Eight-year follow up result of the OTOASOR trial: The Optimal Treatment Of the Axilla - Surgery Or Radiotherapy after positive sentinel lymph node biopsy in early-stage breast cancer: A randomized, single centre, phase III, non-inferiority trial.

INTRODUCTION: The National Institute of Oncology, Budapest conducted a single centre randomized clinical study. The OTOASOR (Optimal Treatment Of the Axilla - Surgery Or Radiotherapy) trial compares completion of axillary lymph node dissection (cALND) to regional nodal irradiation (RNI) in patients with sentinel lymph node metastasis (pN1sn) in stage I-II breast cancer. PATIENTS AND METHODS: Patients with primary invasive breast cancer (cN0 and cT ≤ 3 cm) were randomized before surgery for cALND (standard treatment) or RNI (investigational treatment). Sentinel lymph nodes (SN) were investigated with serial sectioning at 0.5 mm levels by hematoxylin-eosin staining. Investigational treatment arm patients received 50 Gy RNI instead of cALND. Adjuvant treatment and follow up were performed according to the actual guidelines. Between August 2002 and June 2009, 1054 patients were randomized for cALND and 1052 patients for RNI. SN was evaluated in 2073 patients and was positive in 526 patients (25.4%). 474 cases were evaluable (244 in the cALND and 230 in the RNI arm), and in the cALND group 94 of 244 patients (38.5%) who underwent completion axillary surgery has additional positive nodes. The two arms were well balanced according to the majority of main prognostic factors. Primary endpoint was axillary recurrence and secondary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: Mean follow-up was 97 months (Q1-Q3: 80-120). Axillary recurrence was 2.0% in cALND arm vs. 1.7% in RNI arm (p = 1.00). OS at 8 years was 77.9% vs. 84.8% (p = 0.060), and DFS was 72.1% in cALND arm and 77.4% after RNI (p = 0.51). The results show that RNI is statistically not inferior to cALND treatment. CONCLUSIONS: The long term follow-up results of this prospective-randomized trial suggest that RNI without cALND does not increase the risk of axillary failure in selected patients with early-stage invasive breast cancer (cT ≤ 3 cm, cN0) and pN1(sn). Axillary radiotherapy should be an alternative treatment for selected patients with sentinel lymph node metastases.

Inguinal sentinel lymph node biopsy for staging anal cancer.

BACKGROUND AND AIMS: The optimal treatment of clinically negative inguinal lymph nodes in patients with primary anal cancer has not yet been clearly defined. The presence of metastases in the inguinal lymph nodes is an adverse prognostic factor for anal cancer. In the present study the feasibility of sentinel lymph node biopsy (SLNB) for staging anal cancer was investigated. PATIENTS AND METHODS: From September 1999 to March 2002, 8 patients with biopsy proven primary anal cancer underwent lymphoscintigraphy and dual-agent guided inguinal SLNB for nodal staging before starting multimodality treatment. RESULTS: Inguinal SLNB was successful in all 8 patients (13 groins). A total of 20 hot and blue SLNs (mean 1,5 (1-2) per groins) were removed. In 2 patients (25%) the SLN was positive for metastasis. CONCLUSIONS: Lymphoscintigraphy followed by dual-agent guided inguinal SLNB is technically feasible for staging patients with primary anal cancer. The detection of metastases in the removed sentinel lymph node(s) may alter the treatment and thus may improve the locoregional control and overall survival of these patients.

[Management of the axilla in breast cancer: evidences and unresolved issues]. / Az axilla kezelése emlórákban: evidenciák és vitatott kérdések.

In this study the evidences governing the management of the axilla were examined and on the base of these evidences, the optimal clinical practice was outlined. Computerized searches for publications, debating specific treatment of axilla, were done of MEDLINE data. Level of evidence was determined using standard criteria: 1. metaanalysis of randomized trials, 2. randomized trial, 3. prospective and retrospective studies, 4. reports and opinion of expert committees and working teams. The probability of lymph node involvement is related directly to the size of the primary tumour, and even with small tumour (up to 10 mm), the risk of nodal metastases is in the order of 10-20%. To date, the best strategy for determining complete lymph node status (qualitative and quantitative information) is through axillary dissection. For an accurate staging, at least ten nodes have to be obtained. Formal axillary sampling does not provide total quantitative data in patients with involved axilla. Sentinel node biopsy is a promising alternative to axillary dissection for staging but it is still under way. Axillary dissection should be omitted in patients with ductal carcinoma in situ since the probability of nodal involvement is less than 1%. In invasive breast cancer, the risk of axillary recurrence in the untreated axilla varies from about 10% to 40%. For women with stage I-II breast cancer at least level I and II axillary node dissection should be offered as the standard procedure to reduce the risk of regional recurrence. Women at high risk of axillary recurrence (> or = 4 involved nodes, < 6 nodes were obtained from a positive axilla) will require axillary irradiation after axillary dissection. However, there is a lack of higher level evidence to support the benefit of post-dissection axillary irradiation. Evidences suggest that axillary irradiation is as effective as axillary dissection in preventing regional recurrence. The following factors have to be considered for decisions regarding dissection or irradiation: patient wishes, general condition, age, the necessity of pathological nodal status for systemic therapy and the risk of post-treatment morbidity. At this time, there is no well defined subgroup of patients in whom axillary intervention can be safely omitted. In selected patients with clinically negative axilla, the decision to observe the axilla rather than use surgery or irradiation should be made jointly between the women and her specialists (surgeon, radiation and medical oncologist). The benefits of axillary treatment in prolonging survival are unclear. Studies have reported different effects on survival. Until evidences remain insufficient, the risk of axillary recurrence has to be minimized, and more and more patients have to be provide to get treatments in randomized clinical trials. Patient should be fully informed about the benefits and the potential side effects of treatments. A combination of radiotherapy and axillary dissection results an increased morbidity rate compared with either alone.

[Retrospective evaluation of surgically treated cases of non-palpable breast tumor]. / A nem tapintható emlótumor miatt operált eseteink retrospektív értékelése.

Between 10.01.1997 and 09.30.1999 authors performed operations on 78 patients who had nonpalpable breast tumors. If mammography was considered abnormal during breast screening program patients were recalled. Besides clinical investigation complimentary mammograms were performed. After sonogram, and if needed, aspiration biopsy cytology (ABC) if necessary core biopsy (CB) was the next investigation. 79 operations were performed on 78 patients (one was patient had synchronous breast tumor). The mean age of the patients was 56.3 years. If the radiological investigations (R4-R5) and/or the ABC (C4-C5) or CB suggested malignancy operation was performed. Mammography suggested malignancy in 60.75% of the patients, it was suggested by ABC in 30.18%, and by CB in 55.5%. The nonpalpable tumor, suspected to be malignant was marked with a wire loop and was excised under anesthesia along with the affected breast sector. The excision and tissue-border around the tumor was checked by specimen mammography performed during the narcosis. No cryohistology was performed. After the specimen mammography, the wound was closed. The final histology of the operations showed malignancy in 40.5%. In their retrospective study the authors evaluated the complete sensitivity and the positive predictive value (PPV) of the preoperative investigations regarding the final histology. They analyse the value of preoperative mammogram, the ABC and CB in malignant and in benign cases. Early diagnosis and surgical treatment is expected to improve significantly the survival of patients with breast cancer. Reduction in the number of unnecessary operations can be expected from increasing the accuracy of radiological and cytological investigations and the adequate usage of core biopsy.

Immunohistochemistry and reverse transcriptase polymerase chain reaction on sentinel lymph nodes can improve the accuracy of nodal staging in breast cancer patients.

In this study the nodal staging sensitivity of sentinel lymph node biopsy (SLNB) with detailed pathological and molecular biological examination has been investigated and compared to that of axillary lymph node dissection (ALND) with routine histological evaluation. Sentinel lymph nodes (SLNs) were removed by the dual-agent injection technique in 68 patients with primary, clinically node-negative breast cancer. Forty-seven patients had negative SLNs according to hematoxylin and eosin (H&E) staining. These H&E-negative SLNs were serially sectioned and examined at 250 microm levels by anticytokeratin immunohistochemistry (IHC). In 14 patients the SLNs were also investigated by cytokeratin 20 (CK20) reverse transcriptase polymerase chain reaction (RT-PCR). SLNB with IHC increased the node-positive rate by 26% (by 40% in tumors less than or equal to 2 cm in size (pT1) and by 9% in tumors more than 2 cm but less than or equal to 5 cm in size (pT2)). The sensitivity of SLNB with IHC was superior to that of ALND with routine histology in pT1 tumors and identical in pT2 tumors. The concordance between histology and RT-PCR was only 21%, and in two of three cases with positive histological results RT-PCR was negative. In conclusion, SLNB with detailed pathological and/or molecular biological evaluation can improve the sensitivity of regional staging. ALND can probably be abandoned in patients with pT1 SLN-negative breast cancer. Further prospective studies are required to determine the clinical significance of these detailed SLN evaluation techniques, but at present these methods are still investigational.

[Feasibility and accuracy of the combined radioisotope and blue-dye guided sentinel lymph node biopsy in breast cancer]. / A kettós jelöléses órszem nyirokcsomó-biopszia sebészi alkalmazhatósága és pontossága emlórákban.

Sentinel lymph node biopsy is a minimally invasive operation for staging regional lymph nodes in breast cancer. This method was introduced in the last decade. However there are some remaining questions regarding labelling, surgical technique, indications, and the pathological examination of the removed sentinel lymph nodes which have to be answered before can be introduced as the routine clinical practice. 98 patients with primary breast cancer underwent double guided (radioisotope and blue-dye) sentinel lymph node biopsy in our department during a surgical feasibility study between December 1997 and February 2000. The operation was successful in 92 patients (94%). False negative rate, sensitivity and accuracy were 15%, 85% and 95% retrospectively. During the learning curve the success rate improved from 83% to 99%, the sensitivity from 79% to 89% and the accuracy from 88% to 97% and the false negative rate decreased from 21% to 11%. In T1 tumors the false negative rate and accuracy were 6% and 98%, while in T2 tumors these were 24% and 86%. Application of a larger particle sized colloid (200-600 nm), subareolar injection and next day operation technique had no effects on the results. Double guided sentinel lymph node biopsy is a sensitive surgical staging procedure which accurately predicts the lymph node status in T1 breast tumors. The technique used by us is easy to reproduce, and learn and is beneficial in technical and radiation protection aspects.

[Initial experiences with sentinel lymph node biopsy in malignant melanoma]. / Melanoma malignum sentinel nyirokcsomójának eltávolításában szerzett kezdeti tapasztalataink.

Elective versus therapeutic lymph node dissection has been a controversial field of the surgical treatment of cutaneous malignant melanoma for more than two decades. The identification and biopsy of the sentinel lymph node in different solid malignancies has become feasible by the method described by Morton in 1992. The sentinel lymph node is the first tumor draining lymph node in the regional lymph node basin. If metastasis is not proven in the sentinel node by detailed histological study those are unlikely in other regional lymph nodes and formal lymph node dissection can be omitted. Patients undergoing surgery for primary cutaneous (intermediate or high risk) melanoma have been initiated in this feasibility study. Of the 40 patients the sentinel lymph node biopsy was unsuccessful in two and at least one positive sentinel lymph node was found in nine patients. The duration of the procedure is between five and 15 minutes. After this feasibility study further prospective and randomized studies are projected.

[The role of intraoperative gamma-probe-guided sentinel lymph node biopsy in the treatment of malignant melanoma and breast cancer]. / Az intraoperatív gamma-próba által vezérelt örszem nyirokcsomó-biopszia jelentösége a melanoma malignum és az emlörák kezelésében.

In the treatment of malignant tumors regional lymphadenectomy is used for two purposes. It is used partly for staging the regional lymph nodes which is a significant and independent prognostic factor and determines the need for adjuvant oncologic treatment and partly for achieving locoregional disease control. Removal of tumor-free lymph nodes by regional lymph node clearance is unnecessary according to our current knowledge. Since the sensitivity and specificity of non-invasive clinical examinations are insufficient in predicting the nodal status the histological study of the regional lymph nodes cannot be abandoned. A new and minimally invasive surgical procedure, the mapping and removal of the first tumor draining lymph node, the sentinel node provides the possibility of pathological nodal staging without performing formal lymphadenectomy. Mapping of the sentinel node can be performed by the use of a radioisotope and intraoperative hand-held gamma-probe or a vital blue dye or a combination of these two. This latter method was used by the authors in 73 patients (25 with malignant melanoma and 48 with breast cancer). Sentinel lymph node biopsy was performed successfully in 92% of patients with melanoma and 90% of patients with breast cancer. In three breast cancer patients the sentinel node inaccurately predicted the axillary status as negative, but is was in 93% accurate in predicting the histologic nodal state. According to our preliminary experiences intraoperative gamma-probe guided sentinel lymph node biopsy is considered a feasible procedure in both malignant melanoma and breast cancer. More experiences are needed before introducing this method in the routine clinical practice.

Correlation of biochemical tumor markers with conventional pathological features in primary breast cancer.

In this prospective study the correlation of pathological with biological prognostic factors and serum tumor markers has been investigated in 574 patients with primary invasive breast cancer. The p53 protein and Bax level correlated positively with tumor size, lymph node status and histological grade. The serum levels of CEA, CA 15.3, TPA-M and TK correlated with tumor extent. There was a significant difference between pre- and postmenopausal breast cancer patients in serum levels of TPA-M and cytosol levels of Bax. Whether these correlations can help in predicting the prognosis of breast cancer by providing additional information with respect to the conventional factors, will have to be investigated by several years of careful clinical follow-up.

[Amyloid goiter]. / Az amyloid golyváról.

Amyloid goitre is at an extremely rare occurrence. Authors review the origin of disease and its symptoms, diagnostic and therapeutic tools. The disease may be due to either primary or secondary systemic or local amyloidosis. Diagnosis may be made even before surgery on anamnestic data, on very rapid growth of thyroid glands, on diffuse appearance, on other symptoms of systemic amyloidosis, on findings of iconographic procedures and on detection of amyloid in aspirates. Final diagnosis is based on histology. Surgical therapy is aiming at avoidance of the existing and the threatening consequences of expanding mass. The outcome is independent from thyroid surgery, it is related to other manifestations of amyloidosis. Concerning with the present case the chronic superior vena cava syndrome and chylous pleural effusion as first described symptoms and asymptomatic hyperthyroxinaemia is emphasised. Neither other organ involvement, nor primary amyloidogenous molecula was found during the 18 months follow up, so patient has secondary and localised amyloidosis.

Surgical chemotherapy in the management of melanoblastoma of the lower extremities.

The therapy of advanced melanoblastomas of the lower extremities is limited. Surgery alone is insufficient due to the extent of the tumor, the radicality of mutilating surgery is questionable because of the existing or suspected subclinical metastasis. To avoid amputation, regional chemoperfusion and simultaneous hemofiltration may be the choice of treatment. Between 1993 and 1995 the authors performed surgical chemotherapy on 21 occasions in 14 patients with advanced melanoblastoma of the lower limb. Partial remission of 4 to 11 months developed in 10 patients, 3 patients achieved subjective improvement for 3 to 6 months, 1 patient had disease progression. Simultaneous application of surgical regional chemotherapy and hemofiltration offers an alternative approach in the management of patients suffering from advanced melanoblastoma.