Surgical Remission Research Articles

Cotard’s Syndrome in Post-Surgical Patients

Cotard’s Syndrome in Post-Surgical Patients

Acromegaly Surgery in Manchester Revisited: The Impact of Reducing Surgeon Numbers and the 2010 Consensus Guidelines for Disease Remission

Introduction: Surgical remission rates for acromegaly depend on tumor morphology, definition of disease remission, and surgical expertise. A previous report from Manchester in 1998 reported an overall surgical remission rate of 27%. We assessed the impact of establishing a specialist pituitary surgery service in Manchester in 2005, with reduced surgeon numbers and use of the 2010 consensus criteria for remission in acromegaly.

Acromegaly surgery in Manchester revisited – The impact of reducing surgeon numbers and the 2010 consensus guidelines for disease remission

Surgical remission rates for acromegaly vary and are dependent on the tumour morphology, biochemical definition of disease remission and surgical expertise. A previous report from the Manchester region in 1998 reported an overall surgical remission rate of 27% using accepted criteria for biochemical remission at the time. The establishment of the 2010 Consensus guidelines further tightens biochemical criteria for remission. This report aims to assess the impact of establishing a specialist pituitary surgery service in Manchester in 2005, with reduced surgeon numbers on the remission rates for acromegaly surgery. Patients with acromegaly undergoing first time endoscopic transsphenoidal surgery between 2005 and 2010 were studied. Surgery was performed by a single surgeon. Review of a prospectively collected acromegaly surgery database was performed with documentation of pre- and postoperative biochemical tests [oral glucose tolerance test (oGTT) and IGF-1], as well as clinical, pathological and radiological data. Definition of disease remission was according to the 2010 Consensus criteria (GH nadir <0·4 μg/l following an oGTT and normalized population matched IGF-1). There were 43 consecutive patients with acromegaly, with 13 (30%) microadenomas and 12 (28%) invasive adenomas. Overall, surgical remission was achieved in 29 (67%) patients. The remission rates were similar between micro (77%), macro (63%) and giant (67%) adenomas. There were nonsignificant trends towards higher remission rates for noninvasive tumours compared with invasive tumours (74%vs 50%) and for patients with a preoperative GH nadir <10 μg/l (73%vs 54%) and IGF-1 standard deviation score <15 (72%vs 54%). Remission rates for acromegaly surgery have improved following establishment of a specialist surgical service, with a reduction in surgeon numbers. Endoscopic trans-sphenoidal surgery remains an effective first-line treatment for achieving biochemical remission in acromegaly, despite the introduction of the more stringent 2010 consensus guidelines.

Outcomes of transsphenoidal surgery in prolactinomas: improvement of hormonal control in dopamine agonist-resistant patients

Few studies have recently re-examined the efficacy of neurosurgery in prolactinoma patients operated for various indications. To analyze outcomes of patients with a prolactinoma treated by transsphenoidal surgery, to identify factors associated with remission and relapse, and to evaluate if surgical debulking allows for better hormonal control in patients with preoperative resistance to dopamine agonists (DAs). This was a retrospective review of patients with a benign prolactinoma followed preoperatively and postoperatively in our department and treated by transsphenoidal surgery (n=63; 45 women; mean age: 31 ± 14 years). Postoperative remission was obtained in 63% of microprolactinomas, 60% of noninvasive macroprolactinomas, and none of the invasive macroprolactinomas. Better remission rate was independently predicted by lower diagnostic prolactin (PRL) levels and by the lack of abnormal postoperative residual tissue (P<0.05). A recurrence of hyperprolactinemia was observed in 34% of patients after a median follow-up period of 36 (7-164) months. In patients with preoperative DA resistance treated again after surgery, there was a significant reduction in PRL levels postoperatively (26 (6-687) ng/ml) vs preoperatively (70 (22-1514) ng/ml; P<0.01) under a lower DA dose, and about half of the patients had PRL normalization. Recurrence of hyperprolactinemia is observed in one-third of prolactinoma patients after surgical remission and may occur as late as 13 years after surgery. Resistance to DA can be considered as a good surgical indication, as partial tumor resection allows for better hormonal control with a lower dose of DAs.

Intensive screening for resected stage II and III colorectal cancer

SUMMARY Disease recurrence continues to be a major cause of death in patients with resected stage II and III colorectal cancer. Distant and local relapses, unless successfully treated surgically, result in patient demise within 5 years in approximately 90% of patients. By contrast, patients who undergo curative-intent surgery and enter surgical remission experience 40–50% 5-year survival. Effective surveillance strategies are needed to improve the rate of colorectal cancer recurrence detection and maximize the chances of curative resections. In this article, we review the strength and shortfalls of the supportive data for intensive surveillance and reflect on the recommendations of various medical associations.

Why do patients with radiation-induced sarcomas have a poor sarcoma-related survival?

Background:This study aims to provide reasons for the poor sarcoma-related survival in patients with radiation-induced sarcoma (RIS).Methods:We performed a case–control study comparing sarcoma-related survival of 98 patients with RIS to that of 239 sporadic high-grade malignant sarcomas.Results:The cumulative sarcoma-related 5-year survival was 32% (95% confidence interval (CI): 22–42) for patients with RIS vs 51% (95% CI: 44–58) for controls (P<0.001). Female gender, central tumour site and incomplete surgical remission were significantly more frequent among RIS patients than in controls. In multivariate analysis incomplete surgical remission (hazard ratio (HR) 4.48, 95% CI: 3.08–6.52), metastases at presentation (HR 2.93, 95% CI: 1.95–4.41), microscopic tumour necrosis (HR 1.88, 95% CI: 1.27–2.78) and central tumour site (HR 1.71, 95% CI: 1.18–2.47) remained significant adverse prognostic factors, but not sarcoma category (RIS vs sporadic).Conclusion:The poor prognosis of RIS patients are not due to the previous radiotherapy per se, but related to the unfavourable factors – central tumour site, incomplete surgical remission, microscopic tumour necrosis and the presence of metastases, the two former factors overrepresented in RIS.

Laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy: a case-control study and 3 years of follow-up

BackgroundLaparoscopic sleeve gastrectomy (LSG) has become a popular surgical procedure among bariatric surgeons. Few studies have compared the efficacy of the procedure to laparoscopic Roux-en-Y gastric bypass (LRYGB). We performed a case-control study to assess the surgical results, weight progression, and remission of co-morbid conditions. MethodsFrom January 2006 to September 2009, we selected 811 patients undergoing LSG as a primary procedure. These patients were matched by age, body mass index, and gender to 786 patients undergoing LRYGB. The complication rate, mortality, and percentage of excess weight loss after 1, 2, and 3 years were analyzed. ResultsThe mean age for the LRYGB and LSG groups was 37.0 ± 10.3 and 36.4 ± 11.7 years, respectively (P = .120). Most of the patients were women (LRYGB 76.6% versus LSG 76.2%; P = .855). The preoperative body mass index before surgery was similar in both groups (LRYGB 38.0 ± 3.2 versus LSG 37.9 ± 4.6 kg/m2; P = .617). The mean operative time was longer for LRYGB (106.2 ± 33.2 versus 76.6 ± 28.0 min; P <.001), and the hospital stay was longer for LRYGB (3.4 ± 4.4 versus 2.8 ± .8 for LSG; P <.001). The early complication rate was 7.1% for LRYGB and 2.9% for LSG (P <.001), and the suture leak rate was .7% for LRYGB and .5% for LSG (P = NS). The percentage of excess weight loss for LRYGB versus LSG at 1, 2, and 3 years was 97.2% ± 24.3% versus 86.4% ± 26.4% (P <.001), 94.6% ± 30.2% versus 84.1% ± 28.3% (P <.001), and 93.1% ± 25.0% versus 86.8% ± 27.1% (P = .082), respectively. The total cholesterol level at 1 year for LRYGB versus LSG was 169.0 ± 32.9 versus 193.6 ± 38.7 mg/dL, respectively (P <.001), and the rate of diabetes remission was similar in both groups (LRYGB 86.6% versus LSG 90.9%). ConclusionLSG has become an acceptable primary bariatric procedure for obesity, with results comparable to LRYGB in this population.

Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis

To study the currently available data of recurrence rates of functioning and nonfunctioning pituitary adenomas following surgical cure and to analyze associated predisposing factors, which are not well established. A systematic literature search was conducted using Medline, Embase, Web of Science and the Cochran Library for studies reporting data on recurrence of pituitary adenoma after surgery, in nonfunctioning adenoma (NF), prolactinoma (PRL) acromegaly (ACRO) and Cushing’s disease (CUSH). Of 557 initially retrieved potential relevant studies 143 were selected. Recurrence in NFA was defined as reappearance of tumor on MRI or CT. Increase of hormone levels above normal limits as set by the authors after initial remission was used to indicate recurrence in the functioning tumor types. Remission percentage was lowest in NFA compared with other tumor types (P < 0.001). Surgery-related hypopituitarism was more frequent in CUSH than in the other tumors (P < 0.001). Recurrence, expressed as percentage of the cured population or as ratio of recurrence and total patient years of follow-up was highest in PRL (P < 0.001). The remission percentage did not improve over 3 decades of publications, but there was a modest decrease in recurrence rate (P = 0.04). Recurrences peaked between 1 and 5 years after surgery. Most of the studies with a sufficient number of recurrences did not apply multivariate statistics, and mentioned at best associated factors. Age, gender, tumor size and invasion were generally unrelated to recurrence. For functioning adenomas a low postoperative hormone concentration was a prognostically favorable factor. In NFA no specific factor predicted recurrence. Recurrence rate differs between pituitary adenomas, being highest in patients with prolactinoma, with the highest incidence of recurrence between 1 and 5 years after surgery in all adenomas. Patients with NFA have a lower chance of remission than patients with functioning adenomas. The postoperative basal hormone level is the most important predictor for recurrence in functioning adenomas, while in NFA no single convincing factor could be identified.

Intraoperative multiple-staged resection and tumor tissue identification using frozen sections provide the best result for the accurate localization and complete resection of tumors in Cushing’s disease

The treatment of choice in Cushing's disease (CD) is surgical removal; however, most tumors are too small to be detected. The objective was to establish a method to achieve the complete removal of tumors on the basis of the results of high-resolution magnetic resonance imaging (MRI), inferior petrosal sinus sampling (IPSS), and a surgical resection technique using frozen biopsy. Eighteen patients who underwent transsphenoidal surgery from 2004 to 2010 were included. High-resolution MRI and IPSS, multiple-staged resection, and tumor tissue identification in frozen sections (surgical and histological identification, SHI) were performed. All patients achieved surgical remission, as confirmed by 24h urinary free cortisol excretion tests. Visible microlesions were identified on the initial MRI in 11 patients (61%). The SHI findings agreed with the MRI findings in 10 of the 11 patients (90.9%) and with IPSS lateralization in 6 of the 11 patients (54.5%). In the 7 patients whose lesions were not visible on the initial MRI, only 1 (14.3%) showed an agreement between IPSS and SHI. In 3 of the 7 patients, the microlesions were identified by additional MRI. The rate of concordance with SHI was 77.8% for the overall MRI and 38.9% for IPSS. High-resolution MRI is better than IPSS for localizing corticotroph adenomas. In patients with lesions not visible on the initial MRI, additional MRI should be performed using a different protocol. Although high-resolution MRI is better for localizing tumors, SHI remains an important approach for removing the tumors completely.

Pseudotumor cerebri during Cushing's disease treatment with ketoconazole

Benign intracranial hypertension (Pseudotumor cerebri) has been described as related to the reduction in steroid levels in Cushing's disease (CD), especially after surgical remission. Ketoconazole is a common and effective adjuvant therapy for hypercortisolism, but the major concern is liver enzyme dysfunction. We describe here the case of a 12-year old girl with CD who developed benign intracranial hypertension during treatment with ketoconazole. She presented headache, vomiting, a black spot on her right temporal visual field, and signs of elevated intracranial pressure. Pituitary image was normal on magnetic resonance image (MRI), and all symptoms improved after treatment with acetazolamide. We call attention to the diagnosis of this disorder in CD patients, especially children on ketoconazole treatment, because it could be confounded with adrenal insufficiency and lead to definitive severe visual impairment.

Osteosarcoma of the pelvis and sacrum: A retrospective analysis of 73 patients.

10039 Background: Treatment of pelvic and sacrum osteosarcoma (OS) poses challenges for local control and outcome. Data are scarce since these patients (pts) are often not eligible for chemotherapy protocols. Methods: All pts with high grade pelvic or sacral OS admitted to the Rizzoli Institute between 1998 and 2010 were included in this retrospective study. Results: 73 pts (40 male) were identified; median age was 32 years (8-72); 60 (82%) had pelvic and 13 (18%) sacral lesions. Fifty-five (75%) pts presented with localized disease. Forty-eight (66%) underwent surgery (and hindquarter amputation in 37% of cases, with adequate surgical margins in 78%). A surgical complete remission (SCR) was achieved in 56% of pts. Chemotherapy: 3 Drugs [cisplatin, adriamycin and standard dose ifosfamide (IFO)] were administered to 16 pts; 4 Drugs (cisplatin, adriamycin, IFO and methothrexate) to 19 pts; 4 Drugs with high dose ifosfamide (HDIFO: 15 gr/m2) in 21. Four pts did not receive chemotherapy; 13 pts received other...

The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols

BackgroundLocal recurrence (LR) in osteosarcoma is associated with very poor prognosis. We sought to evaluate which factors correlate with LR in patients who achieved complete surgical remission with adequate margins. Patients and methodsWe analyzed 1355 patients with previously untreated high-grade central osteosarcoma of the extremities, the shoulder and the pelvis registered in neoadjuvant Cooperative Osteosarcoma Study Group trials between 1986 and 2005. Seventy-six patients developed LR. ResultsMedian follow-up was 5.56 years. No participation in a study, pelvic tumor site, limb-sparing surgery, soft tissue infiltration beyond the periosteum, poor response to neoadjuvant chemotherapy, failure to complete the planned chemotherapy protocol and biopsy at a center other than the one performing the tumor resection were significantly associated with a higher LR rate. No differences were found for varying surgical margin widths. Surgical treatment at centers with small patient volume and additional surgery in the primary tumor area, other than biopsy and tumor resection, were significantly associated with a higher rate of ablative surgery. ConclusionsPatient enrollment in clinical trials and performing the biopsy at experienced institutions capable of undertaking the tumor resection without compromising the oncological and functional outcome should be pursued in the future.

The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing’s disease

Rapid assessment of adrenal function is critical following transsphenoidal surgery (TSS) for Cushing's disease (CD) in order to determine surgical efficacy. We hypothesize that there may be a role for ACTH measurement as a rapid indicator of adrenal function. Following surgery for CD, glucocorticoids were withheld and paired plasma ACTH and serum cortisol levels were measured every 6 h. Post-operative hypocortisolemia was defined as serum cortisol <2 mcg/dl or a serum cortisol <5 mcg/dl with the onset of symptoms of adrenal insufficiency within 72 h. We studied 12 subjects, all female, mean age 44.6 years (range 25-55), including 13 surgeries: nine subjects attained hypocortisolemia. Plasma ACTH levels decreased more in subjects with hypocortisolemia (0.9 pg/ml/hr, P = 0.0028) versus those with persistent disease (0 0.2 pg/ml/hr, P = 0.26) within the first 48 h after surgery. In contrast to subjects with persistent disease, all subjects with hypocortisolemia achieved a plasma ACTH <20 pg/ml by 19 h (range 1-19 h). Four of the nine subjects with hypocortisolemia achieved plasma ACTH <20 pg/ml by 13 h and the remaining five subjects by 19 h. Hypocortisolemia occurred between 3-36 h following achievement of a plasma ACTH <20 pg/ml. In CD, a reduction in postoperative plasma ACTH levels differentiates subjects with surgical remission versus subjects with persistent disease. The utility of plasma ACTH measurements in the postoperative management of CD remains to be determined.

From Chordomas to Gliomas: Putting the Brakes on Brachyury

Introduction: Chordomas are tumors that arise from the osseous spine and skull base and compromise 2%–4% of all bone cancers. The locally invasive nature of these cancers and the radio- and chemoresistance that they exhibit makes complete surgical resection and remission a major therapeutic challenge. Recent molecular interrogation of chordomas has revealed a critical gene duplication of the mesenchymal developmental transcription factor Brachyury (T gene) in all familial chordomas, suggesting a gain of function mutation. We hypothesize that the overexpression of Brachyury is a pivotal molecular event in the progression of chordomas and other notoriously aggressive malignancies of the neuroaxis, including gliomas and gliosarcomas.

Effectiveness of surgical weight loss on the remission of type 2 diabetes mellitus: A systematic review

Effectiveness of surgical weight loss on the remission of type 2 diabetes mellitus: A systematic review

Solitary skeletal osteosarcoma recurrence. Findings from the Cooperative Osteosarcoma Study Group

Solitary skeletal osteosarcoma (OS) manifestations distant from the site of the primary tumor rarely arise as only sign of disease recurrence. This report reviews 38 patients with high-grade central OS of the limbs or axial skeleton and initial complete surgical remission (CR) who developed first recurrences as solitary osseous lesions distant from the primary tumor. The Cooperative Osteosarcoma Study Group (COSS) database was used to evaluate patient-, tumor-, and treatment-related variables and outcomes. Thirty-eight patients (27 males and 11 females; 36 limb and 2 axial primaries) developed solitary osseous recurrences a median of 2.1 years (range: 0.5-14.3) from primary diagnosis. Relapses involved axial (24), extremity (10), or craniofacial bones (4). Treatment for recurrence included surgery (28), radiotherapy (10), and chemotherapy (27). After a median follow-up of 1.9 years (range: 0.1-21.2) from first recurrence for all 38 patients and 5.5 years (0.3-21.2) for 16 survivors (10 in continuous second CR), 2- and 5-year overall and event-free survival (EFS) probabilities were 55% and 34% and 34% and 27%, respectively. A long interval to recurrence (>1.5 years) predicted for better overall (P < 0.001) and EFS (P = 0.005). For 21 patients achieving a second CR, 2- and 5-year overall and EFS probabilities were 81% and 61% and 52% and 49%, respectively, while only 1/17 others survived beyond 5 years (P < 0.001). Survivors (14/16) had also received second-line chemotherapy. First solitary skeletal recurrences of OS should be treated with curative intent. Some presumed bone metastases may represent second primary OSs.

The common consensus criteria have high predictive values for long-term postoperative acromegaly remission

The aim of this work was to retrospectively study the long-term reliability of the common consensus endocrinological criteria for the assessment of postoperative remission of acromegaly. In 96 consecutive patients, surgical remission of acromegaly following transsphenoidal surgery was considered to be present when, without adjuvant treatment, 3 months postoperatively there was no clinical evidence of persisting disease, and, according to the common consensus criteria for acromegaly remission, GH was suppressed to < 1 μg/l during the oral glucose tolerance test (OGTT) and insulin like growth factor-1 (IGF-1) was within normal limits. The results of the second postoperative week, 3 months postoperative, and the most recent follow-up OGTT and IGF-1 measurements were used to calculate the positive and negative predictive values of the following endocrinological criteria of acromegaly remission: the common consensus criteria for acromegaly remission, GH suppression to < 1 μg/l during OGTT and IGF-1 within normal limits. Sensitive IRMA (≤ 0.3 μg/l) and RIA (≤ 32 μg/l) assays for GH and IGF-1 were used. The surgical remission rate of acromegaly was 72.9%. At a median follow-up of 5.06 years, the recurrence rate of acromegaly was 2.08%. Overall, the common consensus criteria for acromegaly remission were the most reliable tests, with the following positive and negative predictive values at 2 weeks postoperatively, 3 months postoperatively and at the most recent follow-up: 68%, 100% and 100%, and 98%, 100% and 100%, respectively. The negative likelihood ratio confirmed that the test qualities of the common consensus criteria for acromegaly remission were superior to the other tests. The common consensus criteria were the most reliable tests for the diagnosis of postoperative acromegaly remission. The positive and negative predictive values of the common consensus criteria for acromegaly remission increased from the second postoperative week to 3 months postoperatively, thereafter reliably indicating the long-term results of transsphenoidal surgery.

Significance of postoperative fluid diuresis in patients undergoing transsphenoidal surgery for growth hormone–secreting pituitary adenomas

Following successful transsphenoidal surgery in patients with growth hormone (GH)-secreting pituitary adenomas, a characteristic fluid diuresis has been described. In this paper the authors aimed to further analyze the degree of fluid diuresis as it relates to postoperative GH levels. Between 2000 and 2008, 85 patients underwent transsphenoidal surgery for a GH-secreting adenoma at the USC University Hospital. A retrospective chart review was conducted. Postoperative fluid intake, output, and balance within 48 hours following surgery, as well as endocrinological data were recorded and analyzed. Patients with postoperative diabetes insipidus and those with insufficient data were excluded from analysis. Seventy-one patients were included in the analysis. The mean age was 46 years (range 16-74 years). There were 36 males (51%) and 35 females (49%). Patients with negative fluid balances at 48 hours after surgery were more than twice as likely to have a GH level of < 1.5 ng/ml (55 vs 25%, p = 0.023). At 48 hours after surgery, patients with a negative overall fluid balance had a significantly lower median GH level than those with a positive overall fluid balance (1.3 vs 2.4 ng/ml, p = 0.039). This difference was even more pronounced in patients with microadenomas and a negative overall fluid balance. By 48 hours following surgery, patients with postoperative Day 1 GH levels < 1.5 ng/ml had, on average, experienced diuresis of fluid > 1.1 L (median 1.5 L) more than patients with GH levels > 1.5 ng/ml. Successful resection of GH-secreting adenomas is associated with a more pronounced fluid diuresis and negative overall fluid balance within 48 hours following transsphenoidal surgery. Patients with a negative fluid balance by postoperative Day 2 have a higher likelihood of having significantly reduced postoperative GH levels that may correlate with long-term surgical remission.

Pseudotumor Cerebri after Surgical Remission of Cushing’s Disease

Pseudotumor cerebri has only been described after successful surgery for Cushing's disease (CD) in case reports. We sought to establish the incidence and timing of its occurrence, identify predisposing factors, characterize the clinical presentations and their severity, and examine the effects of treatment in patients who underwent surgery for CD. This study was conducted at two tertiary care centers: The University of Virginia and the National Institutes of Health. We conducted a retrospective review of 941 surgeries for CD (723 adults, 218 children) to identify patients who developed pseudotumor cerebri after surgery for CD and examine the associated clinical features. Seven children (four males, three females; 3%), but no adults, developed pseudotumor cerebri postoperatively. All underwent resection of an ACTH-secreting adenoma, and postoperative serum cortisol reached a nadir of less than 2 microg/dl. After surgery, all were placed on tapering hydrocortisone replacement therapy. Within 3-52 wk, all seven patients experienced symptoms of pseudotumor cerebri and had ophthalmological examination demonstrating papilledema. One patient had diplopia from a unilateral VIth nerve palsy. Six patients were still on steroid replacement at onset of symptoms. In three patients, a lumbar puncture demonstrated elevated opening pressure. Four patients were treated successfully with a lumbar puncture, steroids, and/or Diamox. Three patients did not receive treatment, and their symptoms resolved over several months. There was no correlation between the degree of hypercortisolism (24-h urinary free cortisol) before surgery and the likelihood of developing pseudotumor cerebri after surgery (P < 0.23). This series demonstrates a 3% occurrence of pseudotumor cerebri in children after successful surgery for CD, but the absence of the syndrome in adults. Pseudotumor cerebri manifests itself within 1 yr of surgery, often while patients are still undergoing replacement steroid therapy. A patient exhibiting signs of intracranial hypertension after surgery for CD should undergo an evaluation for pseudotumor cerebri. Recognition of the symptoms and treatment should correct and/or prevent ophthalmological sequelae.

Medical treatment of Cushing's disease: Overview and recent findings.

Cushing's disease, due to pituitary adrenocorticotropic hormone (ACTH) hypersecretion, is the most common etiology of spontaneous excess cortisol production. The majority of pituitary tumors causing Cushing's disease measure <1 cm and the excess morbidity associated with these tumors is mostly due to the effects of elevated, nonsuppressible, ACTH levels leading to adrenal steroid hypersecretion. Elevated circulating cortisol levels lead to abnormal fat deposition, hypertension, diabetes, coronary artery disease, osteoporosis, muscle weakness and psychological disturbances. At experienced centers, initial surgical remission rate via transnasal, transphenoidal resection approaches 80% for tumors less than 1 cm, but may be as low as 30% for larger lesions and long-term recurrence in all groups approaches 25%. Residual disease may be managed with more radical surgery, pituitary-directed radiation, bilateral adrenalectomy, or medical therapy. This paper addresses current and novel therapies in various stages of development for Cushing's disease.