Turkish Ministry of Health, 2nd Turkish Medical General Assembly Clinical Oncology Study Group Report.

OBJECTIVE: There is an increase in the incidence of cancer, and consequently in mortality rates, both in the world and in Turkey. The increase in the incidence and mortality rate of cancer are more prominent in our country as well as in other developing countries. The aim of this workshop was to determine the current status on prevention, screening, early diagnosis and treatment of cancer in our country, to identify related shortcomings, specify solutions and to share these with health system operators, and to aid in implementation of these systems. Developments on palliative care were also evaluated. MATERIALS AND METHODS: The current situation in the practice of clinical oncology, related drawbacks, problems encountered during multidisciplinary approach and their solutions were discussed under several sub-headings during a 3-day meeting organized by the Turkish Ministry of Health (Türkiye Cumhuriyeti Saglik Bakanligi-TCSB) with participation of 16 scientists from Turkey and 6 from abroad, and the conclusions were reported. RESULTS: It is expected that the newly established Turkish Health Institutes Association (Türkiye Saglik Enstitüleri Baskanligi-TÜSEB) and the National Cancer Institute (Ulusal Kanser Enstitüsü) will provide a new framework in the field of oncology. The current positive findings include the increase in the number of scientists who carry out successful trials in oncology both in Turkey and abroad, the implementation of the national cancer registry program by the Cancer Control Department and the breast cancer registry program by the Turkish Federation of Breast Diseases Societies (Türkiye Meme Hastaliklari Dernekleri Federasyonu-TMHDF), and introduction of Cancer Early Diagnosis, Screening, and Training Centers (Kanser Erken Tani, Tarama ve Egitim Merkezi-KETEM) for the application of community-based cancer screening programs. In addition to these, obvious shortcomings related to education, implementation, management and research issues were also determined, and policy and project proposals to address these issues were presented. Collaboration with relevant organizations in the implementation of these studies was supported. CONCLUSION: Both the incidence and mortality rates of cancer are increasing in Turkey. The widespread deficiencies in population-based screening and in effective treatment lead to an increase in delay in diagnosis and mortality. Despite improvements in data recording, screening and treatment over the last 10 years, extensive, organized, population-based screening programs and fully equipped early diagnosis and treatment centers are required. Enhancement of basic cancer epidemiologic, translational, genetic and molecular research studies is essential in our country. Improvements on pain treatment and palliative care of patients with chronic and terminal cancer are also required.

Bilateral conjunctival MALT lymphoma mimicking chronic conjunctivitis.

BACKGROUND: The diagnosis of conjunctival lymphoid tu-mors is straightforward when they present with a characteristic salmon-pink, pebbly, multinodular appearance. However, rarely a diffuse clinical presentation is encountered, and this may mimic chronic conjunctivitis of other etiologies. CASE REPORT: A 60-year-old man was referred to our clinic with bilateral conjunctival masses in May 2005. With the assumption of chlamydial conjunctivitis, without microbiological or histopathological evidence, tetracycline ointment and oral doxycycline 100 mg twice daily were prescribed. Although a partial response was achieved, 2 months after the treatment, the patient's complaints returned. On second referral to our clinic in March 2006, the patient was re-evaluated. He presented with bilateral conjunctival masses resembling conjunctival lymphoma, and a bilateral diagnostic biopsy was performed. Histopathological evaluation of the biopsy specimens revealed mucosa-associated lymphoid tissue (MALT) lymphoma. The patient received CVP chemotherapy (cyclophosphamide, vincristine, prednisolone). After 6 courses of chemotherapy, he achieved partial remission in both eyes. Currently, 28 months after CVP, sustained remission is obtained. CONCLUSIONS: In these cases, a high index of suspicion is required if one is to avoid a delay in diagnosis, and the importance of correct early diagnosis is obvious.

Preoperative serum leptin levels in patients with breast cancer.

Leptin is an adipocyte-derived protein and plays an important role in the control of body weight by acting as a neurohormone regulating energy balance and food intake in the hypothalamus. The high serum leptin levels and the overexpression of leptin receptors have been documented in breast cancer patients, but the levels never checked preoperatively. In the present study, the relationship between preoperative serum leptin levels of the breast cancer patients and the healthy controls were evaluated. The serum leptin levels in 30 breast cancer patients were compared to 30 healthy female volunteers. In addition, the association of serum leptin levels and the various well-known risk factors were studied. Serum leptin levels of patients with breast cancer (28.55 + 19.7 ng/ml) were tended to be higher than those of controls (26.43 + 19.4 ng/ml), but it did not reach statistical difference (P = 0.712). There was significant correlation between the expression of ER, PR, and serum leptin levels (P = 0.018 and 0.037, respectively), but not with the HER-2/neu receptor expression (P = 0.067). Also association was not found between the tumor size, lymph node involvement, and the levels of serum leptin (P = 0.235, 0.34, and 0.86, respectively). The serum leptin level was also found to be similar in premenopausal (24.85 +/- 18.14 ng/ml) and postmenopausal (30.49 +/- 17.19 ng/ml) patients (P = 0.235). The preoperative serum leptin levels in breast cancer patients were similar to healthy controls. In subset analysis, the significant correlation between the leptin level and hormonal status was noted, but association with HER-2/neu was not detected. These findings should be confirmed with larger studies.

5-Fluorouracil induces arterial vasoconstrictions but does not increase angiotensin II levels.

Because the mechanisms of 5-Fluorouracil (5-FU) cardiotoxicity have not yet been completely identified, prophylactic options are not available. To our knowledge, there are no published data investigating the use of angiotensin converting enzyme (ACE) inhibitors for 5-Fluorouracil-associated cardiotoxicity. In this study, we aimed to evaluate the influence of 5-FU administration on the diameter of the brachial artery and the levels of angiotensin II. The patients were administered bolus 5-FU/leucovorin in the study group. Angiotensin II and troponin T assays, complete blood cell counts, hepatic and renal function tests were analyzed in five consecutive blood samples in the initiation, just after termination, and on 24, 48, and 72 h after termination of the regimen. Pre- and post-treatment angiotensin II and troponin T assays, complete blood cell counts, hepatic and renal function tests were also analyzed in the control group. Brachial arterial diameters were measured and recorded in all patients before and after the treatment. A total of 59 patients were included in this study. Thirty one out of 59 patients (52.5%) were in the 5-FU study group and the remaining 28 patients (47.5%) were in the control group. Basal and post-treatment brachial artery diameters in the 5-FU study group were 0.436 +/- 0.51 and 0.423 +/- 0.50 cm, respectively (P = 0.001). The corresponding values in the controls were 0.3954 +/- 0.50 and 0.3957 +/- 0.49 cm, basal and post-treatment, respectively (P = 0.979). Angiotensin II levels were not changed significantly at serial measurements (P = 0.496). Moreover, the corresponding measurements were not statistically different in both two groups treated with and without 5-FU (P = 0.372). The pathophysiology of 5-FU-induced cardiac toxicity has not yet been elucidated. In the present study, 5-FU-associated vasoconstriction was not dependent on angiotensin II levels, thus we suggest that the prophylactic administration of ACE inhibitors cannot prevent cardiotoxicity in these patients. The underlying mechanisms of cardiotoxicity related to 5-FU might be multifactorial; nevertheless, further prospective investigation for the toxic effects of fluoropyrimidines on the coronary endothelium and myocardium are needed.

Neoadjuvant chemotherapy for locally advanced breast cancer: a single center experience.

Neoadjuvant chemotherapy (NAC) is one of the treatment options for patients with locally advanced breast cancer (LABC). Preoperative chemotherapy potentially may reduce the extent of the surgery and offers the opportunity to assess the chemosensitivity of the tumor in vivo. Herein, we evaluated the results of NAC in Turkish LABC patients. We retrospectively analyzed 73 LABC patients. Anthracycline/taxane-based chemotherapy regimens were administered. Patients were stratified according to age, menopausal status, type of surgery, response to the treatment, histopathological properties, and survival. After 3-6 cycles of chemotherapy, patients were re-staged radiologically and surgery was performed in operable patients. Adjuvant chemotherapy was administered as needed. The median age was 45 (29-93) at the time of diagnosis. Sixteen percentage of patients were younger than 35 years of age and 45.2% were premenopausal. Median follow-up time was 20.2 months. Sixty-seven out of 73 patients responded to therapy (89%). Breast conserving surgery was possible in the 15% of the patients. In histopathological analysis, lymph node invasion was detected in 85%. The estrogen (ER) and progesterone (PR) receptor were positive in 78.1% and c-erb-B2 was positive in 17.5% of patients. The median disease-free survival (DFS) was 44 months (SE: 9; %95 CI: 27.1-60.8), overall survival (OS) was not reached at the time of analysis. Three-year DFS and OS were 58% and 91.9%, respectively. In a multivariate Cox regression analyses; no demographic or pathologic prognostic parameter predicted overall survival. In recent years, NAC in breast cancer has become a viable treatment option for patients with LABC. NAC is not commonly applied in Turkey. The response rate to NAC in Turkish breast cancer patients is encouragingly high. Broader efforts should be made to evaluate breast cancer patients preoperatively at tumor boards for proper treatment sequence.

Neoadjuvant chemotherapy followed by interval cytoreductive surgery in patients with unresectable, advanced stage epithelial ovarian cancer: a single centre experience.

BACKGROUND: Recent data has shown that the use of neoadjuvant chemotherapy (NAC) significantly reduces tumor burden before optimal cytoreductive surgery (CS) and is associated with an improved overall survival (OS). The aim of our study was to evaluate response to treatment and survival of patients with advanced epithelial ovarian cancer (EOC) who received NAC followed by interval cytoreductive surgery (ICS). METHODS: Fifty-two patients with advanced EOC treated with NAC followed by ICS were retrospectively analyzed. Response to NAC, progression-free survival (PFS), and OS were evaluated. By using univariate and multivariate analyses, the predicted survival rates by the factors were analyzed. RESULTS: Median age of patients at diagnosis were 62 years (range 33-77). The serous cell type was the most common histology (98%). The majority of patients (94%) received a combination therapy of paclitaxel and carboplatin. A median of four cycles of NAC was administered. At the end of NAC, the clinical complete response (CR) with normal clinical examination and normal serum CA 125 level was achieved in 40 patients (77%). Moreover, a radiological CR and a radiological partial response were obtained in 35 patients (67%) and in 16 patients (31%), respectively. ICS was considered standard in 45 (86%) patients. Optimal cytoreduction could be achieved in 43 of 52 patients (83%). After ICS, pathological CR was established in 15 of 52 patients (29%). At the median follow-up of 25 months (range 9-102), 2-year PFS and OS were 31 and 90%, respectively. The median PFS time was 13.3 months (SE 1.1, 95% CI 11-15) and the median OS time was 47.5 months (SE 5.8, 95% CI 36.1-59). The univariate analysis showed that optimal or suboptimal cytoreduction and perioperative blood transfusion were important prognostic factors on OS for patients who received NAC. Patients treated with optimal cytoreduction had significantly better median OS (52.5 months, 95% CI 45-60) than patients who underwent suboptimal cytoreduction (24.2 months, 95% CI 11.3-37) (P = 0.001). Furthermore, the cytoreduction type (optimal vs. suboptimal), surgical procedure (standard vs. non-standard), and perioperative blood transfusion were independent prognostic factors of OS by multivariate analysis (chi (2) = 9.28, P = 0.002, HR 0.28, 95% CI 0.003-0.37; chi (2) = 4.44, P = 0.035, HR 0.15, 95% CI 0.026-0.87; chi (2) = 9.24, P = 0.002, HR 0.75, 95% CI 0.014-0.79, respectively). CONCLUSIONS: This study demonstrates that NAC is associated with improved OS for patients with advanced EOC who received NAC followed by ICS. Additionally, our results showed that cytoreduction type, surgical procedure, and perioperative blood transfusion were independent prognostic indicators of OS for patients with advanced EOC who received NAC. Thereafter, NAC may be an alternative treatment to primary cytoreduction.

CD8+CD28- cells and CD4+CD25+ regulatory T cells in the peripheral blood of advanced stage lung cancer patients.

AIM: To evaluate the CD8+CD28- and CD4+CD25+ regulatory T (Treg) cells in addition to other some lymphocyte subgroups in peripheral blood of advanced stage lung cancer patients. METHODS: The study group (n = 28) comprised chemotherapy and radiotherapy naïve patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The control group (n = 22) consisted of age- and sex-matched healthy volunteers. Flow cytometry was used to count T cells, natural killer (NK) cells and CD4+CD25 Treg cells, and for CD8+ T cell subgroup analysis. Flow cytometry was performed and annexin V binding was used for apoptotic cell evaluation. RESULTS: In patient group, the percentage of CD8+CD28- cells among lymphocytes was elevated, and there was also an increase in the CD28-/CD28+ cell ratio among CD8 lymphocyte population. The distribution of CD8 cells was different in lung cancer patients when compared with the control group. The absolute count of CD4+CD25(bright) cells and the percentages of these cells among total lymphocytes were higher in the patient group. The Annexin V(+) cell percentages among CD8+CD28- and CD8+CD28+ lymphocytes were higher in the patient group than in the control group. No differences were found between the NSCLC and SCLC patients with respect to the hematological parameters and the distribution of lymphocyte subgroups. In NSCLC patients, the percentage of CD8+CD28- cells among the lymphocyte population was higher in patients with stage IV than those with stage III. CONCLUSION: These findings may reflect the possibility of tumor-induced immunosuppression and they should be complemented with further studies.

Myasthenia gravis and autoimmune Addison disease in a patient with thymoma.

The association of thymoma with myasthenia gravis has been well documented. However, the relationship between these two syndromes and Addison disease are very rarely encountered in clinical practice. We report on a 32-year-old man who underwent a resection for thymoma 48 months ago. The diagnosis of Addison disease was made followed by a diagnosis of myasthenia gravis on the basis of a high titer of acetylcholine receptor levels. The treatment of oral prednisolone 7.5 mg/day and oral prostigmine 180 mg/day was initiated. His symptoms and physical signs were improved after this treatment. To our knowledge, this is the fourth reported case of thymoma synchronously associated with myasthenia gravis and Addison disease.

Metastasis of lobular breast carcinoma to the uterus in a patient under anastrozole therapy.

BACKGROUND: Metastasis of extragenital neoplasms to the uterus are rarely encountered, and usually occur as a manifestation of advanced disease. Lobular carcinoma is the most common type of breast cancer that metastasizes to the uterus. CASE REPORT: We report on a 56-year-old woman who 3 years previously was diagnosed with invasive lobular carcinoma of the breast and was treated with surgery followed by chemotherapy and radiotherapy. While the patient was on adjuvant anastrozole therapy for 2 years, she complained of vaginal bleeding. Because of endometrial thickening and a uterine leiomyoma detected during abdominal ultrasonographic ex-amination, a total hysterectomy with bilateral salpingo-oophorectomy was performed. Histopathologic examination of the specimens revealed carcinoma infiltration of the myometrium, endometrium, cervix, uterine tube, and left ovary. Immunohistochemical staining of tumoral cells with pancytokeratin and gross cystic disease fluid protein (GCDFP-15) proved the diagnosis of metastatic lobular breast carcinoma to the uterus. CONCLUSION: To our knowledge, this is the second case of lobular breast carcinoma metastasized to the uterus under anastrozole therapy. In women with lobular breast cancer under adjuvant anastrozole therapy, who present with vaginal bleeding, uterine metastasis of lobular carcinoma should be considered in the differential diagnosis.

Peripheral blood gamma-delta T cells in advanced-stage cancer patients.

Gamma-delta T (gammadelta T) cells form a subgroup which has been reported to play a role in both natural and acquired immunity. Their levels have been found to increase in some tumour tissues. The aim of this study was to investigate the ratio of gammadelta T cells to all T cells in the peripheral blood of advanced-stage cancer patients; the level of gammadelta T cells expressing the Vdelta2-T-cell receptor (TCR) chain; NKG2D receptor expression; and apoptotic (Annexin-V) gammadelta T-cell levels. Twenty patients with advanced-stage cancer and 13 healthy controls were included. No statistical differences were found between control and patient groups in terms of the gammadelta T/total T-cell ratio (P=0.53), the Vgamma2-TCR expressing gammadelta T-cell ratio (P=0.19) or the Annexin-V ratio (P=0.48). However, NKG2D expression in gammadelta T cells was significantly different between the control and patient groups (P=0.014). In summary it was shown that the levels of NKG2D receptors, which are responsible for the cytolytic effect of gammadelta T cells, were lower in cancer patients than in healthy adults. However, no significant differences were observed in the other parameters studied between groups.

Breast cancer in association with thyroid disorders.

BACKGROUND: The relationship between breast cancer and thyroid diseases is controversial. Discrepant results have been reported in the literature. The incidences of autoimmune and nonautoimmune thyroid diseases were investigated in patients with breast cancer and age-matched control individuals without breast or thyroid disease. METHODS: Clinical and ultrasound evaluation of thyroid gland, determination of serum thyroid hormone and antibody levels, and fine-needle aspiration of thyroid gland were performed in 150 breast cancer patients and 100 control individuals. RESULTS: The mean values for anti-thyroid peroxidase antibodies were significantly higher in breast cancer patients than in control individuals (P = 0.030). The incidences of autoimmune and nonautoimmune thyroid diseases were higher in breast cancer patients than in control individuals (38% versus 17%, P = 0.001; 26% versus 9%, P = 0.001, respectively). CONCLUSION: Our results indicate an increased prevalence of autoimmune and nonautoimmune thyroid diseases in breast cancer patients.

Thrombotic thrombocytopenic purpura associated with ticlopidine.

Thrombotic thrombocytopenic purpura is a syndrome characterized by hemolytic anemia, thrombocytopenia, neurological symptoms, fever and renal dysfunction. Although the syndrome is usually associated with various infections, vasculitis and pregnancy, rarely can it be associated with certain neoplasms and drugs such as ticlopidine. A 63-year-old woman, who had undergone coronary angioplasty and had been started on ticlopidine, was admitted to our clinic with a history of vomiting, fatigue, hematuria and deterioration in her cognitive abilities. Thrombotic thrombocytopenic purpura was diagnosed on the basis of neurological changes, an increase in LDH, urea, creatinine, indirect bilirubin levels, anemia and peripheral smear findings. Treatment was initiated with daily plasmapheresis and complete clinical and laboratory recovery developed. The patient was discharged after 14 days.

Muscle metastasis as initial manifestation of epidermoid carcinoma of the lung.

Typical sites of squamous cell carcinoma of lung metastases include liver, brain, bones, pulmonary and adrenal glands. In advanced dissemination it can rarely involve the skeletal muscle. The patient in this case report was a 46-year-old man, with no significant medical history. He was admitted to hospital because of a large swelling on his left thigh. Investigations resulted in a diagnosis of primary squamous cell carcinoma of the lung. Biopsy of the left great adductor muscle produced similar pathology to that of the lung primary. This case report describes a skeletal muscle metastasis as the first sign of metastatic disease.

Acute myeloblastic leukemia achieving complete remission with amifostine alone.

Amifostine, a phosphorylated thiol-amine, is known as a cytoprotective agent especially for cisplatin containing chemotherapies. Apart from the cytoprotective role, Amifostine could also be used in the treatment of hematologic malignancies such as myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML), as a treatment option or for potentiating the effects of cytotoxic agents. We tried to use Amifostine in a patient with AML, which did not respond to conventional cytotoxic chemotherapy and aimed to publish the results. The patient was a 77-year-old male patient, he was diagnosed as AML by peripheral blood smear and bone marrow aspiration. Treatment commenced with low dose cytosine arabinoside (Ara-C) but the therapy should have ceased due to patient intolerance. The patient refused further therapy and he was offered to have Amifostine treatment. Amifostine was administered 200 mg/m2 three times a week, with ciprofloxacin, pentoxifyllin and dexamethasone. Dramatic response was obtained after 8 weeks of administration. Blast rate was reduced from 35 to 7% in bone marrow aspiration; pancytopenia was restored to normal levels. This remission was maintained through 8 more weeks. Amifostine treatment was restarted after he relapsed but this time he did not respond to the treatment and died of gastrointestinal bleeding on the 8th week of treatment.

A Case Report: Large Granular Cell Leukemia/Lymphoma (LGL).

We presented a 64-year-old male patient with T-large granular cell leukemia/lymphoma with an agressive clinical course. Large granular lymphocytes were noted on peripheral blood smear. The phenotyping of the cells was typical T-cell lineage [CD2 (+), CD3 (+), CD5 (+)]. Clonal rearrangement of the T-cell receptor gene (TCR) was demonstrated by DNA hybridization technique. Large granular cell leukemia/lymphoma is a distinct entity with spesific clinicobiological aspects. The clinical spectrum is wide and immunophenotyping and genotyping studies need to make a diagnosis.