Characteristics of local recurrence of lung cancer and possibilities for surgical management.

PURPOSE: To investigate the correlation between stage and histopathological characteristics of patients with lung cancer and local recurrence, as well as the incidence and the characteristics of local recurrence along with the possibility of surgical retreatment. METHODS: Studied were 51 patients with locally relapsing lung cancer, initially treated surgically from 2003 to 2007. The operations performed ranged from conservative wedge resections, standard lobectomies and pneumonectomies to extensive resections of the entire lung and chest wall. All patients underwent regular follow-up including thoracic CT scan every 3 months. RESULTS: All patients were diagnosed with local recurrence after a median of 10 months (range 1-30) after primary surgery with curative intent. There was no statistically significant link between type of surgery and time to local recurrence. Patients with pathological stage I,II, and IIIa had a significantly longer time to local recurrence than those with stage IIIb and IV. Local recurrence sites were the bronchial stump, mediastinal lymph nodes, the remaining lung parenchyma, chest wall and a combination of these. Surgical retreatment was possible in 20 of 51 patients (39.27percnt;). Chest wall was the commonest localization (20 of 51; 39.2%), also the most frequent in the group of surgically retreated patients (13 of 20; 65%). Squamous cell cancer (SCC) was the predominant histological type (38 of 51; 74.5%), followed by adenocarcinoma (9 of 51; 17.7%). CONCLUSION: SCC is the commonest locally relapsing lung cancer. The type of the initial surgical procedure didn't have any impact on the incidence of local recurrence, but the extent and completeness of surgery did. The time to local recurrence heavily depended on the primary tumor pathological stage. Chest wall was the commonest relapse site, and the most suitable for surgical retreatment, which was related to the quality of surgery.

Clinical and pathological response to induction chemotherapy used as a prognostic factor in inflammatory breast cancer. Single institution experience.

PURPOSE: To evaluate clinical and pathological characteristics of patients with inflammatory breast carcinoma (IBC). Also, to evaluate the importance of achieved clinical and pathological responses to induction chemotherapy (iCT) and their role in the prognosis of IBC. METHODS: The medical records of 81 female patients with stage IIIB IBC, diagnosed between January 2008 and December 2010 at the Institute for Oncology and Radiology of Serbia (IORS) were evaluated. Almost all of the patients received anthracycline-based iCT. After 3-4 cycles of iCT, the clinical response (defined as complete response/CR, partial response/PR, stable disease/SD and disease progression/ PD) was assessed. Also, pathological response to iCT (defined as pathological complete response/pCR, near complete response/pNCR, partial response/pPR and no change/ pNC) was estimated in patients who had undergone surgery. All first metastatic sites were recorded. RESULTS: Clinical CR/PR was observed in 61.8% of the patients, while the pathological response (pCR, pNCR/near complete response, and pPR) rate in patients who had undergone surgery was 70%. During follow-up 22 (27.2%) patients developed PD (8 responders and 14 non-responders). Most common metastatic sites were the skeleton in non-responders and the liver in responders. Central nervous system (CNS) metastases developed in 24% of non-responders while no responder developed such metastases. Non-responders had shorter OS compared to responders, but without statistical significance. CONCLUSION: Although the number of the patients analysed in this study is relatively small, we believe that response to iCT could be used as a prognostic marker, since patients who initially failed to respond to iCT showed a higher risk for PD with development of distant metastases, primarily in bones and CNS, and shorter survival.

The significance of HER-2 amplification and the size and type of pathological unicentric, initially operable clinical stage I and IIA/IIB breast cancer, in determining the treatment strategy.

PURPOSE: In order to determine the initial treatment strategies for primary operable unicentric breast cancer, the possible relationships of the amplification of human epidermal growth-factor receptor-2 (HER-2), with age, menstrual status, tumor pathological size (pT), histopathological tumor type (HP) and kind of surgical treatment were studied. METHODS: Analysed were 301 patients treated initially by surgery in the period 2006-2009. HP tumor type, pT and HER-2 status (using firstly immunohistochemistry and then chromogenic in situ hybridization/CISH) were determined. The patients were divided into 2 subgroups according to the presence (CISH+)/absence (CISH-) of HER-2 amplification. RESULTS: Data on pT and HER-2 analyses were available for 293/301 (98.3%) patients with ductal (DC) and lobular carcinoma (LC). Amplification of HER-2 was found in 66 (21.9%) patients. No significant difference between the two subgroups regarding age (p=0.08), menstrual status (p>0.05) and kind of operation (p>0.05) was found. HP showed statistically significant difference between DC (55; 83.3%) and LC (11; 16.7%) patients with HER-2 amplification (p<0.01). Further HP analysis of the type of cancer within the pT category as a subgroup showed significantly higher frequency of HER-2 amplification in DC patients for pT1 (p<0.01) and in pT2 + pT3pN0 (p<0.05) compared with patients with LC. CONCLUSION: This study showed a significantly higher incidence of HER-2 amplification in DC tumors, especially in pT1 and pT2, than in LC, which may influence the options in treatment strategies in primary unicentric operable DC type of breast cancer.

The CD34-microvascular density in colorectal cancer patients.

PURPOSE: To investigate the influence of the angiogenesis parameter CD34 microvascular density (MVD) on overall survival of colorectal cancer (CRC) patients. METHODS: Thirty-one CRC patients were followed-up for 72 months after curative colorectal operation. Blood vessels measurement was done using the CD34-MVD immunochemistry method, and light microscopy. RESULTS: MVD was inversely correlated with patients' survival. MVD value < 35 proved as independent good prognostic factor, and patients with this value lived during the 72-month follow up after surgery, while a MVD value > 65 was an independent poor prognostic factor and such patients died within 11 months after radical surgery for CRC (p<0.01). CONCLUSION: According to these results, the CD34-MVD seems to be a significant prognosticator of overall survival in CRC patients.

Surgical anatomy of the pyramidal lobe and its significance in thyroid surgery.

AIM: The purpose of this prospective study was to highlight some new findings about anatomical and morphological variations of the thyroid pyramidal lobe and to emphasise the necessity and importance of exploration of the visceral compartment of the neck and resection of this structure in primary thyroid operations. METHOD: We analysed 100 consecutive primary thyroid operations with additional pathological examination of the specimens. RESULTS: A pyramidal lobe was found in 61% of the cases. The lobe of Lalouette was found more often in women (61.96%) than in men (50%) and more often (67.3%) in patients less than 50 years old than in those older than 50 (54.2%). The lobe branched off more frequently from the midline (49.18%) than from other parts of the isthmus; its length ranged from 8 - 40 mm, with a median length of 20.13 mm. In diffuse thyroid diseases, the lobes were always pathologically involved and significantly longer. CONCLUSION: Since the pyramidal lobe is a normal component of the thyroid gland, of varying position and size, with pathological changes in benign and malignant diseases, it should always be examined during thyroid surgery and mandatorily removed in total and subtotal thyroidectomies.

PTEN protein expression in postmenopausal steroid receptor positive early breast cancer patients treated with adjuvant tamoxifen.

PURPOSE: Since one of possible causes of resistance to antiestrogen therapy in steroid receptor positive (SR+) breast cancer (BC) patients is an alteration of PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways, the aim of this study was to determine the PTEN protein expression in postmenopausal patients with steroid SR+ BC treated with adjuvant tamoxifen, to investigate the association of PTEN protein expression with tumor histology, size and grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) statuses and disease outcome. METHODS: This was a retrospective analysis of 78 postmenopausal stage I/II SR(+)BC patients treated with adjuvant tamoxifen. PTEN protein expression and ER, PR and HER2 status were determined using immunohistochemistry. RESULTS: The distribution of PTEN protein expression according to tumor histology was as follows: PTEN+ status in 27/43 (62.8%) patients with ductal and in 26/35 (74.3%) patients with lobular carcinomas; and PTEN(-) status in 16/43 (37.2%) patients with ductal and in 9/35 (25.7%) patients with lobular carcinomas. Disease relapse was observed in 38/78 patients: 14/53 (26.4%) of PTEN(+) BC subgroup and 24/25 (96%) of PTEN(-) subgroup (x(2), p=0.018). There were no significant associations between PTEN protein expression and tumor histology, size and grade, and ER, PR and HER2 expression. Patients with PTEN(-) had significantly shorter disease-free interval (DFI) and overall survival (OS) (for both, log rank test, p <0.01) compared to PTEN(+) BC patients. CONCLUSION: Our results suggest that PTEN protein expression might be of prognostic significance in postmenopausal SR(+) BC patients treated with adjuvant tamoxifen.

[Mammography in detection clinically occult breast carcinoma].

AIM: The significance of mammography in detection of nonpalpable breast cancer MATERIAL AND METHODS: This prospective study was conducted at the Institute for oncology and radiology of Serbia in Belgrade. It involved 198 asymptomatic women with performed screening mammography, 154 specimen mammography, out of wich 38 had stereotaxic mark, "ex tempore" biopsy, while 44 women had "ex tempore" biopsy and adequate surgery. RESULTS: Screening mammography revealed suspect microcalcifications in 148 cases, impaired structural tissue in 59 and focal condensation in 55 cases. Histologic examination verified breast carcinoma in 80 patients with very statistical significance of ductal type, especially comedo subvariant (p < 0.001). Pleomorphic microcalcifications smaller than 0.5 mm of grouped or segmented form are statistically very significant for malignity (p < 0.001) as well as associated microcalcifications with altered architectony and focal tissue condensation (p < 0.001). CONCLUSION: Mammography has great significance in detection of occult breast carcinoma which are not only preinvasive, but olso microinvasive and invasive. This fact leads to the neccesity of introduction of legal obligation for mammography screening, especially for women aged between 50 and 70 years.

Antimelanoma immunity in vitiligo and melanoma patients.

Cutaneous melanoma and vitiligo are diseases etiology of which evolves around melanocytes. The nature of immunological disturbances associated with these diseases is not elucidated. The experiments performed in this work were aimed to determine antimelanoma immunotoxicity in patients with melanoma and patients with vitiligo. Twelve patients with melanoma, ten patients with vitiligo and seventeen healthy volunteers were studied. The cytotoxicity of PBMC was evaluated indirectly through determination of target melanoma (Fem-x) or control tumor (HeLa) cell survival, in the presence of 15% of AB or autologous sera, by MTT test. The mean values of antimelanoma cytotoxicity in AB serum were similar in both patients groups and in controls. However, the frequency of patients with the enhanced cytotoxicity against melanoma cells, in relation to control tumor cells, was lower in both patients groups than in controls. The intensity of antimelanoma cell-mediated cytotoxicity in melanoma patients, in the presence of autologous serum, was significantly lower in comparison to that found in control subjects and vitiligo patients (p<0.014, in both cases). This indicates that some factors from melanoma patient's sera contribute to impairment of the cytotoxicity of autologous PBMC, while other factors from the serum of vitiligo patients and control subjects enhanced their PBMC antimelanoma cytotoxicity.

Case-control study of female thyroid cancer--menstrual, reproductive and hormonal factors.

A case-control study including 204 histologically verified female thyroid cancer patients and an equal number of hospital controls individually matched with cases by sex, age (+/- 2 years), place of residence and time of hospitalization was performed during the period 1996-2000. In the analysis of data, univariate and multivariate conditional logistic regression, methods were applied. According to multivariate analysis, out of hormonal, menstrual and reproductive characteristics, risk factors for thyroid cancer were spontaneous abortions (odds ratio: OR = 1.89, 95% confidence interval (CI) = 1.03-3.50), oral contraceptives use (OR = 2.34, 95% CI = 1.31-4.18) and thyroid enlargement during pregnancy (OR = 16.44, 95% CI = 3.81-70.80). However, none of these three factors remained independently related to thyroid cancer after adjustment for other factors, which were significantly associated with thyroid cancer in the present study (history of residence in endemic goitre area, history of goitre or thyroid nodule, history of other endocrine diseases, radioactive iodine therapy, occupational exposure to various chemicals, family history of thyroid gland diseases and malignant tumours as well as intake of cruciferous vegetables and other vegetables, and consumption of smoked meat and cheese).

[Principles of lymph node surgery in differentiated thyroid carcinoma]. / Principi hirurgije limfnih nodusa kod diferentovanog tiroidnog karcinoma.

Surgery is the initial therapy in differentiated thyroid carcinoma (DTC). The surgery is performed on organ of tumor origin and regional lymphatic basins. The aim of surgery in DTC is to eradicate all tumor foci, cure the most number of patients, reduce recurrence and mortality rate, and provide good quality of life. There is no doubt between oncologists that the surgery for thyroid carcinoma has no alternative. The extent of surgery is matter of actual controversies. It should be performed by well trained surgeons. Dissection of central and biopsy of supraclavicular and lower third of jugulo-carotid chain of neck lymph nodes is the integral part of surgery in DTC, together with total thyroidectomy. If lymph node metastases are found in jugulo-carotid chain, modified radical neck dissection, unilateral or bilateral is indicated. Dissection of mediastinal lymph nodes should be performed too in cases of involvement. The extent of primary surgery should be dictated by stage of disease and prognostic factors. The quality of surgery and incidence of complications depends prognostic factors, as well as on surgeon's skill and experience. That is why the surgeon is factor of prognosis in treatment of patients with DTC.

[Identification of sentinel lymph nodes in thyroid carcinoma]. / Provera strazarskih limfnih nodusa kod tiroidnog karcinoma.

Sentinel lymph node (SLN) was defined as the first lymph node that the tumor would drain to, within that tumors regional lymphatic basin. In 1998, Kelemen and coworkers have published the first results on SLN lymphonodectomy in thyroid carcinomas. Different methods have been used in a goal of lymphatic mapping (application of vital blue dye and/or radiocolloid). In a period from 2001 to 2003 we have performed SLN biopsy in 64 patients with thyroid tumors. There were 12 cases of thyroid carcinoma. SLN identification rate was 73.44%. We found no false positive or negative results on definitive histopathology. The impact of lymph node metastases in differentiated thyroid carcinoma is still controversial. The management of cervical lymph nodes varies from berry picking to modified radical neck dissection. There is a significant disproportion in percentage of pre and intraoperatively enlarged lymph nodes (27-45%) and histologically confirmed lymph node metastases (80-90%) in papillary thyroid carcinoma. In the current literature the average rate of SLN identification is 91% (66-100%) and when identified, the SLN accurately predicts the disease status of the neck in most patients (80-100%). The SLN biopsy for thyroid carcinoma is good and feasible technique for estimating the cervical lymph node status.

[Medullary carcinoma of the thyroid gland: effect of postoperative transcutaneous radiotherapy on local control and results of treatment]. / Medularni karcinom stitaste zlezde: uticaj postoperativne transkutane zracne terapije u lokalnoj kontroli i rezultatima lecenja.

In the period of Octo. 01, 1987. up to Dec. 31, 1998. retrospective-prospective, non-randomized study was conducted at IORS, which included 36 patients diagnosed with thyroid gland medullar cancer. Our study had the following aims: evaluation of treatment results following probability of total survival, survival without signs of disease and disease-free interval until local recurrence of the disease and influence of parameters of transcutaneous radiotherapy (intensity of total tumor dose and length of disease-free interval from date of performed operation to beginning of radiotherapy). After finished treatment, median of the patient follow-up was 37.75 months (3.5 up to 141 months); probability of total five-year survival was 62.61% and of 10 year survival was 23.48%. Probability of 5-year survival, without signs of disease was 37.13%, and of 10-year survival 18.56%. As to radiotherapy parameters intensity of total therapy dose was statistically insignificant, while time interval to beginning of transcutaneous radiotherapy, shorter than 2 months, was statistically significant in relation to prognosis of disease outcome.

Therapeutic implications of the kinetics of immunomodulation during single or combined treatment of melanoma patients with dacarbazine and interferon-alpha.

The therapy of metastatic melanoma has not given satisfactory results. Single chemo- or immunotherapeutic agents in the adjuvant setting or combined chemoimmunotherapy for metastatic disease have generally been evaluated only in terms of clinical benefit. Considering that dacarbazine (DTIC) and interferon-alpha (IFN-alpha) are among the most frequently used agents in the treatment of melanoma, the aim of this study was to evaluate the kinetics of immunological changes during adjuvant treatment of melanoma patients with DTIC or with IFN-alpha monotherapy, as well as by their combination in metastatic disease. The evaluated immunological parameters showed significant early increase in the activity of NK (natural killer) cells, CD4/CD8 ratio, CD4+ T cell number in patients treated with combined chemoimmunotherapy and an increase in expression of the early activation antigen CD38 on CD8+ cytotoxic T cells, both, in patients treated with combined chemoimmunotherapy and with IFN-alpha alone, while, no significant change in any one parameter was detected in the group of patients receiving DTIC. The kinetics of the observed immunological changes, restricted to combined chemoimmunotherapy, indicate that the engagement of antitumor immune response appears early but is short-lived and that this favorable effect should be augmented and prolonged by the timely introduction of additional immunomodulating agents.

Electrochemotherapy on liver tumours in rabbits.

Electrochemotherapy (ECT) is a new therapeutic approach combining the effects of a low-permeant cytotoxic drug, bleomycin (BLM), administered i.v. and cell-permeabilizing electric pulses (EPs) locally delivered to tumours. The transient permeabilization of the cell membrane by the EPs allows free access of BLM to its intracellular targets, largely enhancing BLM's cytotoxic effects. ECT efficacy has been proved so far on transplanted subcutaneous murine tumours and on subcutaneous metastases in humans. Here, we present the first study of the effects of ECT on tumours transplanted to livers in rabbits. We used a recently developed EP applicator consisting of an array of parallel and equidistant needles to be inserted in tissues. Effects of EPs alone or of ECT were assessed by histological analysis, tumour growth rates and survival of the treated animals. A transient blood hypoperfusion was seen in the electropulsed areas, with or without BLM, related to EP-dependent vasoconstriction but this had no major effects on cell survival. Long-term effects depended on the presence of BLM at the time of EP delivery. Almost complete tumour necrosis was observed after ECT, resulting from both BLM direct cytotoxic effects on electropermeabilized tumour cells and indirect effects on the tumour vessels. A large reduction in tumour growth rate and significantly longer survival times were scored in comparison with control rabbits. Moreover, ECT of liver tumours was well tolerated and devoid of systemic side-effects. When ECT was associated with a local interleukin 2-based immunotherapy, increased local anti-tumour effectiveness as well as a large decrease in the number of metastases were observed. Thus, ECT could become a novel treatment modality for liver tumours and other solid internal malignancies.

Malignant tumors in families of thyroid cancer patients.

A case-control study comprised 177 patients with various types of thyroid cancer and the same number of hospital controls individually matched by age, sex and place of residence. Malignant tumors were more frequent among first and second degree relatives of cases as compared to controls. The odds ratio (95% confidence interval) was 2.43 (1.33-4.44) and 5.33 (1.77-16.01) respectively. The most frequent were cancers of uterus and stomach with odds ratio of 6.00 (1.61-22.36) and 9.00 (1.64-49.35). Thyroid cancer was present only in first-degree relatives of two cases and none of controls.

[Mechanisms in onset of postoperative immunodepression and its importance in the surgical treatment of cancer patients]. / Mehanizmi nastanka postoperativne imunodepresije i njen znacaj za hirursko lecenje onkoloskih bolesnika.

Postoperative immunodepression is inevitable transient path of operative trauma. Changes in the immunologic status are related to the duration of the anesthesia and surgery procedure. Mortality and morbidity and recurrence rate may be related with immunodepression.

Pharmacokinetics and antitumor effects of mitoxantrone after intratumoral or intraarterial hepatic administration in rabbits.

The intratumoral (i.t.) delivery of anticancer drugs aims at controlling tumor growth and thereby provides palliative treatment for liver neoplasms. Mitoxantrone is a good candidate for local or regional administration because (1) its metabolism is mainly hepatic, (2) it has a steep dose-response curve for multiple solid tumors, and (3) its fixation in tissues is sustained without vesicant effects after extravasation. We compared the tolerance, pharmacokinetics, and antitumor effects of mitoxantrone on hepatic VX2 tumors in rabbits treated with i.t. intraarterial hepatic (i.a.h.) or i.v. mitoxantrone, i.t. ethanol; or i.t. 0.9% NaCl and in control animals. Tumor growth rates (TGRs) were evaluated at 9 days after treatment. Myelosuppression was the limiting toxicity of i.v. mitoxantrone at 1.5 mg/kg (maximal tolerated dose, MTD), but neither i.t. nor i.a.h. administration led to hematologic toxicity at the same dose. The mitoxantrone retained in tumors after i.t. administration was seen as blue-stained areas of complete necrosis according to histologic analysis. Pharmacokinetic parameters showed a significantly decreased systemic exposure to the drug after both regional treatments, although the i.a.h. route appeared to have an edge over the i.t. route. TGRs were significantly reduced after i.t. mitoxantrone (81 +/- 62%), i.a.h. mitoxantrone (337 +/- 110%), and i.t. ethanol treatments (287 +/- 117%) as compared with control values (886 +/- 223%; p < 0.01). Treatment with i.v. mitoxantrone (816 +/- 132%) had no antitumor effect, nor did NaCl injections (868 +/- 116%). Mitoxantrone given i.t. induced the highest antitumor effects, resulting in a 3.5-fold reduction in TGRs as compared with i.a.h. mitoxantrone and i.t. ethanol treatments (p < 0.02). Treatment with i.t. mitoxantrone provided efficient antitumor therapy without producing major side effects. This method should be considered as palliative treatment for nonresectable liver tumors and other localized malignancies.