Cardiotoxicity of radiation therapy in esophageal cancer.

With a development of radiotherapeutic techniques, availability of radiotherapy data on cardiotoxicity, and slowly improving esophageal cancer outcomes, an increasing emphasis is placed on the heart protection in radiation treated esophageal cancer patients. Radiation induced heart complications encompass mainly pericardial disease, cardiomyopathy, coronary artery atherosclerosis, valvular heart disease, and arrhythmias. The most frequent toxicity is pericardial effusion which is usually asymptomatic in the majority of patients. The use of modern radiotherapy techniques is expected to reduce the risk of cardiotoxicity, although this expectation has to be confirmed by clinical data.

The Time Between Chemoradiation and Surgery for Rectal Carcinoma Negatively Influences Mesorectal Excision Quality.

Total mesorectal excision quality (TMEq) is a prognostic factor associated with local recurrence in rectal adenocarcinoma. Neoadjuvant chemoradiotherapy (NCRT) reduces the risk of tumor recurrence, but may compromise TMEq. The time between NCRT and surgery (TTS) and how it influences TMEq and tumor control were evaluated. In prospective registry, 236 patients after NCRT and TME were analyzed. NCRT involved radiotherapy with 45 Gy to the pelvis, plus tumor boost dose 5.4 Gy with concurrent 5-fluorouracil infusion. NCRT was followed by TME after 9 weeks on average (median 9.4 ± SD 2.5). TMEq was parametrically analyzed by standard three-grade system. With median follow-up of 47.5 months, 3-year overall survival (OS) was 83.8%, disease-free survival (DFS) was 77.7%, and 6.4% was the rate of local recurrence (LR). TTS was not associated with OS, DFS, or LR. TMEq was found to be associated with LR in univariate analysis, but not in multivariate, where pathological tumor stage and resection margins remained dominant predictors. TMEq was negatively influenced by inferior location of the tumor, longer TTS, higher tumor and nodal stage, presence of tumor perforation, perineural invasion, and close/positive resection margins. Nonetheless, TTS remained a strong predictor of TMEq in multivariate analyses. TTS was proven to be an independent predictor of TMEq. With longer TTS, fewer complete TME with intact mesorectal plane were observed. However, TTS was not associated with survival deterioration or tumor recurrence. These were negatively influenced by other factors interfering with TMEq, especially by pathological tumor stage and resection margins.

Interactions Between Anti-Vegf Therapy and Antitumor Immunity as a Potential Therapeutic Strategy in Colorectal Cancer.

There is a growing corpus of evidence indicating that anti-VEGF therapy may normalize the abnormal tumor vasculature with the potential to re-program the tumor immune microenvironment to a more immunosupportive profile. Tumor vessel normalization increases tumor perfusion, and, consequently, oxygen and nutrient supply, and thus can be assumed to improve the general response to anticancer immunotherapy. The increased antitumor immunity responses seen following anti-VEGF therapy may also be associated with the inhibition of the immunosuppressive action deployed by VEGF on effector T cells. Bearing in mind the recent advances of combination immunotherapy, combinations of anti-VEGF therapy with immune checkpoint inhibitors now appear to represent an attractive strategy. Key to the successful implementation of a combination strategy for treating cancer is understanding the interaction of these two therapeutic interventions, particularly in regards to appropriate reprogramming of the tumor immune microenvironment to improve antitumor immunity.

Simulations of centriole of polarized centrosome as a monopole antenna in immune and viral synapses.

The immune synapse (IS) is a temporary interface between an antigen-presenting cell and an effector lymphocyte. Viral synapse is a molecularly organized cellular junction that is structurally similar to the IS. Primary cilium is considered as a functional homologue of the IS due to the morphological and functional similarities in architecture between both micotubule structures. It has been hypothesized that endogenous electromagnetic field in the cell is generated by a unique cooperating system between mitochondria and microtubules. We are extending this prior hypothesis of the endogenous electromagnetic field in the cell postulating that polarized centriole in immune and viral synapse could serve as a monopole antenna. This is an addition to our hypothesis that primary cilium could serve as a monopole antenna. We simulated the distribution of electric field of centriole of polarized centrosome as a monopole antenna in immune and viral synapse. Very weak electromagnetic field of polarized centriole of CD8+ T lymphocyte in IS can contribute to the transport of cytolytic granules into the attacked (cancer) cell. Analogically, very weak electromagnetic field of polarized centriole in viral synapse of infected CD4 cells can aid the transport of viruses (human immunodeficiency virus) to non-infected CD4 cells. We hypothesized that healthy organisms need these monopole antennas. If, during the neoplastic transformation, healthy cells lose monopole antennas in form of primary cilia, the IS aims to replace them by monopole antennas of polarized centrioles in IS to restore homeostasis.

The changes of tumour vascular endothelial growth factor expression after neoadjuvant chemoradiation in patients with rectal adenocarcinoma.

AIM OF THE STUDY: The aim was to examine the effects of neoadjuvant chemoradiotherapy on VEGF expression in patients with locally advanced rectal cancer. MATERIALS AND METHODS: A total of 53 patients with locally advanced rectal cancer were retrospectively studied. Neoadjuvant treatment comprised external beam radiation (50.4 Gy/28 fractions) with continuous infusion of 5-fluorouracil. Four to 6 weeks after the chemoradiotherapy, the patients underwent surgical resection. Immunohistochemistry was performed to assess VEGF expression in the pretreatment biopsies and in resected specimens. RESULTS: Resection with microscopic residual tumour (R1) was performed in two patients while in the remaining 51 patients radical resection with microscopically negative margins (R0) was possible. Downstaging after preoperative chemoradiotherapy was observed in 34 patients (64%). After chemoradiotherapy 24 patients (45%) had decreased VEGF expression, in 20 patients (38%) there was no change, and in two patients it was not possible to assess the dynamics of VEGF expression due to pathologic complete response after chemoradiotherapy. The five-year overall survival (OS) rate was 56% (95% CI: 43-70%). Although the median OS was 2.5 times shorter in patients who experienced decreased VEGF expression during therapy, this difference did not reach statistical significance. VEGF expression was not significant in Cox regression analysis or log-rank test. VEGF expression decreased after neoadjuvant chemoradiotherapy in most patients with rectal adenocarcinoma examined. This decrease was associated with a trend of inferior prognosis. CONCLUSIONS: VEGF expression decreased after neoadjuvant chemoradiotherapy in most patients examined. This decrease was associated with a trend of inferior prognosis.

Association of the combined parameters including the frequency of primary cilia, CD8+ tumor infiltrating lymphocytes and PD-1 expression with the outcome in intestinal cancer.

PURPOSE: Primary cilium (PC) is considered to be a functional homologue of the immune synapse. Microtubule structures, PC of cancer associated fibroblasts and immune synapses between cytotoxic CD8+ tumor infiltrating lymphocytes (TILs) and cancer cells, are regularly found in varying amounts in the microenvironment of solid tumors. The purpose of this study was to find out the potential association and combined prognostic significance of the frequency of PC, PD-1 and CD8+ TILs in patients with intestinal cancer. METHODS: The frequency of PC, programmed cell death protein-1 receptor (PD-1) expression and the frequency of stromal and intraepithelial CD8+TILs were evaluated in samples of colorectal adenocarcinoma (32 patiens) and small bowel cancer (8 patients). RESULTS: The median frequency of PC was 0.25%. The expression of PD1 was <5% in 34 patients, 5-25% in 5 patients and 26-50% in 1 patient. The frequency of stromal CD8+ TILs was negative in 3 patients, <25% in 26, 26-50% in 10 and >50% in 1 patient, respectively. Intraepithelial CD8+ TILs were not detectable in 14, <25% in 24 and 26-50% in 2 patients, respectively. Statistically, the frequency of PC and PD-1 positivity were significantly associated (p=0.004). An association between the PC frequency and intraepithelial CD8+ TILs was of borderline statistical significance (p=0.059). An index combining the frequency of PC and stromal CD8+ TILs, but not the combination of frequency of PC and intraepithelial CD8+ TILs, was of borderline prognostic significance (p=0.067). CONCLUSIONS: The present study provides the first data on the potential association and combined prognostic significance of frequency of PC, PD-1 and CD8+ TILs in patients with intestinal cancer.

Prognostic significance of the frequency of primary cilia in cells of small bowel and colorectal adenocarcinoma.

PURPOSE: The primary cilium is a solitary, sensory, immotile microtubule-based structure that arises from the centrosome and is projected from the surface of most human cell types. It has been hypothesized that primary cilia could serve as a tumor suppressor organelle. The objective of this pilot study was to investigate the presence and frequency of primary cilia in cells of small bowel and colorectal adenocarcinoma and to evaluate the prognostic significance of their frequency. METHODS: The presence of primary cilia in cells in samples of small bowel (8 patients) and colorectal adenocarcinoma (32 patients) was evaluated. The primary cilia of cells were immunofluorescently labeled using primary monoclonal anti-acetylated agr;-tubulin antibody and cell nuclei were labeled using DAPI. RESULTS: Primary cilia were identified in all examined specimens. The median frequency of primary cilia was 0.49% in cells of small bowel cancer and 0.22% in cells in colorectal cancer. Overall survival according to frequency of primary cilia in all intestinal adenocarcinomas was significantly longer in patients with higher frequency (≥ 0.187) than in patients with lower frequency of primary cilia (< 0.187) in univariate analysis (p=0.007) and also in the Cox proportional hazard model (p=0.032). Overall survival according to frequency of primary cilia in colorectal adenocarcinoma was significantly longer in patients with higher frequency (≥ 0.187) than in patients with lower frequency of primary cilia (< 0.187) (p=0.028). CONCLUSIONS: The present pilot study provides the first evidence of the prognostic significance of the frequency of primary cilia in small bowel and colorectal adenocarcinoma. Because of significantly higher median frequency of primary cilia in the rare small bowel adenocarcinoma than in the frequent colorectal adenocarcinoma (p<0.001), the results of this study support a potential role for primary cilia as a biomarker in these types of cancer.

Gastric and Colorectal Metastases of Lobular Breast Carcinoma: A Case Report.

BACKGROUND: Occurrence of gastric metastasis as the first symptom of breast carcinoma with a long period of latency before presentation of the primary breast carcinoma is rare. CASE REPORT: A patient with gastric metastasis as the first symptom of lobular breast carcinoma, treated by neoadjuvant preoperative chemoradiotherapy and total gastrectomy, with complete local control. Fourteen months after presentation of the gastric metastasis a primary lobular breast carcinoma was discovered, treated by radiotherapy, chemotherapy and hormonal treatment with complete local response. Twenty-three months after diagnosis of breast cancer multiple colorectal metastases from the breast cancer occurred, which were treated by chemotherapy and hormonal treatment. Eighty-six months after diagnosis of gastric metastasis the patient died due to progression of cancer. CONCLUSIONS: Metastases to gastrointestinal or gynaecological tracts are more likely in invasive lobular carcinoma than invasive ductal cancer. The pathologist should determine whether or not they check estrogen and progesterone receptor status not simply by signet ring cell morphology but also by consideration of clinic-pathological correlation of the patient, such as the presence of a past history of breast cancer, or the colorectal localization of poorly differentiated carcinoma, which may occur less frequently than in the stomach.