985. Eighteen patients aged 18 to 68 years (mean age, 41 yr) were followed in detail. Fifteen patients were women. None had previously received conventional radiotherapy, but pituitary microsurgery had been performed in two patients, and one patient had had an adrenalectomy. In the remaining 15 patients, radiosurgery was the primary therapy. RESULTS Sixty-four patients had one stereotactic treatment, and 25 patients had two or more treatments. No complications were observed during treatment and the immediate follow-up period. At follow-up, 17 patients had died 1 to 20 years after the first treatment. No deaths were related to the treatment. In our 18 patients, the follow-up time after the first radiosurgical treatment was 12 to 22 years (mean follow-up period, 17 yr). Urinary cortisol levels gradually normalized in 83% of the patients. No recurrences were observed. Pituitary hormone insufficiencies developed in about two of every three patients and occurred even more than 10 years after treatment. Eight patients had transient hyperprolactinemia. The patients' vision and visual fields were unaffected, and none of them had signs of radiation-induced side effects such as brain tumors or brain necrosis. CONCLUSION Stereotactic radiosurgery is a safe and effective method in the treatment of patients with adrenocorticotropic hormone-producing pituitary tumors, and the effect of treatment is long-lasting. Stereotactic radiosurgery is mainly a complement to microsurgery because of its gradually appearing effect and the occurrence of pituitary insufficiency. New pituitary deficiencies may be found more than 10 years after treatment.

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Phase Ib/II study of pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (PLANET).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.369 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 369-369

Author(s):

Michael Morse ◽

Daniel M. Halperin ◽

Hope Elizabeth Uronis ◽

David S. Hsu ◽

Herbert Hurwitz ◽

...

Keyword(s):

External Beam Radiotherapy ◽

Locoregional Therapy ◽

Somatostatin Analogue ◽

Antitumor Effects ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Best Response ◽

Secondary Endpoints ◽

Clinical Trial Information ◽

Experienced Treatment

369 Background: Pembrolizumab has antitumor activity in a subset of GEP-NETs patients. We hypothesized that the lanreotide, by its antitumor effects and reduction of serotonin, a modulator of immunity, would synergize with pembrolizumab in low/intermediate grade GEPNETs. Methods: GEP-NETs patients who had progressed on a prior somatostatin analogue received lanreotide 90mg sq and pembrolizumab 200mg IV every 3 weeks until progressive disease or intolerable toxicity. The primary endpoint was ORR at any time on study and secondary endpoints were PFS and OS. Results: 22 patients were treated (F/M 10/12; Caucasian/AA/other 10/7/5; GI/pancreatic 14/8; median Ki67 5%, median time since diagnosis 5.3 yrs (IQR 2.3-7.9 yrs)). Prior octreotide LAR/lanreotide/both was administered to 20/1/1. Patients had a median of 2 prior systemic therapies (range 1-9) and six had prior locoregional therapy and 3 external beam radiotherapy. Of the 12 tumors analyzed thus far, 4 had detectable PD-L1 expression and 11 had detectable TILs. A median of 6 pembrolizumab doses (range 2-15) and 7 lanreotide doses (range 2-15) were administered. Six patients experienced treatment related SAEs (abdominal pain, pneumonitis, colitis, and hyperglycemia, all related to the pembrolizumab). Selected treatment related adverse events included: Hypothyroidism 23%, colitis 9%, hyperglycemia 14%, and pneumonitis 5%. Best response by RECIST 1.1 was SD/PD/Not available:39/52/9% and by irRECIST was 43/48/9%. Median PFS was 5.4 months (95% CI 1.7-8.3 mo). The median overall survival at a median follow-up of 15 months was not reached. Peripheral blood immunologic correlates will be reported subsequently. Conclusions: In a population of GEP-NET patients, progressing on a median of 2 prior therapies, including prior somatostatin analogue therapy, a minority of whom had PD-L1 expressing tumors, the combination of lanreotide and pembrolizumab produced stable disease in approximately 40% of patients. No new safety signals were identified. Clinical trial information: NCT03043664.

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The effect of somatostatin analogue on chiasmal dysfunction from pituitary macroadenomas

Journal of Neurosurgery ◽

10.3171/jns.1989.71.5.0687 ◽

1989 ◽

Vol 71 (5) ◽

pp. 687-690 ◽

Cited By ~ 37

Author(s):

André Warnet ◽

José Timsit ◽

Philippe Chanson ◽

Pierre-Jean Guillausseau ◽

Françoise Zamfirescu ◽

...

Keyword(s):

Tumor Volume ◽

Visual Fields ◽

Somatostatin Analogue ◽

Tumor Shrinkage ◽

Content Type ◽

Gh Secretion ◽

Visual Improvement ◽

Long Acting ◽

Pituitary Macroadenomas

✓ The long-acting somatostatin analogue SMS 201-995 has been shown to be efficient in the treatment of somatotropic and thyrotropic adenomas. In some cases, it can suppress adenoma secretion and lead to tumor shrinkage. Pituitary macroadenomas are often associated with a vision-threatening chiasmal syndrome. In this series, SMS 201-995 was administered subcutaneously to eight patients with pituitary macroadenomas of various types responsible for severe long-lasting visual defects. An obvious improvement of both visual fields and acuity occurred in six patients, in two of these during the first 4 to 6 hours of treatment; in two patients, gonadotropic adenomas were unresponsive. Maximal improvement (normalization of visual fields in three cases) occurred within 6 to 45 days and was sustained during the 1- to 12-month follow-up period. This effect seems independent of the type of adenoma since the adenomas secreting growth hormone (GH) and thyroidstimulating hormone and silent corticotropic-secreting adenomas responded as well as did two of the non-functioning adenomas. In one acromegalic patient visual improvement was obtained while the abnormal GH secretion remained unaltered. In all cases but one, no tumor shrinkage could be demonstrated. These data demonstrate that SMS 201-995 can rapidly improve the chiasmal syndrome due to pituitary macroadenoma, and suggest that this effect might be independent of a reduction in tumor volume.

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Intratumoral Hemorrhage in Jugular Foramen Schwannoma after Stereotactic Radiosurgery: A Case Report

10.21203/rs.3.rs-45418/v1 ◽

2020 ◽

Author(s):

Mariko Kawashima ◽

Hirotaka Hasegawa ◽

Masahiro Shin ◽

Yuki Shinya ◽

Nobuhito Saito

Keyword(s):

Stereotactic Radiosurgery ◽

Rare Complication ◽

Jugular Foramen ◽

Venous Stasis ◽

Lower Cranial Nerve ◽

Intratumoral Hemorrhage ◽

Cranial Nerve Palsies ◽

Neurological Conditions ◽

Clinically Significant

Abstract Background: Clinically significant intratumoral hemorrhage is an extremely rare complication of stereotactic radiosurgery (SRS) for benign tumors.Case Presentation:Here, we present the case of a 64-year-old man who underwent SRS for a relatively large dumbbell-shaped left jugular foramen schwannoma and thereafter developed intratumoral hemorrhage. On post-SRS day 3, he developed lower cranial nerve palsies with radiographically evident tumor expansion. His neurological conditions had gradually improved thereafter; however, he suddenly developed headache, dizziness, and mild hearing deterioration at seven months due to intratumoral hemorrhage. We managed the patient conservatively, and eventually his symptoms improved except for slight ataxia and hearing deterioration. Follow-up images at three years from SRS demonstrated significant tumor shrinkage. This is the first report describing intratumoral hemorrhage after SRS for jugular foramen schwannoma.Conclusions:Transient expansion of the tumor and subsequent venous stasis around the tumor may have played a role in the hemorrhage. Intratumoral hemorrhage should be considered as a rare but potential complication of SRS for jugular foramen schwannomas.

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Management and outcomes of pituitary apoplexy

Journal of Neurosurgery ◽

10.3171/2014.10.jns141204 ◽

2015 ◽

Vol 122 (6) ◽

pp. 1450-1457 ◽

Cited By ~ 31

Author(s):

Tarun D. Singh ◽

Navid Valizadeh ◽

Fredric B. Meyer ◽

John L. D. Atkinson ◽

Dana Erickson ◽

...

Keyword(s):

Pituitary Adenoma ◽

Functional Outcomes ◽

Pituitary Apoplexy ◽

Histopathological Examination ◽

Visual Fields ◽

Visual Field Defects ◽

Ocular Motility ◽

Cranial Nerve Palsies

OBJECT This study was undertaken to analyze the predisposing factors, clinical presentation, therapeutic management, and clinical recovery in patients with pituitary apoplexy, with an emphasis on the long-term visual, endocrine, and functional outcomes. METHODS The authors performed a retrospective analysis of consecutive cases involving patients treated at Mayo Clinic between 1992 and 2013. Patients were included in the study only if they had 1) abrupt onset of severe headache or visual disturbance in the presence of a pituitary adenoma and 2) radiological or surgical confirmation of a pituitary mass. The primary endpoints of analysis were the visual (ocular motility, visual fields, and visual acuity), endocrine, and functional outcomes (using the modified Rankin Scale). RESULTS Eighty-seven patients were identified (57 males and 30 females, mean age 50.9 years, range 15–91 years). Twenty-two patients (25.3%) had a known pituitary adenoma. Hypertension was the most common associated factor (39%). Headache was the most frequent presenting symptom (89.7%), followed by visual abnormalities (47.1%). Cranial nerve palsies were present in 39% and visual field defects in 34.1%. MRI detected hemorrhage in 89% patients, as compared with 42% detected by CT scan. Sixty-one patients (70.1%) underwent surgery during acute hospitalization (median time from apoplexy 5 days, IQR 3–10 days), 8 (9.2%) had delayed surgery, and 18 (20.7%) were treated conservatively. Histopathological examination revealed adenoma with pure necrosis in 18 (30%), pure hemorrhage in 4 (6.7%), and both in 6 (10%) patients. Four patients died during hospitalization. The average duration of follow-up was 44.2 ± 43.8 months. All survivors were independent and had complete resolution or substantial improvement in eye movements and visual fields at the last follow-up. Many patients needed long-term hormonal replacement with levothyroxine (62.7%) and cortisol (60%). Daily desmopressin was needed in 23% of all surgical patients at 3 months (versus none of the medically treated) and this requirement decreased slightly over time. Regrowth of pituitary adenoma was seen in 7 patients (8.6%). There were no statistically significant differences in any of the outcome measures across the treatment groups. CONCLUSIONS The outcome of most patients with pituitary apoplexy is excellent. Selected patients can be managed conservatively, and patients with severe neuro-ophthalmological deficits treated with early surgery can achieve an excellent recovery.

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Corticosteroids Replacement in a Patient With Panhypopituitarism and COVID-19 Infection

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1180 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A578-A579

Author(s):

Gowri Karuppasamy ◽

Zaina Abdelhalim Alamer ◽

Samman Rose ◽

Ibrahim Abdulla Al-Janahi

Keyword(s):

Pituitary Adenoma ◽

Adrenal Insufficiency ◽

Hormone Replacement ◽

Hypogonadotropic Hypogonadism ◽

Adrenal Crisis ◽

High Dose ◽

Pituitary Hormone ◽

Secondary Hypothyroidism ◽

Stress Dose

Abstract Background: Hypopituitarism refers to complete or partial insufficiency of pituitary hormone secretion and patients require lifelong hormone replacement. Those with ACTH deficiency rely on exogenous glucocorticoids and at times of intercurrent illness require stress doses to prevent an adrenal crisis. The benefits and adverse effects of corticosteroids for treatment of COVID-19 pneumonia are currently under investigation. We report our experience in a patient with COVID-19 pneumonia who received high dose corticosteroids for panhypopituitarism. Clinical Case: A 51-year-old man presented with one-week history of fever and generalized weakness. He had been diagnosed with a non-functional pituitary macro-adenoma causing panhypopituitarism 1 year ago when he developed generalized tonic-clonic seizures. He underwent trans-sphenoidal resection of the pituitary adenoma. However, he then discontinued his hormonal therapy and was lost to follow up. He had postural hypotension but was not tachypneic or hypoxemic. He tested positive for COVID-19 and chest x-ray showed prominent bilateral broncho-vascular markings; he was hospitalized as mild COVID-19 pneumonia. Laboratory investigations revealed secondary adrenal insufficiency, secondary hypothyroidism and hypogonadotropic hypogonadism. MRI of the pituitary now showed persistence of the pituitary macroadenoma, measuring 3.5 x 3.7 x 2.4 cm in dimensions, causing sellar obliteration and left cavernous sinus invasion. Treatment with stress dose steroids, Hydrocortisone 50 mg 4 times daily was initiated, followed by thyroid hormone replacement with Levothyroxine 125 mcg daily. He also received antivirals and supportive care for COVID-19, guided by local hospital protocol. After significant clinical improvement, steroids were tapered down and he was discharged on a maintenance dose of 20 mg hydrocortisone per day in divided doses. The patient was stable at outpatient follow up after one month. He was started on testosterone replacement for erectile dysfunction due to hypogonadotropic hypogonadism. He was offered surgery for complete resection of the residual pituitary adenoma, but he declined and preferred to continue medical therapy. Conclusion: Hypopituitarism is associated with significant morbidity and premature mortality, a key risk factor being cortisol deficiency. Adrenal crisis is a life-threatening medical emergency and remains an important cause of death in patients with adrenal insufficiency. These patients are also vulnerable to develop severe complications from COVID-19 infection due to the absence of normal cortisol responses to stress. Despite receiving stress dose corticosteroids, this high-risk patient recovered from COVID-19 pneumonia without complications. These findings support the use of corticosteroids when necessary for treatment of coexisting conditions in patients with COVID-19.

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Intratumoral hemorrhage in jugular foramen schwannoma after stereotactic radiosurgery: A case report

Surgical Neurology International ◽

10.25259/sni_550_2021 ◽

2021 ◽

Vol 12 ◽

pp. 479

Author(s):

Mariko Kawashima ◽

Hirotaka Hasegawa ◽

Masahiro Shin ◽

Yuki Shinya ◽

Nobuhito Saito

Keyword(s):

Stereotactic Radiosurgery ◽

Rare Complication ◽

Jugular Foramen ◽

Venous Stasis ◽

Benign Tumors ◽

Lower Cranial Nerve ◽

Intratumoral Hemorrhage ◽

Cranial Nerve Palsies ◽

Clinically Significant

Background: Clinically significant intratumoral hemorrhage is a rare complication of stereotactic radiosurgery (SRS) for benign tumors. Case Description: Here, we present the case of a 64-year-old man who underwent SRS for a relatively large dumbbell-shaped left jugular foramen schwannoma (JFS) and thereafter developed intratumoral hemorrhage. On post-SRS day 3, he developed lower cranial nerve palsies with radiographically evident tumor expansion. His neurological conditions had gradually improved thereafter; however, he suddenly developed headache, dizziness, and mild hearing deterioration at 7 months due to intratumoral hemorrhage. We managed the patient conservatively, and eventually, his symptoms improved except for slight ataxia and hearing deterioration. Follow-up images at 4 years from SRS demonstrated significant tumor shrinkage. This is the first report describing intratumoral hemorrhage after SRS for JFS. Conclusion: Transient expansion of the tumor and subsequent venous stasis around the tumor may have played a role in the hemorrhage. Intratumoral hemorrhage should be considered as a rare, but potential complication of SRS for JFSs.

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Long-term follow-up after intraoperative radiotherapy (IORT) for breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10594 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10594-10594

Author(s):

U. S. Kraus-Tiefenbacher ◽

C. Herskind ◽

L. Bauer ◽

F. Melchert ◽

F. Wenz

Keyword(s):

Breast Cancer ◽

Tumour Size ◽

External Beam Radiotherapy ◽

Intraoperative Radiotherapy ◽

Quadratic Model ◽

Treatment Modalities ◽

Partial Breast Irradiation ◽

Linear Quadratic ◽

X Ray

10594 Background: IORT for breast cancer with new treatment modalities is becoming increasingly important. In our department IORT is delivered by a mobile x-ray source (Intrabeam) producing isotropic 50 kV x-ray fields. Because this treatment modality includes single high doses to the normal breast tissue, careful evaluation of early and late toxicity is mandatory. Methods: Between 2/02 and 12/05 161 patients received IORT either as a tumour-bed boost (103) before 46 Gy external beam radiotherapy (EBRT) or as partial breast irradiation (58). Median age was 64.6 years (35–95), median tumour size was 15 mm (1–45). Spherical applicators (2.0 -5.0 cm diameter) were inserted into the tumourbed, giving a single dose of 20 Gy. Follow-up (f/u) included physical examination and ultrasound 1 week, 2 months, then every 6 months after therapy and mammography at yearly intervals. Radiobiological modelling of the expected spatial distribution of late reaction was done for typical cases using the linear-quadratic model with special consideration of relative biologic effectiveness, spatial dose distribution and dose rate. Results: Mean (f/u) time was 22 months. Minor postoperative side effects included erythema (5%), delayed wound healing (4%), mastitis (1%) and hematoseroma (4%). A fibrotic induration of the tumour bed was observed in 9, 18, 22, 23 and 26% of the patients at 2, 6 12, 24 and 36 month (f/u). Reoperation was required in 2 patients after 10 and 12 months, one mastectomy due to a fibrotic change of the whole breast and one local drainage of a fat necrosis. Conclusions: Although 2/3 of the patients were treated with a combination of IORT and EBRT, acute reactions in all patients were mild. Predominant late effect was an induration of the tumour bed which slowly began to resolve 1–3 years after therapy. The low level of clinically late reactions observed so far is in agreement with radiobiologic predictions from radiobiological modelling. No significant financial relationships to disclose.

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Rathke’s Cleft Cyst Abscess—An Unusual Guest in The Sella

Indian Journal of Neurosurgery ◽

10.1055/s-0041-1726600 ◽

2021 ◽

Author(s):

Piyush Lodha ◽

Srinivas Rao P ◽

Vijay Sheker Reddy Danda ◽

Gollapudi Prakash Rao

Keyword(s):

Visual Fields ◽

Empty Sella ◽

Abscess Formation ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Mass ◽

Empty Sella Syndrome ◽

Rim Enhancement ◽

Bitemporal Hemianopia

AbstractAbscess formation within a Rathkes’s cleft cyst (RCC) is extremely rare, particularly at a young age. We report the case of a young girl with abscess formation in RCC. A 21-year-old female presented with headache, vomiting, visual deterioration and features suggestive of hypopituitarism. She had bitemporal hemianopia with impairment of visual acuity. MRI revealed a cystic lesion in the sella with suprasellar extension and peripheral rim enhancement. On the basis of history and imaging, this was indistinguishable from more commonly encountered pituitary pathology. She underwent transsphenoidal decompression, which revealed yellowish purulent material that when cultured grew Staphylococcus epidermidis. Histological examination revealed numerous neutrophils and cyst wall lining with features characteristic of RCC. Postoperatively, she received antibiotics and replacement therapy for hypopituitarism. Three months later, she experienced deterioration in visual fields. Considering persistent disease, she underwent redo surgery which revealed similar findings. Postsurgery, pituitary MRI revealed an empty sella syndrome. Thereafter, follow-up for 1 year was stable with permanent diabetes insipidus and multiple pituitary hormone deficiency on supplementation. Although uncommon, we recommend considering RCC abscess as a differential diagnosis of a pituitary mass lesion, as predicting its presence can be difficult preoperatively. Persistent or recurrent disease is common in these cases, so timely diagnosis and adequate surgical drainage leads to lower morbidity and mortality.

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Intraoperative, postoperative and long-term oncosurgical safety of therapeutic mammaplasty

Orvosi Hetilap ◽

10.1556/oh.2013.29660 ◽

2013 ◽

Vol 154 (33) ◽

pp. 1291-1296 ◽

Cited By ~ 1

Author(s):

László Romics Jr. ◽

Sophie Barrett ◽

Sheila Stallard ◽

Eva Weiler-Mithoff

Keyword(s):

Recurrence Rate ◽

Tumour Size ◽

Breast Conservation ◽

Malignant Lesion ◽

Surgical Techniques ◽

Incomplete Resection ◽

Immediate Reconstruction ◽

Oncological Safety

Introduction: (Pre)malignant lesion in the breast requiring mastectomy conventionally may be treated with breast conservation by using oncoplastic breast surgical techniques, which is called therapeutic mammaplasty. However, no reliable data has been published so far as regards the oncological safety of this method. Aim: The aim of the authors was to analyse the oncological safety of therapeutic mammaplasty in a series of patients. Method: 99 patients were treated with therapeutic mammaplasty and data were collected in a breast surgical database prospectively. Results were analysed with respect to intraoperative, postoperative and long-term oncological safety. Results: Incomplete resection rate was 14.1%, which correlated with tumour size (p = 0.023), and multifocality (p = 0.012). Time between surgery (therapeutic mammaplasty) and chemotherapy was similar to time between conventional breast surgeries (wide excision, mastectomy, mastectomy with immediate reconstruction) and chemotherapy (mean 29–31 days; p<0.05). Overall recurrence rate was 6.1%, locoregional recurrence rate was 2% during 27 month (1–88) mean follow-up. Conclusions: Since literature data are based on relatively short follow-up and low patient number, it is highly important that all data on therapeutic mammaplasty is collected in a prospectively maintained breast surgical database in order to determine true recurrence after long-follow-up. Orv. Hetil., 2013, 154, 1291–1296.

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