Serap Akyurek

Waldeyer's ring lymphomas: Treatment results and Prognostic factors

Optimal management of patients with localized Waldeyer’s ring (WR) lymphoma remains controversial due to the lack of randomized studies and heterogenous grouping of most reported series. In this retrospective study, we have evaluated the possible prognostic factors and treatment outcome of WR non-Hodgkin’s lymphoma. Between December 1993 and February 2000, 32 patients with WR lymphoma, stage I (11 patients) and stage II (21 patients) were treated. There were 17 male patients and 15 female patients with a median age of 47 years. The distribution among different anatomical sites were as follows: tonsils in 16 (50%), nasopharynx in 10 (31%), base of tongue in 6 (19%). According to Working Formulation, 10 had high-grade, 17 intermediate grade, 3 low-grade, and 2 had unclassified lymphomas. Combined chemotherapy and radiotherapy was the primary modality of therapy for intermediate or high-grade lymphoma. Radiotherapy alone was employed only in low-grade WR lymphomas. Chemotherapy was median 6 courses of CHOP (cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisolone) in 26 patients and CEOP (cyclophosphamide, doxorubicin, etoposide, and prednisone). Radiotherapy volume was involved field and the median dose was 40 Gy. Median follow-up is 40 months (ranged from 6–82 months). Overall survival and disease-free survival (DFS) rates at 3 years are 100% and 92%, respectively. Two patients developed recurrence, both salvaged with further chemotherapy. Only one patient died because of other reasons. International Prognostic Index score (≤2 vs. >2) is found to be an important prognostic factor for DFS. The other significant prognostic factors for DFS are performance status and serum levels of alkaline phosphatase and lactate dehydrogenase. Our results suggest that combined chemotherapy and involved field radiotherapy is appropriate treatment for stage I-II WR lymphoma. International Prognostic Index is the strongest predictor for DFS.

Possible Association between Nanobacteria and Malignant Microcalcifications in Breast Cancer

To the Editor: Breast calcifications are deposits of calcium that can be seen on a mammogram of the breast. There are two types: macrocalcifications and microcalcifications. Microcalcifications are one of the most common abnormalities detected on screening mammography for breast cancer. Microcalcifications are tiny specks of calcium in the breast. They may appear alone or in clusters. Calcifications associated with benign conditions are usually larger, fewer in number, widely dispersed, and round. However, less than 10% of microcalcifications suspect on mammography are associated with a malignancy on follow-up biopsy. Two distinct forms of microcalcification are found in breast disease. The more commonly recognized type is basophilic and nonbirefringent and consists predominantly of calcium phosphates (type II). The other type is a birefringent, colorless crystal that is composed of calcium oxalate (type I). Oxalate calcifications (type I) are generally associated with proliferating, but noninvasive diseases of the breast, whereas calcium phosphate in the crystalline form of hydroxyapatite is usually correlated to invasive malignant tumors (1). Data in the literature suggest that deposition of the bone-specific mineral hydroxyapatite results from an active biological process, the mechanism of which has not yet been elucidated. Nanobacteria have recently been described as novel microorganisms characterized by small size, slow growth, and the ability to form calcium phosphate crystals at neutral pH and at physiologic calcium and phosphate concentrations. They are gram negative, have a unique structure and apparent nucleic acid, and their growth in vitro is best inhibited by tetracycline. Nanobacteria have been discovered in human and cow blood and commercial cell culture serum, and have been hypothesized to mediate tissue calcifications (2). Nanobacteria have been isolated from demineralized kidney stone extracts (3). One study provides anatomic evidence that calcified human arterial and valvular tissue contain nanometer-size particles that share characteristics of nanoparticles recovered from geologic specimens, mammalian blood, and human kidney stones and were observed by transmission electron microscopy in a calcified human mitral valve. The anatomic and ultrastructural evidence of the existence of nanoparticles in calcified human tissue was also strengthened by immunohistochemical microscopy and in vitro culture of nanoparticles (4). Moreover, one interesting study showed that nanobacteria promote crystallization of psammoma bodies in ovarian cancer (5). Taken together, since malignant microcalcifications consist of mostly calcium phosphate in the crystalline form of hydroxyapatite, and nanobacteria has been shown to contribute to different benign and malignant calcifications in the form of calcium phosphate crystals, nanobacteria may also contribute to malignant calcifications in breast cancer. This proposal needs to be validated by microbiological analysis of microcalcified breast cancer tissue.

Tobacco Smoking and Breast Cancer

To the Editor: Tobacco smoke is carcinogenic for upper and lower respiratory tract organs and can also be involved in the carcinogenesis of many tumors of a nonrespiratory nature (i.e., tumors in the cervix, pancreas, and bladder). Furthermore its effects on human endocrine function are well established (1). As a result of the antiestrogenic effects of smoking, female smokers might experience earlier natural menopause, higher rates of infertility, accelerated bone loss, increased risk of osteoporotic fractures, and decreased risk of endometrial and breast cancers (2,3). Although recent analyses have suggested an increased active smoking risk among women with particularly long or prepregnancy exposure, most studies that have examined active smoking and breast cancer have concluded that there is little indication of increased risk (4). In contrast to the direct lung exposure to tobacco smoke, the mammary gland is indirectly exposed to metabolites of tobacco smoke. Breast cancer risk assessment is associated with a woman’s age at the beginning of her exposure to smoke. A woman who started smoking during childhood or premenopause may have an increased risk of breast cancer (5–7). One study reported that early exposure to tobacco smoke (before 17 years of age) can increase breast cancer risk approximately 20%, regardless of the duration of exposure to smoke, the age at first birth and menopause, and other potential confounders, such as alcohol consumption and obesity (8). It has been reported that postmenopausal women who were first exposed to tobacco smoke only after their first childbirth have the same risk of breast cancer as nonsmokers, regardless of the duration of exposure to smoke, presumably due to the antiestrogenic influences of smoking (9). Tobacco smoke produces diverse polycyclic aromatic hydrocarbons, including carcinogens such as benzopyrene, which is mutagenic for the p53 suppresser gene in humans, and 7,12-dimethylbenzanthracene, an inductor of mammary tumors in animals (10). Mutations of p53 tumor suppresser gene are found in 15–30% of breast cancer patients. Hematogenous dissemination of tobacco smoke carcinogens can produce carcinogenesis in the mammary ductal epithelium (11). Studies have shown that smoking is associated with p53 mutational status of breast tumors, and these mutations were similar to those observed in lung cancer (10,11). This provides further evidence that tobacco smoke exposure is associated with breast carcinogenesis. Therefore the occurrence of p53 mutations in breast tumors seems to be associated with tobacco smoke exposure at diagnosis (11). These results are consistent with p53 protein overexpression in current cigarette smokers (12). However, the exact mechanisms of the p53 mutations of breast tumors remain unclear, although those mutations may change the aggressiveness of the tumor. Moreover, smoking can lead to modifications in the lung, including increasing permeability and altering local immune function, making breast cancer cells more susceptible to lung metastasis (13). Epidemiologic studies have shown a higher rate of fatal breast cancer among smokers, which may be explained by an association between smoking and pulmonary metastatic disease (14). Scanlon et al. (15) showed that tobacco smoke is a risk factor for pulmonary metastases among women with breast cancer. Of particular interest is the finding that among women with invasive metastatic breast cancer to the lung, more of them are smokers (16). In summary, chronic exposure to cigarette smoke can be a risk factor for breast cancer, at least in premenopausal women, and can induce mutations such as the p53 mutation in breast cancer cells. On the other hand, such mutations may change the aggressiveness of the tumor. Furthermore, the same exposure can cause changes in the microvasculature and host organ, transforming the lung into a susceptible organ for invasion and growth of breast cancer cells.

Evaluation of the Radiation Pneumonia Development Risk in Lung Cancer Cases

BACKGROUND Concurrent chemo-radiotherapy is the recommended standard treatment modality for patients with locally advanced lung cancer. The purpose of three-dimensional conformal radiotherapy (3DCRT) is to minimize normal tissue damage while a high dose can be delivered to the tumor. The most common dose limiting side effect of thoracic RT is radiation pneumonia (RP). In this study we evaluated the relationship between dose-volume histogram parameters and radiation pneumonitis. This study targeted prediction of the possible development of RP and evaluation of the relationship between dose-volume histogram (DVH) parameters and RP in patients undergoing 3DCRT. MATERIALS AND METHODS DVHs of 41 lung cancer patients treated with 3DCRT were evaluated with respect to the development of grade ≥ 2 RP by excluding gross tumor volume (GTV) and planned target volume (PTV) from total (TL) and ipsilateral (IPSI) lung volume. RESULTS Were admitted statistically significant for p<0.05. CONCLUSIONS The cut-off values for V5, V13, V20, V30, V45 and the mean dose of TL-GTV; and V13, V20,V30 and the mean dose of TL-PTV were statistically significant for the development of Grade ≥ 2 RP. No statistically significant results related to the development of Grade ≥ 2 RP were observed for the ipsilateral lung and the evaluation of PTV volume. A controlled and careful evaluation of the dose-volume histograms is important to assess Grade ≥ 2 RP development of the lung cancer patients treated with concurrent chemo-radiotherapy. In the light of the obtained data it can be said that RP development may be avoided by the proper analysis of the dose volume histograms and the application of optimal treatment plans.

The effect of tianeptine in the prevention of radiation-induced neurocognitive impairment

Radiation-induced neurocognitive impairment is an undesirable radiation-induced toxicity and a common health problem in patients with primary or metastatic brain tumor. It greatly impairs quality of life for long-term brain tumor survivors. Hippocampus is the most important brain structure for neurocognitive functions. It has been shown that radiation affects the hippocampal neurogenesis due to either induce the apoptosis or reduce the precursor cell proliferation in the hippocampus. Radiation-induced microglial inflammatory response is also negative regulator of neurogenesis. Tianeptine is a clinically effective antidepressant that induces neurogenesis. It has also been shown that tianeptine is able to reduce apoptosis and cytoprotective against the effects of proinflammatory cytokines in the hippocampus. Given the putative role of impaired hippocampal neurogenesis in radiation-induced neurocognitive impairment we think that tianeptine can be effective for preventing radiation-induced neurocognitive impairment by increasing hippocampal neurogenesis.

Angiotensin 1–7 and risk for breast cancer recurrence

We read with great interest the article by Rodgers et al. [3]. In their phase I/II dose escalation study, they tried to determine the safety and efficacy of Angiotensin 1–7 in patients with breast cancer. Their data showed that Angiotensin 1–7 might be beneficial in attenuating multilineage cytopenias following chemotherapy at a dose of 100 lg/kg per day. Although Angiotensin 1–7 is a hematopoietic agent that stimulates the proliferation of multipotential and differentiated progenitor cells in cultured bone marrow and human cord blood, Angiotensin-II, analog of Angiotensin 1–7 has a wide spectrum of target tissues, including breast epithelial cells. It acts as a growth factor both in normal and cancer epithelial cells and promotes angiogenesis [2, 4]. The presence of undetected micrometastases, isseminated before or around the time women receive local treatment for ‘early’ breast cancer, is assumed to be the reason why many subsequently develop overt distant metastases ultimately causing death. Adjuvant chemotherapy can reduce recurrence rates and improve survival for some women [1]. Taken all together, since Angiotensin has a stimulatory effect on the growth of breast cancer cells, giving Angiotensin 1–7 for attenuation of multilineage cytopenias following chemotherapy might additionally increase angiogenesis around the micrometastatic cells and excite them to proliferate as well. Therefore, use of Angiotensin 1–7 as a growth factor for hematopoitic system might be cautioned. We believe that further studies are needed to confirm its effects on long-term survival of breast cancer patients.

Overcoming trastuzumab resistance with nordihydroguaiaretic acid

We congratulate Youngren and his colleagues for their fascinating study showing that nordihydroguaiaretic acid (NDGA) inhibits the IGF)1 and c-erbB2/HER2/ neu receptors and suppresses growth in breast cancer cells [1]. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody, which targets an epitope in the extracellular domain of the HER2 protein. Preclinical models demonstrated that this antibody has significant anti-tumor activity as a single agent and has synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancer that overexpress HER2 have shown that trastuzumab has clinical activity when used as first-, secondor third-line monotherapy, and improves survival when used as first-line therapy in combination with chemotherapy [2]. Unfortunately 30–40% of HER2overexpressing cancer cells respond to treatment with trastuzumab, and the clinical benefit of the drug is limited by the fact that most cancers become resistant to trastuzumab therapy in less than 12 months [3]. Mechanism of resistance to trastuzumab therapy includes overexpression of the insulin-like growth factor receptor (IGF)1R), downregulation of p27kip1 and loss of PTEN [4]. Moreover, Lu et al. [3,5] showed that in breast cancer cell models that overexpress HER)2, an increased level of IGF-IR signaling seems to interfere with the action of trastuzumab by reducing p27 (Kip1) protein level by increased degradation. Therefore, use of NDGA alone or combination with trastuzumab may prevent or delay development of resistance to trastuzumab in breast cancer cells. Further in vitro and in vivo studies are warranted to support this proposal.

Treatment outcome and prognostic factors for adult patients with medulloblastoma: The Rare Cancer Network (RCN) experience

BACKGROUND AND PURPOSE The optimal treatment for adults with newly diagnosed medulloblastoma (MB) has not been defined. We report a large series of cases from the Rare Cancer Network. MATERIAL AND METHODS Thirteen institutions enrolled 206 MB patients who underwent postoperative radiotherapy (RT) between 1976 and 2014. Log-rank univariate and Cox-modeled multivariate analyses were used to analyze data collected. RESULTS Median patient age was 29 years; follow-up was 31 months. All patients had the tumor resected; surgery was complete in 140 (68%) patients. Postoperative RT was given in 202 (98%) patients, and 94% received craniospinal irradiation (CSI) and, usually, a posterior fossa boost. Ninety-eight (48%) patients had chemotherapy, mostly cisplatin and vincristine-based. The 10-year local control, overall survival, and disease-free survival rates were 46%, 51%, and 38%, respectively. In multivariate analyses, Karnofsky Performance Status (KPS) ≥80 and CSI were significant for disease-free and overall survival (P ≤ .04 for all); receiving chemotherapy and KPS ≥80 correlated with better local-control rates. CONCLUSIONS Patients with high KPS who received CSI had better rates of disease-free and overall survival. Chemotherapy was associated with better local control. These results may serve as a benchmark for future studies designed to improve outcomes for adults with medulloblastoma.

Comment on “Serum human epididymis protein 4 is associated with the treatment response of concurrent chemo-radiotherapy and prognosis in patients with locally advanced non-small cell lung cancer” by Lan WG et al.

We read the above interesting article by Dr. Lan et al. [1]. The authors assessed the role of human epididymis protein 4 (HE4) in the diagnosis and prognosis of patients with locally advanced non-small cell lung cancer (LA-NSCLC) who underwent concurrent chemo-radiotherapy. HE4 serum levels were obtained from 218 patients with the diagnosis of LA-NSCLC and control group before the treatment. HE4 was measured by enzyme-linked immunosorbent assay (ELISA) with immunoassay kit. Their results suggested that the serum patients with high HE4 serum levels had shorter relapse-free survival (RFS) and overall survival (OS) and HE4 level can discriminate the responders. They concluded that serum HE4 levels may be a useful prognostic biomarker for LA-NSCLC patient receiving concurrent chemo-radiotherapy. After the approval as a novel serum biomarker for early diagnosis and monitoring of ovarian cancer by Food and Drug Administration (FDA), the HE4 is thought as one of the most promising new biomarker [2]. HE4 which is a WAP 4-disulphide core domain 2 (WFDC2) gene products is a family of protease inhibitors and probably has a role in innate immunity and is over-expressed in both serum and tumoral tissues of many patients with the diagnosis of cancer [2, 3]. There are growing data about the both diagnostic and prognostic value of HE4 in different cancer subtypes. Therefore, the authors touched on a current topic. We have couple of concerns regarding this article. First, some reports suggested that HE4 concentrations increased with the age and smoking index [4]. In addition, the concentration of HE4 was changed when there is an alteration in renal function particularly in premenopausal women [5]. Therefore, we wonder if the authors performed a subgroup analysis with respect to the age, smoking status, and renal function of the patients. In addition, the authors evaluated the serum HE4 levels only at enrollment, why did not they reevaluate the serum HE4 levels after treatment? The serum level of HE4 after the chemo-radiotherapy might have given an additional idea about the prognosis. Moreover, the authors could compare the pre-treatment and post-treatment values of HE4. Finally, the higher levels of serum HE4 levels associated with shorter RFS and OS according to the relevant data as well as the result of this valuable study; however, the authors concluded as ‘‘our data show that the patients’ with higher HE4 level tend to have a higher response rate to chemo-radiotherapy and had a better prognosis indicated by RFS and OS’’ at the end of the introduction part. We wonder how the authors interpret this relation. We consider that the authors’ response to the above comments would clarify their interesting and valuable work.

Comparison of 2-Dimensional and 3-Dimensional Conformal Treatment Plans in Gastric Cancer Radiotherapy

BACKGROUND Postoperative chemoradiotherapy is accepted as standard treatment for stage IB-IV, M0 gastric cancer. Radiotherapy (RT) planning of gastric cancer is important because of the low radiation tolerance of surrounding critical organs. The purpose of this study was to compare the dosimetric aspects of 2-dimensional (2D) and 3-dimensional (3D) treatment plans, with the twin aims of evaluating the adequacy of 2D planning fields on coverage of planning target volume (PTV) and 3D conformal plans for both covering PTV and reducing the normal tissue doses. MATERIALS AND METHODS Thirty-six patients with stage II-IV gastric adenocarcinoma were treated with adjuvant chemoradiotherapy using 3DRT. For each patient, a second 2D treatment plan was generated. The two techniques were compared for target volume coverage and dose to normal tissues using dose volume histogram (DVH) analysis. RESULTS 3DRT provides more adequate coverage of the target volume. Comparative DVHs for the left kidney and spinal cord demonstrate lower radiation doses with the 3D technique. CONCLUSIONS 3DRT produced better dose distributions and reduced radiation doses to left kidney and spinal cord compared to the 2D technique. For this reason it can be predicted that 3DRT will result in better tumor control and less normal tissue complications.