Oncology-Led Early Identification of Nutritional Risk: A Pragmatic, Evidence-Based Protocol (PRONTO).

Nutritional issues, including malnutrition, low muscle mass, sarcopenia (i.e., low muscle mass and strength), and cachexia (i.e., weight loss characterized by a continuous decline in skeletal muscle mass, with or without fat loss), are commonly experienced by patients with cancer at all stages of disease. Cancer cachexia may be associated with poor nutritional status and can compromise a patient's ability to tolerate antineoplastic therapy, increase the likelihood of post-surgical complications, and impact long-term outcomes including survival, quality of life, and function. One of the primary nutritional problems these patients experience is malnutrition, of which muscle depletion represents a clinically relevant feature. There have been recent calls for nutritional screening, assessment, treatment, and monitoring as a consistent component of care for all patients diagnosed with cancer. To achieve this, there is a need for a standardized approach to enable oncologists to identify patients commencing and undergoing antineoplastic therapy who are or who may be at risk of malnutrition and/or muscle depletion. This approach should not replace existing tools used in the dietitian's role, but rather give the oncologist a simple nutritional protocol for optimization of the patient care pathway where this is needed. Given the considerable time constraints in day-to-day oncology practice, any such approach must be simple and quick to implement so that oncologists can flag individual patients for further evaluation and follow-up with appropriate members of the multidisciplinary care team. To enable the rapid and routine identification of patients with or at risk of malnutrition and/or muscle depletion, an expert panel of nutrition specialists and practicing oncologists developed the PROtocol for NuTritional risk in Oncology (PRONTO). The protocol enables the rapid identification of patients with or at risk of malnutrition and/or muscle depletion and provides guidance on next steps. The protocol is adaptable to multiple settings and countries, which makes implementation feasible by oncologists and may optimize patient outcomes. We advise the use of this protocol in countries/clinical scenarios where a specialized approach to nutrition assessment and care is not available.

Frequency of Body Weight Loss is an Independent Prognostic Factor of First-Line Treatment Outcomes in Metastatic Colorectal Cancer.

One of the main features of wasting in cancer is an involuntary weight loss which is most pronounced in gastrointestinal tract tumors and leads to worse clinical outcomes. The aim of this study is to analyze the frequency of body weight loss (FBWL) as an additional prognostic factor in the treatment of patients with metastatic colorectal cancer (mCRC).In this observational, single-center study, data were retrieved for 236 patients treated for mCRC. FBWL was defined as a percent of change in weight divided by weeks of therapy. Patients were stratified into two groups according to the median of FBWL which equaled to the loss of 0.05%/week. Patients who lost >0.05%/week (N = 116) had shorter progression-free survival (PFS) in the first-line treatment, then the ones who lost <0.05%/week (N = 120); 28.3 vs 46.3 weeks, respectively. Cox regression model showed that FBWL and sidedness were significant predictors of PFS, while age, sex and ECOG were not. Significantly more patients with stable weight were also eligible for second-line treatment. In conclusion, stabilization of body weight is important and independent predictor of longer PFS in first-line therapy of patients with mCRC.

The pathogenesis of bone metastasis in solid tumors: a review.

Owing to its frequent occurrence and severe clinical picture, bone metastasis is an important problem in the clinical course of tumor diseases. Bone metastasis develops when the physiological remodeling process is disrupted by tumor cells via the same molecular mechanisms used by native bone cells. The process includes molecular crosstalk between osteocytes and osteoblasts and osteoclasts. Osteolytic bone metastasis, most often seen in breast cancer, is characterized by promoted differentiation and function of osteoclasts and reduced osteoblast function. Tumor cells take advantage of factors released by bone tissue resorption, thus establishing a vicious cycle that promotes the metastatic process. In osteoblastic metastasis, most often seen in prostate cancer, osteoblast function and differentiation are promoted, while osteoclast activity is reduced, resulting in net gain of bone tissue. Mechanisms involved in the early stages of bone metastasis and cancer cell dormancy have been understudied, and their exploration may pave the way for potential therapeutic strategies. Tumor affects the bone marrow microenvironment via exosomes, soluble factors, and membrane-bound ligands. In this way, an initial lesion is established, which after a variable duration of disseminated tumor cells dormancy progresses to an overt condition. The current review deals with basic mechanisms involved in bone metastasis formation and propagation. We illustrated a disparity between the diversity and number of factors included in the disease pathophysiology and the number of available and developing therapeutic options. We also examined new therapeutic strategies affecting molecular pathways.

Prognostic value of circulating Bcl-2 and anti-p53 antibodies in patients with breast cancer: A long term follow-up (17.5 years).

BACKGROUND: Apoptosis inhibition is a major tumorigenic factor. Bcl-2 dysregulation and TP53 mutation status, which may correlate with autoantibody generation, contribute to impaired apoptosis. OBJECTIVE: This study aimed to investigate the prognostic value of circulating Bcl-2 and anti-p53 antibodies (p53Abs) in a 17.5-year follow-up of breast cancer patients. We also analyzed the correlations of Bcl-2 and p53Abs with various clinicopathological parameters in order to assess their impact on tumor aggressiveness. METHODS: Serum Bcl-2 and p53Abs levels were analyzed by the enzyme-linked immunosorbent assay (ELISA) in 82 patients with invasive breast cancer and twenty individuals without malignancy. RESULTS: Serum Bcl-2 and p53Abs levels in breast cancer patients were significantly higher than those in controls. Patients with high levels of Bcl-2 (cut-off 200 U/ml) had a poorer prognosis (17.5-year survival) than those with lower Bcl-2 values. In combined analysis the subgroup of patients with elevated p53Abs (cut-off 15 U/ml) and elevated Bcl-2 (cut-offs 124 U/ml and 200 U/ml) had the worse prognosis in 17.5-year survival. In correlation analysis p53Abs and Bcl-2 were associated with unfavorable clinicopathological parameters. CONCLUSIONS: Our results suggest that breast cancer patients with high serum levels of p53Abs and Bcl-2 present an especially unfavorable group in a long follow-up.

Should we treat pain in the elderly palliative care cancer patients differently?

Opioids are considered the cornerstone of pain management in palliative care. Available data suggest that older patients use different analgesics and lower opioid doses compared to younger patients. However, it has not been elucidated yet whether such dosing is associated with worse pain levels or shorter survival in the palliative care setting. We evaluated the relationship among pain scores, quality of life, opioid dose, and survival in palliative care cancer patients in a hospice setting. A total of 137 palliative care cancer patients were analyzed prospectively. We divided patients into two groups using the age of 65 as a cut-off value. Younger patients exhibited significantly higher pain ratings (5.14 vs. 3.59, p=0.01), although older patients used almost 20 mg less oral morphine equivalent (OME) on arrival (p=0.36) and 55 mg OME/day less during the last week (p=0.03). There were no differences in survival between the two groups (17.36 vs. 17.58 days). The elderly patients also used nonsteroidal analgesics less often and paracetamol more often. Hence, using lower opioid doses in older palliative care cancer patients does not result in worse pain rating, and could be a plausible approach for pain management in this patient group.

Kinase Inhibitors in the Treatment of Thyroid Cancer: Institutional Experience.

Although most patients with thyroid cancer have a favorable clinical course, some patients develop a more aggressive type of cancer and exhibit more rapid disease progression with worse prognosis. Those patients usually exhibit mutations of proteins such as tyrosine kinase enzymes that play a significant role in regulation of tumor proliferation and spreading. Development of targeted therapies is based on the inhibition of mutated kinases which are involved in the MAPK signaling pathway. The aim of this study was to present the initial results of clinical experience with kinase inhibitors in patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and medullary thyroid cancer (MTC) who exhibited rapid disease progression. A total of 17 adult patients (11 women, mean age 53.3 years) managed for progressive, metastatic disease were included in the study. Twelve patients with DTC and PDTC were previously tested for BRAF mutations, of whom nine that had tumor tissue negative for the BRAF V600E mutation received sorafenib, while three patients with tumors harboring the BRAF V600E mutation were treated with vemurafenib. Patients with MTC were treated with sunitinib, vandetanib, and sorafenib. Two patients with tumors harboring the BRAF mutation treated with vemurafenib showed restoration of radioiodine uptake. Most of patients showed significant improvement in disease status but of limited duration until disease progression. Although there was an improvement in progression-free survival, future research has to achieve a greater and longer-lasting response, probably by utilizing combined targeted therapy.

Leukocytoclastic vasculitis associated with sorafenib treatment for hepatocellular carcinoma.

Small-vessel vasculitis is an uncommon diagnosis associated with many causes, including certain medication. Characteristic findings are immune complex deposition, vessel wall damage, and erythrocyte extravasation. We present a case of a 77-year-old man with advanced hepatocellular carcinoma who was treated with sorafenib. Twenty days post introduction to sorafenib, the patient experienced high fever and painful purpura on the lower limbs. The results of the skin biopsy confirmed the diagnosis. More extensive diagnostics was undertaken, which excluded other possible causes of vasculitis and infectious disease. Following a full recovery, after the steroid treatment was completed, sorafenib has been continued until the progression of the carcinoma. This is the second described case of hepatocellular carcinoma associated with sorafenib treatment and leukocytoclastic vasculitis. Sorafenib is a potential cause of vasculitis, and clinicians should bear in mind to differentiate it from hand-foot skin reaction, which is a common side effect of multikinase inhibitors. The result of our assessment is important considering that vasculitis requires more specific diagnostic procedures, treatment, and often drug discontinuation.

[CANCER PATIENTS FOLLOW-UP ­ CROATIAN SOCIETY FOR MEDICAL ONCOLOGY CLINICAL GUIDELINES Part IV: planocellular head and neck cancer, oesophageal cancer, gastric cancer, colorectal cancer].

Treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not being based on prospective studies, yet on the expert's opinion of a precise oncological center or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures' algorithm in follow­up of oncological patients after primary treatment, in patients with planocellular head and neck cancer, oesophageal cancer, gastric cancer and colorectal cancer.

[CANCER PATIENTS FOLLOW-UP ­ CROATIAN SOCIETY OF MEDICAL ONCOLOGY CLINICAL GUIDELINES Part II: renal cell cancer, urinary bladder cancer, prostate cancer, testicular cancer]. / PRACENJE ONKOLOSKIH BOLESNIKA ­ KLINICKE PREPORUKE HRVATSKOG DRUSTVA ZA INTERNISTICKU ONKOLOGIJU HLZ-a II. dio: rak bubrega, rak mokracnog mjehura, rak prostate, rak testis.

The treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not based on prospective studies, but on the experts opinion of individual oncological centers or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures algorithm in the follow­up of ­oncological patients after primary treatment, in patients with renal cell cancer, urinary bladder cancer, prostate cancer and testicular cancer.

Significance of surgery for prognosis of GIST in cohort from transitional healthcare settings.

OBJECTIVE: Despite significant improvement in survival of gastrointestinal stromal tumors (GIST) due to use of tyrosine kinase inhibitors, surgery still represents the important part of clinical management. The aim of our study was to retrospectively analyze prognosis of GIST depending on the success of surgical treatments and utilization of chemotherapy in transitional country with relatively limited resources. METHODS: cohort of consecutive patients operated for GIST in tertiary medical center, within time frame 1999-2012. RESULTS: 54 patients, in age range 20-85 years (63.3 ± 14.7), male to female ratio 28 (51.9%):26 (48.1%), respectively. Complete excision with clean resection margins (R0) was obtained in 44 (81.5%)of total patients i.e. 44/47 (93.6%) of localized GISTs. Mean follow up was 3.9 ± 3.3 years and 19 patients (35.2%) received imatinib. Rate of overall survival was 40 (74.1%), disease-free survival 31 (57.4%) and 20 (37.0%) experienced recidivism. Follow-up parameters showed significant difference in connection with utilization of imatinib, completeness of resection and existence of metastatic disease (all p < 0.05). ROC analyzes revealed critical value of Ki-67 > 9% as significant predictor of long-term mortality; sensitivity 64.3% [95%CI = 35.1-87.2]; specificity 75.0% [58.8-87.3]; (AUC = 0.693; p = 0.049). CONCLUSION: Rate of complete resections in studied sample of patients from transitional background was overall peer comparable with reports from the developed countries. On the other hand, relatively dominant prognostic position of surgical treatments might be consequence of limited utilization of adjuvant treatment with tyrosine kinase inhibitors.

Role of Ki-67 as a prognostic factor in gastrointestinal stromal tumors.

AIM: To investigate primarily the prognostic value of Ki-67, as well as other parameters, in gastrointestinal stromal tumors (GISTs). METHODS: Ki-67, c-KIT, platelet-derived growth factor receptor-alpha (PDGFRα), smooth muscle actin (SMA), CD34, S100 were stained for immunohistochemistry which was performed on formalin-fixed, paraffin-embeded sections on representative block from each case. Proliferation index counted by Ki-67 antibody was calculated as a number of positive nuclear reaction over 100 cells. Immunoreactivity for c-KIT and PDGFRα was evaluated semiquantitatively (weak, intermediate, strong) and for c-KIT type of reactivity was analyzed (cytoplasmic, membrane and "dot-like" staining). Immunoreactivity for SMA, CD34 and S100 were was evaluated as positive or negative antigen expression. Pathologic parameters investigated in this study included tumor size, cell type (pure spindle, pured epitheloid mixed spindle and epitheloid), mitotic count, hemorrhage, necrosis, mucosal ulceration. Clinical data included age, gender, primary tumor location and spread of disease. χ² test and Student's t-test were used for comparisons of baseline characteristics. The Cox's proportional hazard model was used for univariable and multivariable analyses. Survival rates were calculated by Kaplan-Meier method and statistical significance was determined by the log-rank test. RESULTS: According to the stage of disease, there were 36 patients with localized disease, 29 patients with initially localized disease but with its recurrence in the period of follow up, and finally, 35 patients had metastatic disease from the very beginning of disease. Tumor originated most commonly in the stomach (41%), small intestine was the second most common location (36%). The mean size of primary tumors was 6.5 cm. The mean duration of follow-up was 60 mo. Multiple parameters were analyzed for their effect on overall survival, but no one reached statistical significance (P = 0.06). Analysis of time to progression/relapse in initially localized disease (univariate analysis), tumor size, mitotic count, Ki-67 and type of d-KIT distribution (cytoplasmic vs membrane/"dot-like") showed statistically significant correlation. In multivariate analysis in the group of patients with localized disease, there were only 2 parameters that have impact on relapse, Ki-67 and SMA (P < 0.0001 and P < 0.034, respectively). Furthermore, Ki-67 was analyzed in localized disease vs localized with recurrence and metastatic disease. It was shown that there is a strict difference between these 2 groups of patients (median value was 2.5 for localized disease vs 10.0 for recurrent/metastatic disease, P < 0.0001). It was also shown that the cut-off value which is still statistically significant in terms of relapse on the level of 6%. The curves for survival on that cut-off level are significantly different (P < 0.04, Cox F). CONCLUSION: Ki-67 presents a significant prognostic factor for GIST recurrence which could be of great importance in evaluating malignant potential of disease.

[Clinical recommendations for treating and monitoring patients with renal cancer]. / Klinicke upute za dijagnozu, lijecenje i pracenje bolesnika oboljelih od raka bubrega.

Clear cell renal carcinoma is the most common kidney cancer. It is generally asymptomatic. A small percentage of patients present with hematuria, flank pain and abdominal mass. It is usually detected accidentally during radiologic examination. The diagnosis of kidney cancer is confirmed by pathohistological findings after completion of the diagnostic process. The decision about treatment is made based on clinical assessment of disease stage and other risk factors. Depending on that, treatment options include surgery, and considering high resistance of kidney cancer on chemotherapy and hormone therapy, use of targeted therapies (immunotherapy, tyrosine kinase inhibitors) and palliative radiotherapy. The following text presents the clinical guidelines in order to standardize procedures and criteria for the diagnosis, management, treatment and monitoring of patients with kidney cancer in the Republic of Croatia.

[Consensus guidelines for diagnosis, treatment and follow-up of patients with gastrointestinal stromal tumors]. / Prijedlog postupnika za dijagnostiku, lijecenje i pracénje oboljelih od gastrointestinalnih stromalnih tumora.

Gastrointestinal stromal tumors are the most common mesenchymal tumors in gastrointestinal tract. They are often asymptomatic and discovered incidentally during endoscopic or barium studies. About 80% GISTs have a KIT (CD 117 antigen) gene mutation. Most affect exon 11, less commonly exon 9,13 or 17, that results in uncontrolled KIT signaling. This led to effective systemic therapies in the form of small molecule inhibitors of the receptor tyrosine kinase such as imatinib mesylat. With the purpose of providing standardized approach to rational and effective diagnostic and treatment algorithm in Croatia, a multidisciplinary session was organized. Results of the session are given in the form of Consensus guidelines.

Lack of prognostic significance of connexin-43 labeling in a series of 46 gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors with variable malignant potential. Connexin-43 (Cx43) is the commonest gap-junction protein and has been frequently investigated in oncology. Our aim was to establish the immunohistochemical expression of Cx43 in relation to GIST location, size, Ki67 index, tumor grade and follow-up.? MATERIALS AND METHODS: The study included postoperative samples of 46 patients treated for GIST in the 1999-2010 time frame. Complete clinical workup was available for 38 patients (82.6%); total surgical resection was carried out in 32 (84.2%) patients, while 13 (34.2%) patients underwent chemotherapy. Median follow-up was 40.7 months (range, 1-134). ? RESULTS: The calculated incidence of GIST in our setting was 11.5 per million. Cx43 was expressed in 43/46 (93.5%) GIST cases, with a significant difference between stomach- and small intestine-derived tumors (p=0.006). Ki67 was 10% on average (range, 1-22) and was not correlated with tumor location (p=0.194). Cx43 did not show significance with regard to tumor size (p=0.264) or higher tumor grade (p=0.658), as opposed to Ki67, which significantly correlated with both (p=0.0048 and p<0.001, respectively). Cx43 and Ki67 were not significantly correlated (p=0.708). Ki67 correlated with time to recurrence (p=0.022). Ki67 >11% was taken as the indication to start imatinib chemotherapy (sensitivity 61.5%, specificity 92.0%, p=0.022). Ten (66.7%) of 15 patients with long-term (>5 years) follow-up were in remission.? CONCLUSION: Cx43 was frequently expressed in GISTs regardless of tumor site. However, no significant relationships to histopathological parameters suggestive for prognosis were found. Further investigations might clarify the roles of Cx43 in GIST oncogenesis.

[Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic neuroendocrine tumors]. / Postupnik za dijagnostiku, lijecenje i pracenje oboljelih od neuroendokrinih tumora gusterace.

Pancreatic neuroendocrine tumors (PETs) are increasingly recognized. In order to assure an optimal treatment of patients and to propose an efficient diagnostic algorithm we were prompted to organize meetings, with participating experts, specialists in different fields of expertise. The idea for the meetings was to try to give a standardized approach, which would in future help in stratification of PET patients. Results of meetings are given in a form of Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic neuroendocrine tumors.

[Imatinib in gastrointestinal stromal tumor treatment--results from University Hospital Centre Zagreb]. / Imatinib u lijecenju gastrointestinalnih stromalnih tumora--Iskustva KBC-a Zagreb.

Gastrointestinal stromal tumours (GIST) may be defined as intraabdominal mesenchymal tumours that express KIT protein or have an activating mutation in class III receptor tyrosine kinase gene (KIT or PDGFRalpha). Most GISTs respond to imatinib mesylate, which selectively inhibits both KIT and PDGFRalpha, and is now considered standard systemic therapy for advanced GIST. We assessed the antitumour response of patients treated with imatinib mesylate who had advanced and/or metastatic (GIST). In the Department of Medical Oncology fourteen (14) patients with advanced GIST were treated in the period from year 2002 to 2004. Imatinib mesylate was applied at the dose of 400 mg daily. Only two patients required dose enlargement up to 800 mg. All tumours had positive immunohystochemical expression of KIT. Median age of patients was 56 years. 12 male patients and 2 female patient was treated. Considering primary site of tumour we had 6 small intestine, 4 mesenterium and 4 gastric tumours. Mean duration of the treatment was 14 months (5 to 30 months). Six patients had partial remission, six had stable disease and two progression. Complete remission has not been achieved in any patient. Side-effects were mild and no patient required dose reduction or treatment discontinuation. Our results show the effectivness of targeted antitumour therapy with imatinib mesylate in advanced and/or metastatic GIST, and correspond to those in literature.

[Gastrointestinal stromal tumors (GIST)--a paradigm of successful targeted therapy of solid tumors]. / Gastrointestinalni stromalni tumori (GIST)--paradigma uspjesnog ciljanog lijecenja solidnih tumora.

Gastrointestinal stromal tumors (GIST) have attracted basic scientists as well as clinicians in the last 10 years. The reason for this is explanation of the pathogenetic mechanism of tumor growth by activation of c-Kit protein, followed by a rationally designed suppressor, a drug named imatinib. It is the first successful therapy for solid tumors to date, although there are other ongoing studies of agents with targeted action on different molecules in different tumors. In 80% of patients there is a clinical benefit from imatinib trreatment. GIST shows great diversity in clinical presentation and some questions still remain, such as malignant potential and prognostic criteria in these tumors. Imatinib therapy demonstrates many favorable effects such as acceptable toxicity and relative mild side effects, excellent quality of life, good patient compliance, etc. There are ongoing trials of new agents designated for target molecules, which would hopefully show benefit after developing resistance to imatinib.

[The value of searching for additional prognostic factors in combination with Nottingham Prognostic Index in breast carcinoma patients]. / Vrijednost istrazivanja dodatnih prognostickih cimbenika u kombinaciji s Nottinghamskim Prognostickim Indeksom u bolesnica s karcinomom dojke.

One of prognostic factors known as Nottingham Prognostic Index (NPI), which is combination of known prognostic factors such as tumor size, grade and axillary node status, is recently in usage in some European countries in clinical practice in prediction of breast carcinoma patients' survival. Therefore, the aim of this study was to verify, according to our experience, the prognostic significance of Nottingham Prognostic Index (NPI) in breast carcinoma patients in association with other new prognostic factors. In this study 148 consecutive specimens of breast carcinoma patients were analyzed. The following data for each patient were collected: age, tumor size, histological grade, axillary lymph node status, overall survival, estrogen (ER), progesterone (PR) receptor expression as well as expression of bcl-2, Ki-67, nm23, HER-2/neu, and p53. The Nottingham Prognostic Index (NPI) was calculated from the pathological information and patients were grouped according to the standard NPI index into: good prognostic group (GPG), moderate prognostic group (MPG), and poor prognostic group (PPG). The correlation of prognostic groups according to the NPI with other prognostic and predictive factors such as age, ER, PR, p53, bcl-2, Ki-67, nm23, Ki-67, Cathepsin D and HER-2/neu on overall survival was analyzed. The results of univariate analysis showed statistically significant correlation between patients' age, NPI prognostic groups and stage of disease with patients survival. When other prognostic factors were correlated with NPI prognostic groups there was not additional prognostic discrimination in given prognostic groups. Only marginally statistically significant influence of p53 expression was found on patient survival between MPG and PPG. It seems that other prognostic factors in combination with NPI prognostic groups do not have in our group of patients practical clinical relevance for the management of patients with breast carcinoma.

Prognostic value of different factors in breast carcinoma.

INTRODUCTION: The aggressive biological behavior of invasive and metastatic cancer is considered to be the most insidious and life-threatening aspect for breast cancer patients. It is mostly the result of changes in many molecular characteristics of tumor cells, including alterations in the mechanisms controlling cell growth and proliferation. AIM: The aim of this retrospective study was to identify predictors of aggressive biological behavior and metastatic potential in breast carcinoma among a number of intrinsic biomarkers of tumor cells such as steroid receptors and oncogene and tumor suppressor gene products. METHODS: Routine formalin-fixed, paraffin-embedded tumor samples were used and sections were stained immunohistochemically with the DAKO Strept ABC method to determine the expression of estrogen receptors (ER), progesterone receptors (PgR), HER-2/neu, bcl-2, Ki-67, p53 and nm23 in 192 consecutive breast carcinoma patients. The results of the quantitative immunohistochemical assays were correlated with clinical and histological data such as patient age, overall survival, tumor size, axillary lymph node status, hystological type, tumor grade, Nottingham prognostic index (NPI) and therapeutic regimens. RESULTS: Univariate analysis revealed that survival was significantly longer for patients with small tumors (P = 0.007), lower tumor grade (P = 0.021), negative axillary lymph nodes (P = 0.002), presence of nm23 protein (P = 0.002), and for patients treated with adjuvant hormonal therapy (P = 0.010). In multivariate analysis the independent factors positively affecting survival were absence of axillary lymph node metastases (P = 0.002), nm23 expression (P = 0.009) and hormonal therapy (P = 0.050). Among patients with positive axillary nodes there was a significantly higher survival rate in patients with nm23 expression compared with nm23-negative patients (P < 0.001). CONCLUSION: Identification of a subset of node-positive breast cancer patients with a more favorable prognosis according to nm23 expression might be clinically useful.

Nm23 gene product expression in invasive breast cancer--immunohistochemical analysis and clinicopathological correlation.

The nm23 gene/protein is a putative metastatic suppressor identified a decade ago in a melanoma cell line. A number of laboratory, clinical and pathological studies have been carried out to define its real biological and biochemical function as a step in a complex metastatic process. In our study we examined the significance of nm23 expression in 164 breast cancer patients, aged 35 to 74 years, in comparison to other parameters such as age, menopausal status, histological grade, tumor size, lymph node status, and hormone receptor status. Overall survival (OS) and disease-free survival (DFS) were analyzed. The median follow-up was 84 months. Significant changes in OS were found for tumor size, nodal involvement and histological grade but there was no convincing correlation with nm23 expression. When patients were stratified according to nm23 expression, it was shown that overall survival in nm23-positive patients was no longer than that in nm23 negative patients. It was also shown that patients who were lymph node negative and older than 50 years had longer OS than nm23-negative patients. A statistical analysis shows that there is a correlation between axillary node status and nm23 expression (p = 0.018) as well as between patients' ages and nm23 expression (p = 0.043). There was no statistically significant correlation between nm23 expression, lymph node status and their combination on DFS.