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Avascular necrosis of hip secondary to sunitinib

We report a case of a 73 year old patient who developed AVN of her left hip while on sunitinib for mRCC.

 

Authors: Dr Muhammad A Khattak, MBBS1, Dr Hilary L Martin, MBBS2, Dr Chris Karapetis,MBBS, FRACP1

1. Oncology Registrar, Flinders Medical Centre

2. Oncology Registrar, Calvary Hospital

 
Corresponding Author: Dr Muhammad A Khattak, Oncology Registrar, Flinders Medical Centre, Flinders Drive, Bedford Park, Adelaide, South Australia – 5042.   Tel: +61 8 8204 5511, Fax: +61 8 8404 2152 , Email: [email protected]

 

Introduction
 
Avascular necrosis (AVN) is a rare musculoskeletal disorder associated with multiple medical conditions and therapeutic interventions. The exact etiology and pathogenesis is not completely understood but is widely thought to be related to microvascular compromise causing bone marrow infarction eventually leading to mechanical failure. Sunitinib (Sutent) is an inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor (PDGFR) and FMS-like tyrosine kinase-3 (FLT3). It is currently being used as first line therapy in the management of metastatic renal cell carcinoma (mRCC).  Avascular necrosis secondary to anti-angiogenic agents is possibly a rare complication of these drugs and the likely pathogenesis is microvascular compromise. We report a case of a 73 year old patient who developed AVN of her left hip while on sunitinib for mRCC.

 

Case report
A 73 year old woman was investigated for chest pain and found to have multiple pulmonary lesions and a mass in her right kidney.  Biopsy of the renal mass (FNA) was performed.  Histology was consistent with renal cell carcinoma (ovoid to irregular, pleomorphic nuclei, dispersed chromatin, obvious, single nucleoli and abundant vacuolated lightly staining cytoplasm).  She was commenced on sunitinib 50mg daily on 9 March 2007.  After a couple of weeks she developed an upper torso rash, mucositis and thrombocytopaenia, and sunitinib was ceased temporarily and recommenced at a dosage of 25mg daily on 20 April 2007 with a planned cycle of four weeks on and two weeks off.  This dosage was tolerated well, with no clear treatment related side effects. A computed tomography (CT) scan performed on 10 July 2007 showed a radiologic response to treatment. Besides sunitinib, the patient was taking the following medications on a daily basis; enalapril 10mg, simvastatin 40mg, diltiazem 360mg, pantoprazole 40mg, furosemide 40mg, hydroxychloroquine 200mg, and thyroxine 100mcg. She had also taken warfarin, which was ceased recently.
She developed left hip pain for the first time in November 2007. A whole body bone scan at that time revealed diffuse uptake involving the left femoral head and neck, which was thought to be atypical for both degenerative change and bony metastatic disease (figure 1).

 

Figure 1. A whole body bone scan revealed diffuse uptake involving the left femoral head and neck.

 

 

She subsequently developed erythema and swelling of the lower limb which was thought to be due to sunitinib.  This was ceased on 19 December 2007 along with her diltiazem and thyroxine.  The patient’s pain deteriorated with time, with reduction in her mobility and restriction of movement at the left hip . She had an antalgic gait. X-ray of the hip revealed degenerative changes, with reduction of the joint space, and altered contour of the left femoral head in addition to collapse. There was no fracture or dislocation. An MRI performed in February 2008 showed a large left hip joint effusion with synovial thickening and a crescentic low signal focus consistent with a fragment of cortical bone. The femoral head demonstrated marked deformity with collapse of the superior contour and crescentic fluid cleft, associated with cortical defect superoanteriorly. The femoral head showed a low T1 and intermediate T2 signal consistent with diffuse edema. The overall appearances were thought to reflect avascular necrosis with collapse of the left femoral head, diffuse edema and advanced secondary degenerative changes (figure 2 and 3).

 

Figure 2. 

 

 

Figure 3. 

 


 
No convincing evidence of metastatic deposits was found. She was referred to an orthopaedic surgeon and a total hip replacement was performed.
The patient did not have any predisposing medical conditions for avascular necrosis of the hip and had never used steroids. She was a non-smoker with minimal alcohol consumption. There was no history of trauma to the left hip and she had never received any radiotherapy. This led to the hypothesis that sunitinib could have led to this through compromise of the microvasculature of the left femoral head (due to its antiangiogenic activity), which is thought to be the main pathologic process underlying this condition eventually leading to mechanical compromise of the hip.

 

Discussion
Osteonecrosis (ON), also known as avascular necrosis (AVN) is a rare musculoskeletal disorder associated with multiple medical conditions and therapeutic interventions. The exact etiology and pathogenesis is not completely understood but is widely thought to be related to microvascular compromise causing bone marrow infarction eventually leading to mechanical failure. According to Kerachain et al , decreased local blood flow to the femoral head and microvascular thrombosis is the most accepted mechanism in the pathogenesis of ON. It is associated with traumatic and various non-traumatic causes including corticosteroid use, smoking, alcohol consumption, radiotherapy (osteoradionecrosis), hyperuricaemia and hyperlipidaemia. Corticosteroid and alcohol use are thought to be associated with >90% of cases .
Sunitinib (Sutent) is an inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor (PDGFR) and FMS-like tyrosine kinase-3 (FLT3). It is currently being used as first line therapy in the management of metastatic renal cell carcinoma (mRCC) and as second line treatment in metastatic gastrointestinal stromal tumours (mGIST). Sunitinib was evaluated in a phase III trial of 750 patients with metastatic clear cell RCC who had not received prior systemic treatment . Patients were randomly assigned to sunitinib or interferon alfa. The updated results published by Motzer et al  showed that the median overall survival was greater in the sunitinib group than in the IFN-alpha group but not statistically significant (26.4 v 21.8 months, respectively; hazard ratio [HR]= 0.821; 95% CI, 0.673 to 1.001; P = 0.051). Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-alpha (P<.001). Objective response rate was 47% for sunitinib compared with 12% for IFN-alpha (P<0.001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).
There have been two of reports of ON related to targeted therapy like bevacizumab and single case reports with sorafenib and sunitinib , . To our knowledge, this is the second case of ON related to suntinib treatment. According to the Naranjo scale  for determining the likelihood of an adverse drug reaction as a side effect of a particular drug compared to other factors, the imputability of sunitinib in this case is ‘probable’ (score 5). Our patient was on diltiazem regularly for management of hypertension before sunitinib was started and its concurrent administration could have lead to toxicity with sunitinib through a pharmacokinetic interaction by inhibiting cytochrome P-450 (CYP3A4) ,  resulting in an increased sunitinib concentration.
Although the targeted agents have revolutionalised the field of medical oncology, we have to be cautious about under recognized and rare side effects of these agents impacting on the quality of life of cancer patients. Osteonecrosis secondary to anti-angiogenic agents is possibly a rare class effect of these drugs and the likely pathogenesis is microvascular compromise eventually ending up in mechanical failure. The treating physician needs to be aware that new onset musculoskeletal hip pain in patients on anti-angiogenic agents could be related to therapy related complication, besides disease progression and secondary skeletal events. Early recognition and prompt treatment of these complications can be beneficial in minimizing the patient symptoms and disability. Therefore, new onset hip pain in a patient on these agents should be investigated sooner rather later with imaging including plain X-rays and MRI.
 

References
1. Kerachian MA, Harvey EJ, Cournoyer D, et al. Avascular necrosis of the femoral head: Vascular hypotheses. Endothelium. 2006 Jul: 13:237-244
2. Mont MA, Hungerford DS. Non-traumatic avascular necrosis of the femoral head. J Bone Joint Surg Am.  1995 Mar: 77:459-74
3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan: 356:115-24
4. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug: 27:3584-90
5. Guillet M, Walter T, Scoazec JY, et al. Sorafenib-induced bilateral osteonecrosis of femoral heads. J Clin Oncol. 2010 Jan: 28: e14. Epub 2009 Nov
6. Mir O, Coriat R, Gregory T, Ropert S, et al. Avascular necrosis of the femoral head: a rare class-effect of anti-VEGF agents. Invest New Drugs. 2011 Aug. 29: 716-8 Epub 2010 Feb
7. Naranjo C, Busto U, Sellers E, et al. A method for estimating the probability of adverse drug reactions.. Clin Pharmacol Ther. 1981 Aug: 30: 239-45
8. Haouala A., Widmer N., Montemurro M, et al. Cardiovascular drug interactions with tyrosine kinase inhibitors. Cardiovascular Medicine. 2010 May: 13: 147-54
9. Izzedine H, Massard C, Spano J, et al. VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. Eur J Cancer. 2010 Jan: 46:  439-48

 
Date added to bjui.org: 21/09/2011


DOI: 10.1002/BJUIw-2011-058-web

 

Spontaneous Regression of Metastatic Type II Papillary Renal Cell Carcinoma

We present the first reported case of metastatic type II papillary RCC with radiographic evidence of spontaneous regression at a non-pulmonary site of proven metastases.

Authors: Nicholas E. Power, Stephen A. Poon, Clarisse Mazzola, Jonathan L. Silberstein, Robert J. Motzer, Ana M. Molina, Snehal G. Patel, Jonathan A. Coleman.  Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
 
Corresponding Author: Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 213, New York, NY10065.  E-mail: [email protected]

Supported by The Sidney Kimmel Center for Prostate and Urologic Cancers and by funds provided by Renal Carcinoma Program Fund.

 

Abstract
 
Spontaneous regression of renal cell carcinoma (RCC) is a rare event that has been almost exclusively associated with the conventional clear cell subtype. We present the first reported case of metastatic type II papillary RCC with radiographic evidence of spontaneous regression at a non-pulmonary site of proven metastases.  We highlight the literature on spontaneous regression of RCC and discuss the unique challenges of non-clear-cell metastatic RCC and new therapies in this setting.
Introduction
Spontaneous regression of renal cell carcinoma (RCC) is a rare event, with most large historic case series citing a 0-1.1% incidence [1]. In the majority of cases reported, metastasis was not confirmed histologically, and conventional clear cell RCC was the identified histology in the primary tumour [2]. Notably, spontaneous regression of papillary RCC (type 2) has been documented only once, at a site of pulmonary metastasis [3]. We report ona case of pT3bN2 high-grade type II papillary RCC in a 63-year-old male with histologically confirmed neck metastasis that spontaneously regressed following cytoreductive partial nephrectomy and retroperitoneal lymph node dissection. Subsequent lymphadenectomy of the site by left-neck dissection was performed following a period of surveillance during which no local or distant progression was identified. Pathology findings revealed 11/47 positive nodes that were consistent with the primary histology. Together with the recently described genetics of type II papillary RCC and the limitations of current systemic therapy in this setting, this case suggests opportunities for additional research.

 

Case Report
 
A 63-year-old male with a 30-year history of sarcoidosis presented with chest pressure of short duration which was investigated at a local emergency department. His cardiac evaluation was negative, but a chest x-ray suggested emphysematous changes and interstitial thickening in the upper lobe of the right lung. A non-contrast CT scan of the chest confirmed a non-specific interstitial pulmonary density in the right upper lobe and suggestion of cystic renal changes in the left kidney.  A dedicated CT scan of the neck and chest identified a 4.0 X 3.1 X 3.2 cm (estimated volume 20.8 cc. Estimated tumour volumes are calculated volumes of an ellipsoid: (xyz)π/6) left thoracic inlet mass lateral to the thyroid (Figure 1) which was the only site of mild hypermetabolic activity on subsequent PET scan.
 

Figure 1a. A dedicated CT scan of the neck and chest. 

 

Figure 1b. A dedicated CT scan of the neck and chest. 
A dedicated CT scan of the neck and chest identified a 4.0 X 3.1 X 3.2 cm (estimated volume 20.8 cc. ) left thoracic inlet mass lateral to the thyroid which was the only site of mild hypermetabolic activity on subsequent PET scan.
 
 
A renal sonogram was interpreted to identify a 1.5 cm simple parapelvic cyst in the left kidney. On fine-needle aspirate of the neck mass, the immunoprofile was positive for CD10, CK7, and vimentin with cytoarchitecture considered suggestive of papillary carcinoma. CT urogram identified a 3.2-cm left lower-pole renal mass with a 2-cm left renal hilar lymph node and a 1.8-cm inter-aortocaval lymph node (Figure 2).

 

Figure 2a-d.  CT urogramCT urogram identified a 3.2-cm left lower-pole renal mass with a 2-cm left renal hilar lymph node and a 1.8-cm inter-aortocaval lymph node
 
Figure 2.  CT urogram
  CT urogram

 

The patient was referred to our institution for further management. His history included prior treatment with corticosteroids for sarcoidosis and a family history remarkable for fatal childhood leukemia in 1 sibling and RCC in 2 first degree relatives including mother and 1 sibling. The details regarding tumoursubtype in these individuals were unavailable, though both had undergone nephrectomy without evidence of disease progression over >10 years of follow up. No familial history of symptomatic uterine fibroids or related abnormalities was evident. Pertinent physical examination findings werenotable for a firm, mobile, non-tender supraclavicular left neck mass, normal pulmonary examination, and no evidence of stigmata related to known genetic syndromes including dermatologic abnormalities.  Genetic counseling and testing was recommended but declined. Following multi-disciplinary evaluation, cytoreductive robot-assisted laparoscopic partial nephrectomy and retroperitoneal lymph node dissection was performed. Pathology revealed 2.2 cm, pT3bN2 high-grade type II papillary RCC with foci of necrosis, renal hilar fat involvement and 14 of 25 nodes positive (Figures 3 and 4).

 

Figure 3
Pathology revealed 2.2 cm, pT3bN2 high-grade type II papillary RCC with foci of necrosis, renal hilar fat involvement and 14 of 25 nodes positive

 

Figure 4
Pathology revealed 2.2 cm, pT3bN2 high-grade type II papillary RCC with foci of necrosis, renal hilar fat involvement and 14 of 25 nodes positive

 

Immunohistochemical stains revealed that the tumour was positive for CK7 and racemase, while negative for CA-IX, CD10, 34BE12, supporting the diagnosis.
In follow-up, a CT scan of the chest, abdomen, and pelvis was completed 6 weeks after surgery. In addition to post-surgical changes at the surgical site, decrease in size of the neck mass to 3.2 X 2.0 X 2.3 cm (estimated volume 7.7cc) was observed and no evidence of new metastases identified. The patient elected to forego systemic therapies and observe. (est. volume 5.4cc) and 2.3 X 1.9 X 1.4 cm (est. volume 3.2cc), respectively; Figure 5], with no evidence of local or distant disease progression identified.

 

Figure 5 a and b. CT scans completed 3 and 6 months postoperativelyCT scans completed 3 and 6 months postoperatively
(est. volume 5.4cc) and 2.3 X 1.9 X 1.4 cm (est. volume 3.2cc), respectively; Figure 5], with no evidence of local or distant disease progression identified.   Figure 5. CT scans completed 3 and 6 months postoperatively

 

By RECIST 1.1 criteria [4], the neck mass regressed from 3.1 cm short axis to 1.9 cm short axis for a total of 39% response, or equivalent to a partial response (PR). As presurgical FDG-PET imaging did not correlate with all sites of proven tumour burden it was not used to evaluate sites of potential disease during follow-up.
After 11 months of surveillance with no evidence of progression or new metastasis, the patient underwent a selective left-neck dissection. This showed 4 positive nodes in neck levels IV and VI and 7 positive nodes from the left superior mediastinal dissection. These were all consistent, morphologically and immunohistochemically, with the primary type II papillary RCC. At his 3-month follow-up visit, there was no evidence of disease progression or new metastasis on CT scan of the neck, chest, abdomen, and pelvis, and he had recovered fully with only mild residual vocal hoarseness.

 

Discussion
 
Contemporary clinical assessment of tumour burden and response to cancer therapeutics is categorized according to the RECIST 1.1 guideline [4]. Spontaneous regression of cancer, as defined by Everson and Cole in 1966 however, is the “partial or complete disappearance of malignant tumour in the absence of all treatment or in the presence of therapy that is considered inadequate”[5]. Their manuscript identified 176 cases of spontaneous regression in multiple types of cancer, including 31 cases of RCC, the most common malignancy exhibiting this behavior. Unfortunately, 84% of the cases had histologic confirmation of the primary tumours but not the metastatic sites. This raises the possibility that the metastatic sites were actually of benign etiology. Contemporary histologic classification of renal tumoursthat now include the papillary type 2 subtype is also a relatively recent development raising the possibility of similar prior witnessed events which were documented differently. Publications have identified numerous cases of spontaneous regression of metastatic tumours, with the lungs being the most common site [5]. Others include brain, bone, liver, regional lymph nodes, and the adrenal glands [6, 7]. The event of cytoreductive intervention preceedingregression has prompted postulation of a humoral response capable of inducing tumour degeneration at the metastatic site. Cytoreductive nephrectomy was performed in approximately half of the reported cases, but other treatments, such as radiation, embolization, and radiofrequency ablation, have been implicated in the literature [5, 8]. The aetiology of spontaneous regression is unknown, but immunologic mechanisms have been hypothesized. In fact, spontaneous regression phenomena initially led to a surge in cytoreductive nephrectomy for advanced renal cancers. Significant complications and poor outcomes tempered the enthusiasm for this approach, but research to identify “biological response modifiers”, as coined in the original publications, continued. The cytokine era of immunotherapy developed out of these efforts, leading, with the discovery and elucidation of the VHL/VEGF pathway, to the current approach of molecular therapeutics [9].
Interestingly, manipulation of the primary tumour is not always required for spontaneous regression. In a clinical trial reported by Oliver et al. in 1989, 73 patients with metastatic RCC were placed on surveillance prior to being considered for therapy with interferon alpha [10].The trial was designed to remove the potential bias of tumour regression. Three complete responses, 2 partial responses, and 4 cases of stable disease >12 months were reported. The 5 cases of spontaneous regression comprised 7% of this cohort.
All published reports of spontaneous regression of RCC in which the histologic subtype was identified have been confirmed cases of clear cell RCC [2], except one recent report by Lim et al where a histologically confirmed pulmonary metastasis for papillary type II RCC arose 6 years after radical nephrectomy and subsequently regressed over the following year [3]. This case represents, to our knowledge, the first documented case of metastatic papillary RCC in a non-pulmonary site exhibiting regression. Metastatic clear cell RCC has experienced a revolution in management with development of targeted therapies. Metastatic papillary RCC, however, has proven resistant to these therapies [11, 12]. While localized papillary RCC carries a favorable prognosis, metastatic papillary RCC is associated with aggressive and rapidly fatal progression [13]. Genetic mutations have been identified with type II papillary RCC, now associated with the heritable condition of hereditary leiomyomatosis and renal cell carcinoma (HLRCC)as the syndromic model [14]. Mutation of fumarate hydratase (FH, a citric acid cycle enzyme catalyzing the conversion of fumarate to malate), localized to 1q42.3-43, has been implicated [14]. Wild type FH acts as a tumour suppressor; loss of heterozygosity studies revealed the loss of the wild type allele in these renal tumours, and there is low to absent enzymatic activity in patients with only leiomyomatosis [15]. However, unlike von Hippel-Lindau, Birt-Hogg-Dube (BHD) syndromes, or hereditary papillary RCC (HPRC), HLRCC kidney findings predominantly manifest as solitary and unilateral renal tumours with little penetrance, affecting 10-15% of HLRCC families (whereas 80-90% of VHL and HPRC families are affected by RCC) [15]. This finding suggests, according to the Knudsen two-hit hypothesis, the relative conservation and rare mutation event involving the wild-type allele leading to type II papillary RCC. The putative cause for regression of tumour at a nodal site of metastases in this case is speculative. Currently utilized agents targeted at the pathways of angiogenesis have been largely ineffective in metastatic papillary RCC[11, 12]. Conceptually, this is not as discouraging as it first appears; rather, it reveals potential avenues of research to identify signaling pathways specific to papillary RCC and, ultimately, to engineer more efficacious treatment for metastatic disease.
As a closing remark, the authors suggest that, in the absence of a more sensitive and specific definition of spontaneous regression of cancer than the one advocated by Everson and Cole in 1966, perhaps a better method may be proposed to stratify the degree of tumour biometric change along the spectrum of regression. One solution would be to adapt the RECIST 1.1 criteria used primarily to assess clinical response to cancer therapeutics. The presented case may be defined as a RECIST 1.1 spontaneous PR.This standard allows comparison across interventions, including clinical trials specific for papillary renal cancer[16]. Quantification of disease burden may also be calculatedusing tumour volume changes from imaging parameters of index tumoursto provide semi-quantitative data, estimated as 85% reduction in volume in this case (Figure 6).

 

Figure 6

Conclusion
 
Histologic and radiographic evidence of partial spontaneous regression of non-pulmonary metastatic type II papillary RCC is presented- the first published case so far as the authors are aware. In the context of the inefficacy of current systemic treatments and the recently described genetics of type II papillary RCC, this case suggests there are exciting opportunities for new research into this disease.

 

References
 
[1] Lokich J. Spontaneous regression of metastatic renal cancer. Case report and literature review. Am J Clin Oncol. 1997 Aug: 20:416-8
[2] Elhilali MM, Gleave M, Fradet Y, et al. Placebo-associated remissions in a multicentre, randomized, double-blind trial of interferon gamma-1b for the treatment of metastatic renal cell carcinoma. The Canadian Urologic Oncology Group. BJU Int. 2000 Oct: 86:613-8
[3] Lim R, Tan PH, Cheng C, et al. A unique case of spontaneous regression of metastatic papillary renal cell carcinoma: a case report. Cases J. 2009: 2:7769
[4] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan: 45:228-47
[5] Everson TC, Cole WH. Spontaneous regression of cancer; a study and abstract of reports in the world medical literature and of personal communications concerning spontaneous regression of malignant disease, Philadelphia,: Saunders, 1966
[6] Snow RM, Schellhammer PF. Spontaneous regression of metastatic renal cell carcinoma. Urology. 1982 Aug: 20:177-81
[7] Wyczolkowski M, Klima W, Bieda W, Walas K. Spontaneous regression of hepatic metastases after nephrectomy and metastasectomy of renal cell carcinoma. Urol Int. 2001: 66:119-20
[8] Sanchez-Ortiz RF, Tannir N, Ahrar K, Wood CG. Spontaneous regression of pulmonary metastases from renal cell carcinoma after radio frequency ablation of primary tumor: an in situ tumor vaccine? J Urol. 2003 Jul: 170:178-9
[9] Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28: 260:1317-20
[10] Oliver RT, Nethersell AB, Bottomley JM. Unexplained spontaneous regression and alpha-interferon as treatment for metastatic renal carcinoma. Br J Urol. 1989 Feb: 63:128-31
[11] Motzer RJ, Bacik J, Mariani T, Russo P, Mazumdar M, Reuter V. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol. 2002 May 1: 20:2376-81
[12] Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008 Jan 1: 26:127-31
[13] Ronnen EA, Kondagunta GV, Ishill N, et al. Treatment outcome for metastatic papillary renal cell carcinoma patients. Cancer. 2006 Dec 1: 107:2617-21
[14] Alam NA, Bevan S, Churchman M, et al. Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43. Am J Hum Genet. 2001 May: 68:1264-9
[15] Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002 Apr: 30:406-10
[16] Reddy EP, Smith MJ, Srinivasan A. Nucleotide sequence of Abelson murine leukemia virus genome: structural similarity of its transforming gene product to other onc gene products with tyrosine-specific kinase activity. Proc Natl Acad Sci U S A. 1983 Jun: 80:3623-7

 

Date added to bjui.org: 30/03/2011 


DOI: 10.1002/BJUIw-2011-001-web

 

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