Novel imaging techniques in refractory pituitary adenomas.

Accurate localization of the site(s) of active disease is key to informing decision-making in the management of refractory pituitary adenomas when autonomous hormone secretion and/or continued tumor growth challenge conventional therapeutic approaches. In this context, the use of non-standard MR sequences, alternative post-acquisition image processing, or molecular (functional) imaging may provide valuable additional information to inform patient management.

Modern imaging in Cushing's disease.

Management of Cushing's disease is informed by dedicated imaging of the sella and parasellar regions. Although magnetic resonance imaging (MRI) remains the investigation of choice, a significant proportion (30-50%) of corticotroph tumours are so small as to render MRI indeterminate or negative when using standard clinical sequences. In this context, alternative MR protocols [e.g. 3D gradient (recalled) echo, with acquisition of volumetric data] may allow detection of tumors that have not been previously visualized. The use of hybrid molecular imaging (e.g. 11C-methionine positron emission tomography coregistered with volumetric MRI) has also been proposed as an additional modality for localizing microadenomas.

11C-methionine PET aids localization of microprolactinomas in patients with intolerance or resistance to dopamine agonist therapy.

PURPOSE: To assess the potential for 11C-methionine PET (Met-PET) coregistered with volumetric magnetic resonance imaging (Met-PET/MRCR) to inform clinical decision making in patients with poorly visualized or occult microprolactinomas and dopamine agonist intolerance or resistance. PATIENTS AND METHODS: Thirteen patients with pituitary microprolactinomas, and who were intolerant (n = 11) or resistant (n = 2) to dopamine agonist therapy, were referred to our specialist pituitary centre for Met-PET/MRCR between 2016 and 2020. All patients had persistent hyperprolactinemia and were being considered for surgical intervention, but standard clinical MRI had shown either no visible adenoma or equivocal appearances. RESULTS: In all 13 patients Met-PET/MRCR demonstrated a single focus of avid tracer uptake. This was localized either to the right or left side of the sella in 12 subjects. In one patient, who had previously undergone surgery for a left-sided adenoma, recurrent tumor was unexpectedly identified in the left cavernous sinus. Five patients underwent endoscopic transsphenoidal selective adenomectomy, with subsequent complete remission of hyperprolactinaemia and normalization of other pituitary function; three patients are awaiting surgery. In the patient with inoperable cavernous sinus disease PET-guided stereotactic radiosurgery (SRS) was performed with subsequent near-normalization of serum prolactin. Two patients elected for a further trial of medical therapy, while two declined surgery or radiotherapy and chose to remain off medical treatment. CONCLUSIONS: In patients with dopamine agonist intolerance or resistance, and indeterminate pituitary MRI, molecular (functional) imaging with Met-PET/MRCR can allow precise localization of a microprolactinoma to facilitate selective surgical adenomectomy or SRS.

Overexpression of Cripto and its prognostic significance in breast cancer: a study with long-term survival.

INTRODUCTION: Cripto is a founding member of the EGF-CFC family, and plays an important role in tumourigenesis, tumour cell proliferation and migration. We aimed to determine the significance of Cripto expression on the survival of patients with breast cancer. METHODS: Immunohistochemical detection of Cripto was performed by using mAb C13 on 120 formalin-fixed paraffin-embedded breast tumour specimens in tissue microarrays. This cohort comprises a series of 120 patients with primary operable breast cancer diagnosed between 1989 and 1995, retrieved from the Concord Repatriation General Hospital breast carcinoma database. RESULTS: Using a cutoff value of 80%, Cripto overexpressed in 57 of the 120 (47.5%) patients. We found significant associations between overexpression of Cripto and the Nottingham Prognostic Index (NPI, p<0.01), histological grade (p<0.01), pathological tumour type (p=0.04), PR (p=0.02) as well as Ki-67 (p=0.02). Univariate analysis reveals that there is a significant correlation between overexpression of Cripto and survival (p=0.0003). Cox regression analysis indicates that the overexpression of Cripto is an independent prognostic factor in breast cancer (HR 2.79, 95%CI 1.20-6.50). CONCLUSION: The unique epitope recognized by mAb C13 is overexpressed on breast tumour tissues. In this series of invasive breast cancers, overexpression of Cripto was more often found in high grade and poor prognosis tumours compared to low grade and good prognosis breast cancers. Moreover, overexpression of Cripto was significantly associated with decreased patient survival.

Patterns of breast cancer relapse.

AIMS: Although breast cancer is the major cause of cancer-related death in women, there is little comprehensive information on long-term outcomes, particularly pertaining to site of relapse. The Strathfield Breast Centre (TSBC) is a multidisciplinary breast clinic that has collected patient data prospectively over 14 years. METHODS: All women with invasive, non-metastatic breast cancer, referred to TSBC from 1989 until 2002, were studied (n=2509). After initial treatment, patients were reviewed at 3-12-month intervals, including annual mammography and/or breast ultrasound. Information was collected on demographics, pre- and post-operative management and patient outcomes. Survival was analysed by the method of Kaplan and Meier. RESULTS: The mean age was 58 years and median follow-up 4 years (range <1-14) with complete data for 81%. In total, 456 patients (18%) had a local, nodal or distant relapse. The most common site of first relapse was to bone (in 125 patients), followed by local recurrence (124), lung (73) and liver (57). The median interval from primary breast surgery until recurrence was 2.3 years and disease-free intervals correlated to survival (p<0.0001). After local recurrence the 5-year survival was 41%, vs. 20% for nodal and 13% for distant recurrence (p<0.0001). Following breast-conserving surgery, the 5-year disease-free survival after local recurrence was 49.4%, vs. 33.1% after chest wall recurrence (p=0.0361). Of distant relapses, bone metastases had the best prognosis, with median survival 2.4 years. CONCLUSION: These data provide information on treatment outcomes in a multidisciplinary setting and statistical information that will be useful when discussing the fears and expectations of patients after the diagnosis of breast cancer.

Extra-axillary sentinel node biopsy in the management of early breast cancer.

AIM: To document of our experience with EAS SNB and evaluate its impact on the staging, management and the associated morbidities of patients with early breast cancer. METHOD: A review of two prospective breast cancer databases identifying all SNB procedures performed at two affiliated breast units from 1998 to 2003. RESULTS: A series of 979 patients underwent lymphatic mapping. Sentinel nodes were successfully identified in 903 patients. There were 142 cases in which lymphoscintigraphy identified EAS. In 17 cases extraaxillary sentinel nodes were identified with lymphoscintigraphy but could not be removed. There were 138 cases where internal mammary nodes (IMN) were removed. Of those IMN removed 25 were positive for metastases and in six of these cases only the IMN was positive. Of the 21 cases where other EAS were identified there was one case in which a supraclavicular sentinel node was positive. Twenty-five of the 26 positive sentinel nodes in EAS were macrometastases and one was a micrometastasis. No significant morbidity resulted from biopsy of EAS SNB. During IMN SNB there were eight pleural breeches, which did not result in pneumothoraces, and one case in which bleeding was difficult to control. CONCLUSION: EAS SNB is technically feasible in the majority of cases. Minimal morbidity occurs after an initial learning phase. IMN SNB was shown to have significant impact on the staging and management in 18% of patients when IMNs were identified with lymphoscintigraphy. The impact of other extraaxillary lymph nodes is more difficult to assess due to small numbers. As there is little morbidity and valuable information is gained in a significant percentage of cases we strongly advocate EAS SNB.

Evaluation of a breast cancer nomogram for prediction of non-sentinel lymph node positivity.

AIMS: This study evaluates the breast cancer nomogram (BCN), an online tool developed by Memorial Sloan-Kettering Cancer Center to determine the rate of non-SLN positivity, in an independent cohort of SLN positive patients. MATERIAL AND METHODS: Available data between 02/2000 and 06/2004 in two prospective databases, 749 cases had successful SLN biopsy including 149 axillary-SLN metastases study cases. These cases had accurately graded tumours up to 9 cm in size and CAD with a minimum total 10 nodes removed. Histopathological assessment of nodes included hematoxylin and eosin staining and/or immunohistochemistry. Computerized BCN was used to estimate probability of non-SLN positivity and compared with actual probability after grouping into deciles. RESULTS: The trend of actual probability in various decile groups was comparable to the predicted probability. An area under the receiver operating characteristic curve was 0.75 as compared to 0.76 in the original study. CONCLUSION: Although this study is small, the results are encouraging and suggest the nomogram is a useful tool to estimate the likelihood of positive axillary non-SLN. However, variations in pathological assessment between centres are the major impediment to widespread application of BCN. If SLN positive patients decline the standard recommendation of CAD or entry into clinical trials evaluating the significance of CAD then the BCN could help in decision making.

Alendronate-induced chemical laryngitis.

Alendronate is a bisphosphonate used in treating osteoporosis. Its recognized side-effects include oesophageal irritation and ulceration. The authors describe a case of laryngitis induced by transient contact of this medication with the laryngeal mucosa. Successful management of this case is also detailed.

Immunochemical study on the contribution of hypolipidaemic-induced cytochrome P-452 to the metabolism of lauric acid and arachidonic acid.

The influence of four hypolipidaemic drugs (clofibrate, WY-14,643, clobuzarit and bezafibrate) on hepatic cytochrome P-450 and fatty acid metabolism in male rat liver microsomes has been investigated. All of the hypolipidaemic drugs tested significantly induced the hydroxylation of lauric acid and, furthermore, this was accompanied by a concomitant 3-fold induction of a specific isoenzyme of cytochrome P-450 (termed cytochrome P-452) as determined by a single radial immunodiffusion technique. In addition, immunochemical quantitation of cytochrome P-452 in control, uninduced rat liver microsomes revealed that this particular isoenzyme constituted 22% of the total carbon monoxide-discernible cytochrome P-450 population. This has led us to the conclusion that cytochrome P-452 is a constitutive cytochrome P-450 isoenzyme and therefore that hypolipidaemic agents function as inducers of constitutive haemoprotein isoenzymes. Cytochrome P-452 plays a significant role in the hydroxylation of lauric acid as evidenced by inhibition of hydroxylase activity in the presence of an anti-P-452 IgG fraction. In addition, this antibody preferentially inhibits the 12-hydroxylation of lauric acid in rat liver microsomes by comparison to the 11-hydroxylase activity. Our studies have also shown that arachidonic acid serves as an excellent substrate for hypolipidaemic-induced cytochrome P-452, resulting in the formation of several metabolites that have been separated by reverse phase HPLC. Furthermore, a specific metabolite (or group of metabolites) of arachidonic acid is induced by clofibrate pretreatment and that the formation of this metabolite(s) is inhibited by an antibody to cytochrome P-452. By comparison, other metabolites of arachidonic acid remain refractory to induction by clofibrate and are not inhibited by the presence of anti-P-452 IgG. In addition, a reconstituted enzyme system containing highly purified cytochrome P-452 actively catalyses the above specific oxidation of arachidonic acid, a reaction that is significantly stimulated by the presence of cytochrome b5. Taken collectively, our data provide compelling evidence that hypolipidaemic agents induce a specific isoenzyme of hepatic microsomal P-450 that readily oxidizes fatty acids and that arachidonic acid may serve as an excellent endogenous substrate for this novel haemoprotein.

Pre-ALL and non-A, non-B hepatitis infection.

We report a case of acute lymphoblastic leukaemia which presented as hypoplastic anaemia following Non-A, Non-B viral hepatitis infection. The role of infection and the mechanisms involved in the evolution of pre-ALL to overt leukaemia remain speculative. However, it is of practical importance to distinguish pre-ALL from aplastic anaemia and the myelodysplastic syndromes during the early pancytopenic phase to avoid inappropriate management.

Non-caseating granulomata associated with hypocellular myelodysplastic syndrome.

Non-caseating granuloma (NCG) remains a histopathological hallmark for sarcoidosis. Although the exact mechanism for NCG formation is unknown, the pathogenesis may involve a disordered antigen presentation in the monocyte/macrophage system, functional abnormalities in activated T-lymphocytes and uncontrolled cytokine production. Similar immunological dysfunction has been described in myelodysplastic syndrome (MDS). However, the association of NCG and MDS is rarely documented. We report a case of hypocellular MDS associated with generalized NCG. Despite treatment for both sarcoidosis and tuberculosis, the patient failed to respond. A clonal myeloid disorder which was initially suppressed by T-cell immunosurveillance evolved after treatment with anti-thymocyte globulin. Although the coexistence of sarcoidosis remains a possibility, the lack of supportive clinical evidence of sarcoidosis, the abnormal appearances of the bone marrow, together with the failure to improve on high-dose steroid favour the clonal myeloid disorder as the sole pathology.

Infiltrating lobular carcinoma--a comparison of diagnosis, management and outcome with infiltrating duct carcinoma.

The treatment and outcomes for 182 patients with lobular carcinoma were compared with 1612 patients with infiltrating ductal carcinoma managed concurrently at The Strathfield Breast Centre. The lobular carcinomas were larger (P < 0.0001) but of lower grade (P < 0.0001). Diagnosis with mammography and FNA was less sensitive in ILC (mammography P = 0.0002, FNA P < 0.0001). Although similar numbers of patients underwent initial attempted conservation, patients with ILC were more likely to have positive margins at attempted breast conservation surgery and the final mastectomy rate was higher (58.2% ILC versus 47% IDC, P = 0.0041). Of the patients who had successful conservation, the local recurrence rates for ILC (3.9%) were equivalent to the patients with IDC (5.3%). There was no significant difference in overall survival (90% ILC, 87% IDC, median follow-up 3.6 years ILC, 4.3 years IDC) or disease free survival (87.9% ILC, 81.6% IDC). Although mastectomy is more likely to be necessary to obtain clear margins, breast conservation therapy is reasonable in patients with infiltrating lobular carcinoma where clear margins can be obtained.

Implications of extranodal spread in node positive breast cancer: a review of survival and local recurrence.

An evaluation of extra nodal spread (ENS) in predicting overall survival and locoregional relapse rates in 311 node positive breast cancer patients was undertaken: the study group comprised 71 patients with ENS and the control group comprised 240 patients with no ENS. A review of pathology reports that described ENS was performed and a scoring system to categorize focal involvement, extensive axillary fat involvement, and positive axillary surgical margins was devised. Median follow up time was 3.1 years. Overall survival, disease specific survival and disease-free survival rates were significantly worse in the study group in comparison with the control group. Poorer survival with more extensive pathological invasion of ENS was demonstrated. Multivariate analysis of disease specific survival in those patient with 1-3 involved lymph nodes demonstrated that ENS positivity was prognostically significant (P=0.013). Although locoregional relapse was increased in the presence of ENS, axillary relapses were uncommon and do not warrant axillary radiation.

Electrical burns to the oral commissure: does splinting obviate the need for commissuroplasty?

Two groups of children who had sustained electrical burns to the oral commissure were compared. The first group (n = 20) underwent splinting of the commissure and the other group (n = 22) did not have splints as part of their treatment regimen. The mean age at the time of burn was 3 years in both groups. The need for commissuroplasty was significantly decreased in the splinted group (P = 0.0007 by Fisher's exact test). Further analysis of the duration of splinting in the splinted group (n = 20) revealed that all seven children who required commissuroplasty underwent splinting for less than 4 months while all 13 children who did not require surgery used their splints for more than 4 months (range 4-8 months).

Screen-detected breast cancer compared to symptomatic presentation: an analysis of surgical treatment and end-points of effective mammographic screening.

BACKGROUND: Mammographic screening has been shown to reduce mortality from breast cancer and to offer more opportunity for breast conservation surgery (BCS). The minimum standards (or surrogate end-points) that need to be achieved by a screening programme if it is to reduce mortality have been derived from the Two County Study. Three surrogate end-points that can be used to gauge the quality of the screening service are that 50% of the identified infiltrating cancers should be < 15 mm; at least 30% of grade 3 cancers should be < 15 mm; and 70% of screen-detected cancers should have a negative axillary dissection. The present study assesses these end-points of effective screening in an urban population referred to The Strathfield Breast Centre (TSBC). The screening end-points and surgical treatment of one group of women referred with a BreastScreen New South Wales (NSW)-detected breast cancer (screen group) were compared to all the other, mostly symptomatic, breast cancer referrals (symptom group). The problems with the current pattern of acceptance of mammographic screening in TSBC's referral area are discussed. METHODS: A prospective non-randomized study was done via analysis of the prospective database at The Strathfield Breast Centre (TSBC). RESULTS: There were 224 women in the screen group and 657 women in the symptom group. The mean tumour size was 18.1 mm in the screen group and 22.1 mm in the symptom group. There were significantly more small invasive cancers (< 15 mm) in the screen group (58%) compared with the symptom group (33%; P < 0.001). In the screen group there were more low-grade tumours but 30% of grade 3 tumours were < 15 mm compared with 16% in the symptom group (P = 0.009). In patients with invasive cancers who underwent axillary dissection, there was a significant difference in axillary node negativity, being 72% in the screen group and 59% in the symptom group (P = 0.003). In the screen group 64% of women had BCS compared with 51% in the symptom group (P = 0.002). CONCLUSIONS: These end-points of effective mammographic screening were met in the BreastScreen NSW group of women who were referred to TSBC despite the biases involved which could lessen the effectiveness of the screening programme. This crudely translated into a significant reduction in breast cancer mortality but selection and lead time bias has to be taken into account in evaluation of these data. There was a significantly greater chance of BCS in the screen group.

Intramuscular capillary hamartoma of the tongue.

Intramuscular vascular lesions in the tongue are rare and are usually the capillary form of haemangioma. A case is described of a lingual mass that resembled intramuscular haemangioma but had unique histological features that do not appear to have been described previously. The term intramuscular capillary hamartoma is suggested to describe it.

Pneumocephalus--an unreported risk of Valsalva's manoeuvre following cochlear implantation.

We describe a case of pneumocephalus as an unusual early postoperative complication following cochlear implantation. The aetiology of this condition we attribute to the patient's habit of 'ear popping' using Valsalva's manoeuvre.

The normal-equivalent: a patient-specific assessment of facial harmony.

Evidence-based practice in oral and maxillofacial surgery would greatly benefit from an objective assessment of facial harmony or gestalt. Normal reference faces have previously been introduced, but they describe harmony in facial form as an average only and fail to report on harmonic variations found between non-dysmorphic faces. In this work, facial harmony, in all its complexity, is defined using a face-space, which describes all possible variations within a non-dysmorphic population; this was sampled here, based on 400 healthy subjects. Subsequently, dysmorphometrics, which involves the measurement of morphological abnormalities, is employed to construct the normal-equivalent within the given face-space of a presented dysmorphic face. The normal-equivalent can be seen as a synthetic identical but unaffected twin that is a patient-specific and population-based normal. It is used to extract objective scores of facial discordancy. This technique, along with a comparing approach, was used on healthy subjects to establish ranges of discordancy that are accepted to be normal, as well as on two patient examples before and after surgical intervention. The specificity of the presented normal-equivalent approach was confirmed by correctly attributing abnormality and providing regional depictions of the known dysmorphologies. Furthermore, it proved to be superior to the comparing approach.

SPECT/CT scans allow precise anatomical location of sentinel lymph nodes in breast cancer and redefine lymphatic drainage from the breast to the axilla.

BACKGROUND: Historical studies of lymphatic drainage of the breast have suggested that the lymphatic drainage of the breast was to lymph nodes lying in the antero-pectoral group of nodes in the axilla just lateral to the pectoral muscles. The purpose of this study was to confirm this is not correct. METHODS: The hybrid imaging method of SPECT/CT allows the exact anatomical position of the sentinel lymph node (SLN) in the axilla to be documented during pre-operative lymphoscintigraphy (LS) in patients with breast cancer. We have done this in a series of 741 patients. The Level I axillary nodes were defined as anterior, mid or posterior. This was related to the anatomical location of the primary cancer in the breast. RESULTS: A SLN was found in the axilla in 97.8% of our patients. Just under 50% of SLNs located in the axilla were not in the anterior group and lay in the mid or posterior group of Level I axillary nodes. There was a SLN in a single node field in 460 patients (63%), two node fields in 261(36%), three node fields in 6 and four node fields in 1 patient. CONCLUSION: Axillary lymphatic drainage from the breast is not exclusively to the anterior (or antero-pectoral) group of Level I nodes. SYNOPSIS: SPECT/CT lymphoscintigraphy shows that the breast does not always drain to the anterior group of Level I lymph nodes in the axilla but may drain to the mid axilla and/or posterior group in about 50% of patients with breast cancer regardless of the location of the cancer in the breast. These data redefine lymph drainage from the breast to axillary lymph nodes.

Supraglottitis and abscess formation.

OBJECTIVE: This case series report aims to raise awareness of the association between supraglottic infection and abscess formation, which has been rarely documented. METHOD: We report a series of four patients who developed cervical abscesses following supraglottic infection. The diagnosis was confirmed by imaging in three patients, and by incision and drainage of pus at direct laryngoscopy in one. RESULTS: All four patients were treated with intravenous antibiotics, steroids and humidification; two also underwent surgical drainage of pus. All made an uneventful recovery. CONCLUSION: The factors that lead to neck abscess formation are poorly understood. Physicians should always be aware of this potential complication. If it is suspected, appropriate neck imaging should be undertaken, after excluding airway copromise; this will aid early diagnosis and treatment.