Breast cancer preoperative 18FDG-PET, overall survival prognostic separation compared with the lymph node ratio.

PURPOSE: To evaluate the overall survival prognostic value of preoperative 18F-fluorodeoxyglucose positron emission tomography (PET) in breast cancer, as compared with the lymph node ratio (LNR). METHODS: Data were abstracted at a median follow-up 14.7 years from a retrospective cohort of 104 patients who underwent PET imaging before curative surgery. PET-Axillary|Sternal was classified as PET-positive if hypermetabolism was visualized in ipsilateral nodal axillary and/or sternal region, else as PET-negative. The differences of 15 years restricted mean survival time ∆RMST according to PET and LNR were computed from Kaplan-Meier overall survival. The effect of PET and other patients' characteristics was analyzed through rankit normalization, which provides with Cox regression the Royston-Sauerbrei D measure of separation to compare the characteristics (0 indicating no prognostic value). Multivariate analysis of the normalized characteristics used stepwise selection with the Akaike information criterion. RESULTS: In Kaplan-Meier analysis, LNR > 0.20 versus ≤ 0.20 showed ∆RMST = 3.4 years, P = 0.003. PET-Axillary|Sternal positivity versus PET-negative showed a ∆RMST = 2.6 years, P = 0.008. In Cox univariate analyses, LNR appeared as topmost prognostic separator, D = 1.50, P < 0.001. PET ranked below but was also highly significant, D = 1.02, P = 0.009. In multivariate analyses, LNR and PET-Axillary|Sternal were colinear and mutually exclusive. PET-Axillary|Sternal improved as prognosticator in a model excluding lymph nodes, yielding a normalized hazard ratio of 2.44, P = 0.062. CONCLUSION: Pathological lymph node assessment remains the gold standard of prognosis. However, PET appears as a valuable surrogate in univariate analysis at 15-year follow-up. There was a trend towards significance in multivariate analysis that warrants further investigation.

Intrathyroidal parathyroid carcinoma presenting as an asymptomatic hypercalcemia: a case report.

INTRODUCTION: A 26-year-old female presented with severe hypercalcemia. She was asymptomatic. Blood analysis revealed high serum calcium (13 mg/dL = 3.25 mmol/L) and elevated intact parathyroid hormone (iPTH) levels (267.5 ng/L). RESULTS: Ultrasonography showed a mixed solid-cystic nodule of 30 mm in the left thyroid lower lobe and a nodular lesion of 14 mm posterior of the thyroid upper pole suggestive for parathyroid adenoma. Sestamibi scan and magnetic resonance imaging (MRI) revealed hyperfunctioning parathyroid tissue posterior of the left thyroid upper lobe. During surgery, a 15 mm nodule in the usual location of the left superior parathyroid was resected. Intraoperative frozen section revealed normal parathyroid tissue and intraoperative PTH levels did not decrease. Left thyroidectomy was performed due to the large solid-cystic nodule. Intraoperative PTH levels normalized 10 min later. Pathologic examination revealed a 28 mm nodule in the lower thyroid pole compatible with a parathyroid carcinoma (PC). Due to positive margins, a completion thyroidectomy was performed. 5-year follow-up showed no recurrence. CONCLUSIONS: PC is a rare entity comprising 0.5-2% of patients with primary hyperparathyroidism. Even more unusual is an intrathyroidal parathyroid gland (0.2%). Only a dozen cases of intrathyroidal PC have been reported. Our case is the second patient reported to be asymptomatic.

An air-containing mediastinal mass in a patient with a primary adenocarcinoma of the right lung.

Objective: The following case report elicits the treatment of a 55-year-old male who was diagnosed with a surinfected mediastinal chyloma as a complication of mediastinoscopy and radiotherapy for a primary adenocarcinoma of the right lung (cT2aN2M0). Methods: The patient was admitted to the hospital after radiographical imaging showed a surinfected mediastinal chyloma. CT-guided percutaneous drainage was performed and via gastroscopy a fistula was diagnosed for which a full covered stent was placed. Then, a right thoracotomy was performed to wash out the chylous cavity, to seal the thoracic duct and to cover the other end of the fistula with an intercostal muscle flap. Results: Postoperative imaging showed a clear reduction of the mediastinal mass with no residual air-fluid level. Realimention was possible three days after placement of the stent. The patient was discharged after 11 days. There was no recurrence of the chyloma. Fistulisation did recur after removal of the stent. Conclusion: Surinfected mediastinal chyloma due to oesopagho-mediastinal fistula is an extremely rare complication after cervical mediastinoscopy and radiotherapy. Open drainage of the chyloma and total coverage of the fistula can control infection and prevent recurrence on short term.

Effects of Multidirectional Vibrations Delivered in a Horizontal Position (Andullation®) on Blood Microcirculation in Laboratory Animals: A Preliminary Study.

BACKGROUND A whole-body vibration technique delivered in a horizontal position through a massage mattress was introduced in 2007. The present study analyzed the effects of different exposure periods to these vibrations on microcirculation of mice. MATERIAL AND METHODS Different periods of vibrations (30Hz) were locally delivered in a horizontal position on the external abdominal skin in 3 randomized groups of mice (N=42). The 3 groups receiving vibrations were compared to an untreated control group (N=14). The 3 experimental groups received 3, 6, and 10 min of vibrations. The in vivo measurement of the arterial and venous diameters was done before and after each vibration period. RESULTS Average venous diameters (µm) after 6 to 10 min of vibrations were significantly increased (7% and 12%, p values 0.026 and 0.013, respectively), but 3 min did not significantly change average venous diameters. Arterial diameters (µm) did not significantly vary after 3, 6, and 10 min. In the control group, variations of arterial and venous diameters during 10 min were not significant. CONCLUSIONS This study shows a vasodilatory effect of low-frequency vibrations. The hypothesis of local cutaneous blood flow increase is retained. A phenomenon of shear stress of the endothelium induced by skin massage generates this local venous vasodilation and blood flow increase.

Anatomical Effects of Axillary Nodes Dissection on Rat Lymphatic System Model: Indocyanine Green Mapping and Dissection.

BACKGROUND: Axillary nodes dissection (AND) is an important risk factor for the appearance of breast cancer-related lymphedema (BCRL). The anatomy and pathophysiology leading to the development of BCRL after AND are not completely understood. Despite the existence of lymphedema models after AND, none of them were able to create lymphedemas without additional chemical inflammatory drugs or auxiliary physical techniques (radiotherapy). In this study, we aimed to describe the anatomical changes of AND on a rat's front leg before and after a new surgery technique. METHODS AND RESULTS: AND was performed on seven Wistar rats with a new, posterior surgical approach. Indocyanine green mapping was done before and after surgery to detect "normal and secondary superficial lymphatic pathways" of the operated rat's front legs. Twelve months after surgery, dissections were performed. Subcutaneous blue dye injection of the hand was used to observe superficial and deep lymphatic pathways. Postsurgery, an acute edema of arm and shoulder appeared and persisted for 14-21 days. However, none of the rats showed a chronic secondary lymphedema. In two cases, seromas also appeared. All rats showed substitution functional lymphatic pathways as perforating lymph vessels around the surgical sites. CONCLUSION: This is the first description of perforating lymph vessels as lymphatic substitution pathways after AND on rats. These results help to understand why a chronic secondary lymphedema could not be created in rats after AND without additional chemical or physical interventions.

Mild Lung Restriction in Breast Cancer Patients After Hypofractionated and Conventional Radiation Therapy: A 3-Year Follow-Up.

PURPOSE: To assess the effect of radiation therapy on lung function over the course of 3 years. METHODS AND MATERIALS: Evolution of restrictive and obstructive lung function parameters was investigated in 108 breast cancer participants in a randomized, controlled trial comparing conventional radiation therapy (CR) and hypofractionated tomotherapy (TT) (age at inclusion ranging 32-81 years). Spirometry, plethysmography, and hemoglobin-corrected diffusing capacity were assessed at baseline and after 3 months and 1, 2, and 3 years. Natural aging was accounted for by considering all lung function parameters in terms of percent predicted values using the most recent reference values for women aged up to 80 years. RESULTS: In the patients with negligible history of respiratory disease or smoking (n=77), the greatest rate of functional decline was observed during the initial 3 months, this acute decrease being more marked in the CR versus the TT arm. During the remainder of the 3-year follow-up period, values (in terms of percent predicted) were maintained (diffusing capacity) or continued to decline at a slower rate (forced vital capacity). However, the average decline of the restrictive lung function parameters over a 3-year period did not exceed 9% predicted in either the TT or the CR arm. Obstructive lung function parameters remained unaffected throughout. Including also the 31 patients with a history of respiratory disease or more than 10 pack-years showed a very similar restrictive pattern. CONCLUSIONS: In women with breast cancer, both conventional radiation therapy and hypofractionated tomotherapy induce small but consistent restrictive lung patterns over the course of a 3-year period, irrespective of baseline respiratory status or smoking history. The fastest rate of lung function decline generally occurred in the first 3 months.

Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma.

UNLABELLED: Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinoma patients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. METHODS: In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with (68)Ga via a NOTA derivative. Administered activities were 53-174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OLINDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. RESULTS: No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of disease. Primary lesions were more variable in tracer accumulation. CONCLUSION: (68)Ga-HER2-Nanobody PET/CT is a safe procedure with a radiation dose comparable to other routinely used PET tracers. Its biodistribution is favorable, with the highest uptake in the kidneys, liver, and intestines but very low background levels in all other organs that typically house primary breast carcinoma or tumor metastasis. Tracer accumulation in HER2-positive metastases is high, compared with normal surrounding tissues, and warrants further assessment in a phase II trial.

Small airways function in breast cancer patients before and after radiotherapy.

Radiotherapy treatments for early stage breast cancer patients potentially affect the lung in its most distal air spaces, and previous studies have indicated consistently low baseline values for diffusing capacity in breast cancer patients. We aimed to quantitatively assess baseline small airway function and the acute effects of radiotherapy in breast cancer patients with no confounding effects from respiratory disease or considerable smoking history. In 60 breast cancer patients selected from an ongoing randomized controlled trial, the small airways function was assessed at baseline and 3 months later, after having received either conventional radiotherapy (CR; n = 26) or hypofractionated tomotherapy (TT; n = 34). All indices of small airway function in breast cancer patients were found to be indistinguishable from healthy controls. The total lung capacity was significantly decreased and ventilation heterogeneity was significantly increased 3 months after baseline in the CR arm, but not in the TT arm. When corrected for hemoglobin and lung volume, pulmonary diffusing capacity was not affected by radiotherapy in either treatment arm. Alternatively, discarding patients receiving chemotherapy or loco-regional treatment did not affect these results. We conclude that middle-aged women with breast cancer, but no history of respiratory disease, have normal baseline small airways function. Conventional radiotherapy induces a restrictive pattern and increases heterogeneity of ventilation, the latter most likely resulting from differential expansion between locally irradiated peripheral lung zones and the remainder of the lung. The TT modality did not lead to any such changes.

Early contralateral shoulder-arm morbidity in breast cancer patients enrolled in a randomized trial of post-surgery radiation therapy.

INTRODUCTION: Shoulder/arm morbidity is a common complication of breast cancer surgery and radiotherapy (RT), but little is known about acute contralateral morbidity. METHODS: Patients were 118 women enrolled in a RT trial. Arm volume and shoulder mobility were assessed before and 1-3 months after RT. Correlations and linear regression were used to analyze changes affecting ipsilateral and contralateral arms, and changes affecting relative interlimb differences (RID). RESULTS: Changes affecting one limb correlated with changes affecting the other limb. Arm volume between the two limbs correlated (R = 0.57). Risk factors were weight increase and axillary dissection. Contralateral and ipsilateral loss of abduction strongly correlated (R = 0.78). Changes of combined RID exceeding 10% affected the ipsilateral limb in 25% of patients, and the contralateral limb in 18%. Aromatase inhibitor therapy was significantly associated with contralateral loss of abduction. CONCLUSIONS: High incidence of early contralateral arm morbidity warrants further investigations.

Diagnostic and prognostic correlates of preoperative FDG PET for breast cancer.

PURPOSE: To explore the preoperative utility of FDG PET for the diagnosis and prognosis in a retrospective breast cancer case series. METHODS: In this retrospective study, 104 patients who had undergone a preoperative FDG PET scan for primary breast cancer at the UZ Brussel during the period 2002-2008 were identified. Selection criteria were: histological confirmation, FDG PET performed prior to therapy, and breast surgery integrated into the primary therapy plan. Patterns of increased metabolism were recorded according to the involved locations: breast, ipsilateral axillary region, internal mammary chain, or distant organs. The end-point for the survival analysis using Cox proportional hazards was disease-free survival. The contribution of prognostic factors was evaluated using the Akaike information criterion and the Nagelkerke index. RESULTS: PET positivity was associated with age, gender, tumour location, tumour size >2 cm, lymphovascular invasion, oestrogen and progesterone receptor status. Among 63 patients with a negative axillary PET status, 56 (88.9 %) had three or fewer involved nodes, whereas among 41 patients with a positive axillary PET status, 25 (61.0 %) had more than three positive nodes (P < 0.0001). In the survival analysis of preoperative characteristics, PET axillary node positivity was the foremost statistically significant factor associated with decreased disease-free survival (hazard ratio 2.81, 95% CI 1.17-6.74). CONCLUSION: Preoperative PET axillary node positivity identified patients with a higher burden of nodal involvement, which might be important for treatment decisions in breast cancer patients.

Scapula alata in early breast cancer patients enrolled in a randomized clinical trial of post-surgery short-course image-guided radiotherapy.

BACKGROUND: Scapula alata (SA) is a known complication of breast surgery associated with palsy of the serratus anterior, but it is seldom mentioned. We evaluated the risk factors associated with SA and the relationship of SA with ipsilateral shoulder/arm morbidity in a series of patients enrolled in a trial of post-surgery radiotherapy (RT). METHODS: The trial randomized women with completely resected stage I-II breast cancer to short-course image-guided RT, versus conventional RT. SA, arm volume and shoulder-arm mobility were measured prior to RT and at one to three months post-RT. Shoulder/arm morbidities were computed as a post-RT percentage change relative to pre-RT measurements. RESULTS: Of 119 evaluable patients, 13 (= 10.9%) had pre-RT SA. Age younger than 50 years old, a body mass index less than 25 kg/m2, and axillary lymph node dissection were significant risk factors, with odds ratios of 4.8 (P = 0.009), 6.1 (P = 0.016), and 6.1 (P = 0.005), respectively. Randomization group was not significant. At one to three months' post-RT, mean arm volume increased by 4.1% (P = 0.036) and abduction decreased by 8.6% (P = 0.046) among SA patients, but not among non-SA patients. SA resolved in eight, persisted in five, and appeared in one patient. CONCLUSION: The relationship of SA with lower body mass index suggests that SA might have been underestimated in overweight patients. Despite apparent resolution of SA in most patients, pre-RT SA portended an increased risk of shoulder/arm morbidity. We argue that SA warrants further investigation. Incidentally, the observation of SA occurring after RT in one patient represents the second case of post-RT SA reported in the literature.

Ultrasound elastography as an objective diagnostic measurement tool for lymphoedema of the treated breast in breast cancer patients following breast conserving surgery and radiotherapy.

BACKGROUND.: Lymphoedema of the operated and irradiated breast is a common complication following early breast cancer treatment. There is no consensus on objective diagnostic criteria and standard measurement tools. This study investigates the use of ultrasound elastography as an objective quantitative measurement tool for the diagnosis of parenchymal breast oedema. PATIENTS AND METHODS.: The elasticity ratio of the subcutis, measured with ultrasound elastography, was compared with high-frequency ultrasound parameters and subjective symptoms in twenty patients, bilaterally, prior to and following breast conserving surgery and breast irradiation. RESULTS.: Elasticity ratio of the subcutis of the operated breast following radiation therapy increased in 88.9% of patients, was significantly higher than prior to surgery, unlike the non operated breast and significantly higher than the non operated breast, unlike preoperative results. These results were significantly correlated with visibility of the echogenic line, measured with high-frequency ultrasound. Big preoperative bra cup size was a significant risk factor for the development of breast oedema. CONCLUSIONS.: Ultrasound elastography is an objective quantitative measurement tool for the diagnosis of parenchymal breast oedema, in combination with other objective diagnostic criteria. Further research with longer follow-up and more patients is necessary to confirm our findings.

Postmastectomy lymphoedema: different patterns of fluid distribution visualised by ultrasound imaging compared with magnetic resonance imaging.

OBJECTIVES: Postmastectomy lymphoedema remains a disabling complication caused by treatment for breast cancer. The increased thickness of the dermal layer and the increased volume of the subcutis represent the most important contributions to the total swelling of the arm. Ultrasound imaging of the subcutaneous layer results in different patterns of reflected ultrasound waves depending on the morphological alternations that occurred due to impaired lymphatic drainage. The aim of this study was to compare these echographic images with those obtained using magnetic resonance imaging to explain the nature of the morphological changes. DESIGN: Observational study. SETTING: Patients were recruited from the Breast Clinic at the University Hospital Brussels. PARTICIPANTS: Seven women (mean age 60 years) with unilateral breast cancer who subsequently developed lymphoedema. MAIN OUTCOME MEASURES: The water displacement technique was applied to determine arm volumes, and echographic and magnetic resonance images were used to evaluate changes in tissue structures. RESULTS: Volumetric measurements of the arm (mean affected arm 3241 ml vs unaffected arm 2538 ml) showed a significant increase in total arm volume of 703 ml (95% confidence interval 324 to 1084 ml). Using echography, the thickness of the dermal and subcutaneous layers showed an average increase of 0.2 to 0.8mm and 3.9 to 7.2mm, respectively. The differences between the affected arm and the unaffected arm for all upper and lower arm measurements (i.e. volumetry, dermal and subcutaneous thickness) were significant, but no significant differences were registered for hand measurements. On echography, the dermis showed uniform changes, with a homogenous hypo-echogenic appearance compared with the contralateral side due to water influx. Different patterns of structural changes could be visualised within the subcutis: (1) uniformly hypo-echogenic due to the diffuse spread of water through the subcutis; (2) hyperechogenic areas surrounded by hypo-echogenic streaks visualised on magnetic resonance imaging as adipose tissue surrounded by fluid embedded in fibrous tissue; and (3) homogenously hyperechogenic due to the overgrowth of adipose tissue with a minimal amount of water. CONCLUSIONS: Echographic images can help to determine the likelihood that complex physical therapy will reduce lymphoedema, and evaluate treatment results by measuring tissue thickness and evaluating tissue consistency.

Survival benefit with radiation therapy in node-positive breast carcinoma patients.

BACKGROUND AND PURPOSE: Postoperative radiation therapy (RT) has been the subject of discussion, especially in patients with one to three positive lymph nodes (< or = 3 pN+) in the axillary dissection. The authors investigated whether postoperative RT provides a survival benefit for pT1-2 pN+ breast cancer patients. PATIENTS AND METHODS: Patients included were selected from the SEER database (NCI--Surveillance, Epidemiology and End Results, release 2000; n = 24,410) and the UZ Brussel database (1984-2002; n = 1,011) according to the following criteria: women aged 25-95, no previous cancer, unilateral pT1-pT2 breast tumors, total mastectomy (ME) or breast-conserving surgery (BCS), postoperative RT, and an axillary dissection showing at least one pathologic lymph node. RESULTS: The overall survival (OS) of patients in the SEER and UZ Brussel databases who received postoperative RT was identical. However, patients in the SEER database who did not receive RT had a significantly worse outcome (p < 0.0001). After ME or BCS, all patients (SEER and UZ Brussel) who had > or = 4 pN+ and received RT had comparable outcomes after 15 years. The 15-year OS in the subgroup with ME and < or = 3 pN+ nodes was 57.0% and 46.6% (p = 0.0004) with RT (UZ Brussel) and without RT (SEER), respectively. For BCS and < or = 3 pN+, the same significant difference in OS at 15 years was seen: 63.8% after RT (UZ Brussel) and 60.4% without RT (SEER; p = 0.0029). CONCLUSION: RT provides a survival benefit in patients with < or = 3 or > or = 4 pN+; the indication for postoperative RT should therefore be adapted in future consensus meetings.

Histological findings compared with magnetic resonance and ultrasonographic imaging in irreversible postmastectomy lymphedema: a case study.

Postmastectomy edema is a current complication after axillary lymph node dissection in cases of breast cancer treatment. Staging is important in order to select those patients who can benefit from complex physical therapy (CPT). Different imaging techniques can be used to evaluate the edema. Ultrasonography (US) is a harmless, cheap, and easily applicable technique to visualize the dermal and subcutaneous tissue, but interpretation of the obtained images is not always evident. The aim of this study was to compare ultrasound images of irreversible edema with tissue histology, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Ultrasonographic images of the edematous dermis show an homogeneous hypoechogenic dermal layer that appears on tissue histology to be less compact, due to the excess of fluid in the interstitium separating the collagen fibres and making it more transparent on light microscopy. MRI of the dermis gives a hyperintense signal, indicating the presence of fluid. In the subcutis, increase of the adipose tissue could be observed on US, MRI, and tissue histology. In the case of lymphedema, the area and perimeter of fat cells is significantly (p < 0.05) increased. Hypoechogenic areas near the muscle fascia are registered on US corresponding with epifascial fluid on MRI, and hyperechogenic branches are embedded within the adipose tissue, on tissue histology seen as large fibrotic septa enclosing adipose cells. MRI has a honeycomb picture corresponding with fluid bound to fibrosis.