Leg Lymphoedema After Inguinal and Ilio-Inguinal Lymphadenectomy for Melanoma: Results from a Prospective, Randomised Trial.

BACKGROUND: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema. METHODS: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex®) > 10 or change of L-Dex® > 10 from baseline. RESULTS: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection. CONCLUSIONS: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups.

Outcomes of routine ilioinguinal lymph node dissection for palpable inguinal melanoma nodal metastasis.

BACKGROUND: Patients who present with palpable inguinal melanoma nodal metastasis have two surgical options: inguinal or ilioinguinal lymph node dissection. Indications for either operation remain controversial. This study examined survival and recurrence outcomes following ilioinguinal dissection for patients with palpable inguinal nodal metastasis, and assessed the incidence and preoperative predictors of pelvic nodal metastasis. METHODS: This was a retrospective clinicopathological analysis of consecutive surgical patients with stage III malignant melanoma. All patients underwent a standardized ilioinguinal dissection at a specialist tertiary oncology hospital over a 12-year period (1998-2010). RESULTS: Some 38.9 per cent of 113 patients had metastatic pelvic nodes. Over a median follow-up of 31 months, the 5-year overall survival rate was 28 per cent for patients with metastatic inguinal and pelvic nodes, and 51 per cent for those with inguinal nodal metastasis only (P = 0.002). The nodal basin control rate was 88.5 per cent. Despite no evidence of pelvic node involvement on preoperative computed tomography (CT), six patients (5.3 per cent) with a single metastatic inguinal lymph node had metastatic pelvic lymph nodes. Logistic regression analysis showed that the number of metastatic inguinal nodes (odds ratio 1.56; P = 0.021) and suspicious CT findings (odds ratio 9.89; P = 0.001) were both significantly associated with metastatic pelvic nodes. The specificity of CT was good (89.2 per cent) in detecting metastatic pelvic nodes, but the sensitivity was limited (57.9 per cent). CONCLUSION: Metastatic pelvic nodes are common when palpable metastatic inguinal nodes are present. Long-term survival can be achieved following their resection by ilioinguinal dissection. As metastatic pelvic nodes cannot be diagnosed reliably by preoperative CT, patients presenting with palpable inguinal nodal metastasis should be considered for ilioinguinal dissection.

Increased expression of TSH receptor by fibrocytes in thyroid-associated ophthalmopathy leads to chemokine production.

CONTEXT: The molecular basis for anatomically dispersed clinical manifestations in Graves' disease (GD) eludes our understanding. Bone marrow-derived, pluripotent fibrocytes represent a subset of peripheral blood mononuclear cells and infiltrate the orbital and thyroid tissues in GD. These cells may be involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO). OBJECTIVE: The objective of the study was to quantify fibrocyte display of functional cell surface TSH receptor (TSHR), identify the profile of chemokines they express after TSHR activation, and determine whether circulating TSHR(+) peripheral blood fibrocytes are more frequent in situ in patients with TAO. DESIGN/SETTING/PARTICIPANTS: Using a newly developed technique, fibrocytes were directly identified in peripheral blood from 31 patients with TAO and 19 healthy subjects receiving care at a multidisciplinary academic center. MAIN OUTCOME MEASURES: The frequency in situ of fibrocytes (collagen 1(+), CD45(+), CD34(+), CD14(+), CD86(+) peripheral blood mononuclear cells) was assessed by multiparameter flow cytometry and correlated to clinical disease activity and smoking status. Levels of TSHR-displaying fibrocytes and their response to TSH and TSHR-activating antibody, M22, were measured by flow cytometry, Luminex, and real-time PCR. RESULTS: The levels of TSHR expression by fibrocytes are substantially higher than those found in orbital fibroblasts. Moreover, the frequency of TSHR(+) fibrocytes in patients with TAO was greater than that in healthy subjects in situ. Their abundance is not influenced by disease activity or smoking history. These cells produce high levels of several cytokines and chemokines including IL-8, regulated upon activation, normal T cell expressed and secreted, and monocyte chemoattractant protein-1 when treated with TSH or M22. TSH induces IL-8 production at the pretranslational level. This induced cytokine can be detected in intact fibrocytes ex vivo. CONCLUSIONS: Frequency of circulating TSHR(+) fibrocytes is markedly increased in patients with TAO, and they express proinflammatory chemokines in response to TSH. Because they infiltrate both orbit and thyroid in GD, they may represent the link between systemic immunoreactivity and organ-specific autoimmunity.

Treatment for breast sarcoma: a large, single-centre series.

AIMS: To report outcomes in breast sarcoma in the context of a major series from a tertiary referral centre. METHODS: Retrospective analysis was performed on patients with histologically-proven breast sarcoma treated between 1996 and 2006. Kaplan-Meier survival curves were constructed and differences assessed by Log-Rank and Wilcoxon tests. RESULTS: 63 patients were identified; 57 underwent treatment with curative intent. 24 patients had undergone previous radiotherapy. 36 patients who underwent primary surgery elsewhere were referred for further treatment, of which 22 had at least one involved margin from primary resection. Surgery performed and margins status varied between patients undergoing primary surgery at this institution (n = 21; WLE = 8, mastectomy = 12, chest wall resection = 1, involved margins = 2 [10%]) or at a referring institution (n = 36; lumpectomy = 25, mastectomy = 11, involved margins = 22 [61%]), although there was no difference in tumour size or previous radiotherapy status. Previous irradiation was associated with poor prognosis. A greater proportion of these patients required primary mastectomy to ensure adequate clearance; the majority of the post-irradiation tumours were angiosarcomas (15/19) and significantly more relapsed locally (P < 0.001). All patient disease-free survival (DFS) rates were 71% at 2 and 42% at 5 years. DFS improved when primary surgery was undertaken at a high-volume sarcoma unit; 2-yr 84%vs75%; 5-yr 58%vs37%. There was a trend towards worse DFS with increasing size and increasing grade of tumour but this did not attain significance. CONCLUSIONS: Radiation-induced breast sarcoma has worse local recurrence rates compared to primary breast sarcoma. Involved margins were fewer at a specialist unit, which may translate into improved outcome.

Diagnostic ability of Barrett's index to detect dysthyroid optic neuropathy using multidetector computed tomography.

OBJECTIVES: The objective of this study was to evaluate the ability of a muscular index (Barrett's Index), calculated with multidetector computed tomography, to detect dysthyroid optic neuropathy in patients with Graves' orbitopathy. METHODS: Thirty-six patients with Graves' orbitopathy were prospectively studied and submitted to neuro-ophthalmic evaluation and multidetector computed tomography scans of the orbits. Orbits were divided into two groups: those with and without dysthyroid optic neuropathy. Barrett's index was calculated as the percentage of the orbit occupied by muscles. Sensitivity and specificity were determined for several index values. RESULTS: Sixty-four orbits (19 with and 45 without dysthyroid optic neuropathy) met the inclusion criteria for the study. The mean Barrett's index values (+/- SD) were 64.47% +/- 6.06% and 49.44% +/- 10.94%in the groups with and without dysthyroid optic neuropathy, respectively (p<0.001). Barrett's index sensitivity ranged from 32% to 100%, and Barrett's index specificity ranged from 24% to 100%. The best combination of sensitivity and specificity was 79%/72% for BI=60% (odds ratio: 9.2). CONCLUSIONS: Barrett's Index is a useful indicator of dysthyroid optic neuropathy and may contribute to early diagnosis and treatment. Patients with a Barrett's index >60% should be carefully examined and followed for the development of dysthyroid optic neuropathy.

Diagnostic ability of barrett's index to detect dysthyroid optic neuropathy using multidetector computed tomography

OBJECTIVES: The objective of this study was to evaluate the ability of a muscular index (Barrett's Index), calculated with multidetector computed tomography, to detect dysthyroid optic neuropathy in patients with Graves' orbitopathy. METHODS: Thirty-six patients with Graves' orbitopathy were prospectively studied and submitted to neuro-ophthalmic evaluation and multidetector computed tomography scans of the orbits. Orbits were divided into two groups: those with and without dysthyroid optic neuropathy. Barrett's index was calculated as the percentage of the orbit occupied by muscles. Sensitivity and specificity were determined for several index values. RESULTS: Sixty-four orbits (19 with and 45 without dysthyroid optic neuropathy) met the inclusion criteria for the study. The mean Barrett's index values (± SD) were 64.47 percent ± 6.06 percent and 49.44 percent ± 10.94 percentin the groups with and without dysthyroid optic neuropathy, respectively (p<0.001). Barrett's index sensitivity ranged from 32 percent to 100 percent, and Barrett's index specificity ranged from 24 percent to 100 percent. The best combination of sensitivity and specificity was 79 percent/72 percent for BI=60 percent (odds ratio: 9.2). CONCLUSIONS: Barrett's Index is a useful indicator of dysthyroid optic neuropathy and may contribute to early diagnosis and treatment. Patients with a Barrett's index >60 percent should be carefully examined and followed for the development of dysthyroid optic neuropathy.

Bilateral progressive enophthalmos as the presenting sign of metastatic breast carcinoma.

A 51-year-old woman, without systemic symptoms, complained of slowly progressive receding eyes. She had severe bilateral enophthalmos and markedly restricted extraocular movements in all fields of gaze. Computed tomography showed an infiltrative homogenous mass filling both orbits. Gynecologic and systemic investigation revealed bilateral lobular breast carcinoma, without metastasis to other organs. She was started on chemotherapy and 2 years after the diagnosis remains in good general health, despite persistence of severe enophthalmos. This case serves to emphasize that bilateral progressive enophthalmos may be the presenting sign of metastatic breast carcinoma even when local symptoms in the breast are absent. Clinicians should be aware of this sign to establish an early diagnosis and treatment.

The immune response to breast cancer, and the case for DC immunotherapy.

The long-held belief that breast cancer is a weakly immunogenic tumor and a poor candidate for immunotherapy should be reappraised. There is ample evidence for the existence of an immune response, which is, however, attenuated by multiple inhibitory factors. Many tumor-associated antigens (TAA) have been identified in breast cancer, some of which appear to play a critical role in tumorigenesis and may be attractive targets for immunotherapy. There is evidence for DC recruitment and activation within breast cancers, and the presence of intratumoral activated DCs impacts favorably upon survival. Furthermore, there is a striking paucity of activated DCs within the primary draining or sentinel lymph nodes of breast cancers. Tumor infiltrating lymphocytes (TIL) are often documented, however, their function is impaired by inhibitory cytokines, increased regulatory T lymphocyte activity, tumor cell MHC molecule alterations, and aberrant Fas ligand expression, amongst others. DCs are recognized as one of the critical interfaces between a cancer and the immune system, and have emerged as a promising platform for cancer vaccination via ex vivo immunomodulation. Clinical evaluation of DC vaccination in breast cancer is still relatively limited, although evolving. This article details evidence for the immune response in breast cancer and its many failings, and reviews the clinical trials and significant preclinical data which, taken together, validate the concept of DC vaccination in breast cancer.