Wojciech Zegarski

Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study

BACKGROUND Improvements in local control are required when using preoperative chemoradiation for cT4 or advanced cT3 rectal cancer. There is therefore a need to explore more effective schedules. PATIENTS AND METHODS Patients with fixed cT3 or cT4 cancer were randomized either to 5 × 5 Gy and three cycles of FOLFOX4 (group A) or to 50.4 Gy in 28 fractions combined with two 5-day cycles of bolus 5-Fu 325 mg/m(2)/day and leucovorin 20 mg/m(2)/day during the first and fifth week of irradiation along with five infusions of oxaliplatin 50 mg/m(2) once weekly (group B). The protocol was amended in 2012 to allow oxaliplatin to be then foregone in both groups. RESULTS Of 541 entered patients, 515 were eligible for analysis; 261 in group A and 254 in group B. Preoperative treatment acute toxicity was lower in group A than group B, P = 0.006; any toxicity being, respectively, 75% versus 83%, grade III-IV 23% versus 21% and toxic deaths 1% versus 3%. R0 resection rates (primary end point) and pathological complete response rates in groups A and B were, respectively, 77% versus 71%, P = 0.07, and 16% versus 12%, P = 0.17. The median follow-up was 35 months. At 3 years, the rates of overall survival and disease-free survival in groups A and B were, respectively, 73% versus 65%, P = 0.046, and 53% versus 52%, P = 0.85, together with the cumulative incidence of local failure and distant metastases being, respectively, 22% versus 21%, P = 0.82, and 30% versus 27%, P = 0.26. Postoperative and late complications rates in group A and group B were, respectively, 29% versus 25%, P = 0.18, and 20% versus 22%, P = 0.54. CONCLUSIONS No differences were observed in local efficacy between 5 × 5 Gy with consolidation chemotherapy and long-course chemoradiation. Nevertheless, an improved overall survival and lower acute toxicity favours the 5 × 5 Gy schedule with consolidation chemotherapy. CLINICAL TRIAL NUMBER The trial is registered as ClinicalTrials.gov number NCT00833131.

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression.

Breast cancer is a major cause of morbidity and mortality in women and its metastatic spread is the principal reason behind the fatal outcome. Metastasis-related research of breast cancer is however underdeveloped when compared with the abundant literature on primary tumors. We applied an unexplored approach comparing at high resolution the genomic profiles of primary tumors and synchronous axillary lymph node metastases from 13 patients with breast cancer. Overall, primary tumors displayed 20% higher number of aberrations than metastases. In all but two patients, we detected in total 157 statistically significant differences between primary lesions and matched metastases. We further observed differences that can be linked to metastatic disease and there was also an overlapping pattern of changes between different patients. Many of the differences described here have been previously linked to poor patient survival, suggesting that this is a viable approach toward finding biomarkers for disease progression and definition of new targets useful for development of anticancer drugs. Frequent genetic differences between primary tumors and metastases in breast cancer also question, at least to some extent, the role of primary tumors as a surrogate subject of study for the systemic disease.

Microarray‐based survey of CpG islands identifies concurrent hyper‐ and hypomethylation patterns in tissues derived from patients with breast cancer

Maintenance of CpG island methylation in the genome is crucial for cellular homeostasis and this balance is disrupted in cancer. Our rationale was to compare the methylation of CpG islands in tissues (tumor, healthy breast and blood) from patients with breast cancer. We studied 72 genes in 103 samples using microarray hybridization and bisulfite sequencing. We observed tumor specific hyper‐ or hypomethylation of five genes; COL9A1, MT1A, MT1J, HOXA5 and FLJ45983. A general drop of methylation in COL9A1 was apparent in tumors, when compared with blood and healthy breast tissue. Furthermore, one tumor displayed a complete loss of methylation of all five genes, suggesting overall impairment of methylation. The downstream, evolutionary conserved island of HOXA5 showed hypomethylation in 18 tumors and complete methylation in others. This CpG island also displayed a semimethylated state in the majority of normal breast samples, when compared to complete methylation in blood. Distinct methylation patterns were further seen in MT1J and MT1A, belonging to the metallothionein gene family. The CpG islands of these genes are spaced by 2 kb, which shows selective methylation of two structurally and functionally related genes. The promoters of FLJ45983 and MT1A were methylated above 25% in 18 primary and metastatic tumors. Concurrently, there was also >10% methylation of healthy breast tissue in 11 and 5 samples, respectively. This suggests that the methylation process for the latter two genes takes place already in normal breast cells. Our results also point to a considerable heterogeneity of epigenetic disturbance in breast cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045‐2257/suppmat.

Neoadjuvant treatment for unresectable rectal cancer: an interim analysis of a multicentre randomized study.

PURPOSE To present an interim analysis of the trial comparing two neoadjuvant therapies for unresectable rectal cancer. METHODS Patients with fixed cT3 or cT4 or locally recurrent rectal cancer without distant metastases were randomized to either 5 × 5 Gy and 3 courses of FOLFOX4 (schedule I) or 50.4 Gy delivered in 28 fractions given simultaneously with 5-Fu, leucovorin and oxaliplatin (schedule II). Surgery in both groups was performed 12 weeks after the beginning of radiation and 6 weeks after neoadjuvant treatment. RESULTS 49 patients were treated according to schedule I and 48 according to schedule II. Grade III+ acute toxicity was observed in 26% of patients in group I and in 25% in group II. There were two toxic deaths, both in group II. The microscopically radical resection (primary endpoint) rate was 73% in group I and 71% in group II. Overall and severe postoperative complications were recorded in 27% and 9% of patients vs. 16% and 7%, respectively. Pathological complete response was observed in 21% of the patients in group I and in 9% in group II. CONCLUSIONS The interim analysis revealed no major differences in acute toxicity and local efficacy between the two evaluated strategies.

Collaborating with the Enemy: Function of Macrophages in the Development of Neoplastic Disease

Due to the profile of released mediators (such as cytokines, chemokines, growth factors, etc.), neoplastic cells modulate the activity of immune system, directly affecting its components both locally and peripherally. This is reflected by the limited antineoplastic activity of the immune system (immunosuppressive effect), induction of tolerance to neoplastic antigens, and the promotion of processes associated with the proliferation of neoplastic tissue. Most of these responses are macrophages dependent, since these cells show proangiogenic properties, attenuate the adaptive response (anergization of naïve T lymphocytes, induction of Treg cell formation, polarization of immune response towards Th2, etc.), and support invasion and metastases formation. Tumor-associated macrophages (TAMs), a predominant component of leukocytic infiltrate, “cooperate” with the neoplastic tissue, leading to the intensified proliferation and the immune escape of the latter. This paper characterizes the function of macrophages in the development of neoplastic disease.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

(18)F-FLT PET/CT in Patients with Gastric Carcinoma.

The aim of the study was to evaluate the usefulness of 18F-FLT PET/CT in the detection and differentiation of gastric cancers (GC). 104 consecutive patients (57 cases of adenocarcinoma tubulare (G2 and G3), 17 cases of mucinous adenocarcinoma, 6 cases of undifferentiated carcinoma, 14 cases of adenocarcinoma partim mucocellulare, and 10 cases of end stage gastric cancer) with newly diagnosed advanced gastric cancer were examined with FLT PET/CT. For quantitative and comparative analyses, the maximal standardized uptake value (SUVmax) was calculated for both the tumors and noninvaded gastric wall. Results. There were found, in the group of adenocarcinoma tubulare, SUVmax 1.5–23.1 (7.46 ± 4.57), in mucinous adenocarcinoma, SUVmax 2.3–10.3 (5.5 ± 2.4), in undifferentiated carcinoma, SUVmax 3.1–13.6 (7.28 ± 3.25), in adenocarcinoma partim mucocellulare, SUVmax 2–25.3 (7.7 ± 6.99), and, in normal gastric wall, SUVmax 1.01–2.55 (1.84 ± 0.35). For the level of 2.6 cut-off value between the normal wall and neoplasm FLT uptake from ROC analysis, all but five gastric cancers showed higher accumulation of FLT than noninfiltrated mucosa. Conclusion. Gastric cancer presents higher accumulation of 18F-FLT than normal, distended gastric mucosa. Significantly higher accumulation was shown in cancers better differentiated and with higher cellular density.

Is mTOR inhibitor good enough for treatment all tumors in TSC patients

Tuberous sclerosis complex (TSC) is an autosomal dominant and multi-system genetic disorder in humans. TSC affects around 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders. TSC is caused by defects or mutations in two genes, TSC1 and TSC2. Loss of TSC1/TSC2 leads to dysregulation of mTOR, resulting in aberrant cell differentiation and development, and abnormal enlargement of cells. TSC is characterized by the development of benign and/or malignant tumors in several organs including renal/liver angiomyolipomas, facial angiofibroma, lymphangiomyomatosis, cardiac rhabdomyomas, retinal astrocytic, renal cell carcinoma, and brain subependymal giant cell astrocytomas (SEGA). In addition, TSC disease causes disabling neurologic disorders, including epilepsy, mental retardation and autism. Particularly problematic are the development of renal angiomyolipomas, which tend to be larger, bilateral, multifocal and present at a younger age compared with sporadic forms. In addition, SEGA block the flow of fluid within the brain, causing a buildup of fluid and pressure that leads to blurred vision and seizures. In the current review, we describe the pathology of TSC disease in key organs and summarize the use of mTOR inhibitors to treat tumors in TSC patients.

Evaluation of FLT-PET/CT usefulness in diagnosis and qualification for surgical treatment of gastric cancer

Aim of the study Evaluation of FLT/PET/ CT usefulness in diagnosis and qualification for surgical treatment of gastric cancer. Material and methods The FLT/PET/CT test was carried out in a group of 50 gastric cancer patients. Based on the test result, a decision followed about the therapeutic procedure to be applied. A comparison was made with regards to the consistency of the cancer growth advancement degree evaluation in the initial preoperative FLT/PET/CT test against the evaluation of postoperative degree of cancer advancement in histopathology. Results In the group of 50 diagnosed patients a surgical treatment was used for 37 patients. 21 resections were performed out of which 19 operations were radical In the group of 16 non-resective operations 2 post-laparotomic patients were selected for inductive treatment. In the group of 13 patients who did not undergo any surgery, 10 were directed to palliative care and 3 for inductive treatment. In the group of 50 patients, the applied FLT-PET/CT test confirmed presence of primary tumor in 49 patients. The presence of increased uptake of FLT in the local lymph nodes during the preoperative FLT-PET/CT test was confirmed in 22 cases. In 14 patients with FLT-PET/Ct N(+) with the M(–) feature resection surgery was performed. The increased uptake of FLT in localizing metastases (nodal and non-nodal) FLT-PET/CT (M+) was detected in 22 patients. The presence of nodal metastases in the postoperative histopathology examination (hpN+) was detected in 14 cases. In these cases preoperative FLT-PET/CT test proved the N(+) feature in 11 patients. The result FLT-PET/CT N(–) was truly negative in 2 patients, and false negative in 1 patient. In the group of 7 operated hpN(–) patients, in 3 patients a preoperative result FLT-PET/ CT N(+) (false positive result) was obtained. The consistency (positive) of nodal metastases identification in FLT-PET/CT as compared to post-surgical histopathology examination scored 11/15, which equals 73.3%. In the group of patients in whom resection surgery was performed, 4 false negative results were obtained [hp(N+), FLT-PET/CT (N–)] and 3 false positive results [hp(N–), FLT-PET/CT N(+)]. Conclusions The initial test results indicate that FLT-PET/CT is an effective method in evaluating the primary tumor and the regional lymph nodes and is useful and beneficial in the diagnosis and further treatment evaluation of gastric cancer. FLT-PET/CT examination facilitates making proper therapeutic decisions – it allows the number of unnecessary laparotomies to be lowered.

The Assessment of the Magnitude of Frontal Plane Postural Changes in Breast Cancer Patients After Breast-Conserving Therapy or Mastectomy – Follow-up Results 1 Year After the Surgical Procedure

Breast cancer is the most common malignancy in Polish women. Management of breast cancer includes surgical treatment as well as adjuvant chemotherapy, radiotherapy, hormonal therapy, and combination regimens. One of the adverse consequences of oncological management of breast cancer may involve changes in frontal plane body posture. The objective of the study was to assess the frontal plane body posture changes in women treated for breast cancer. A prospective study including 101 of female breast cancer patients subjected to surgical treatment in the period from October 2011 to October 2012 (mastectomy was performed in 51 cases while breast conserving therapy was administered in the remaining 50 cases). The body posture in the frontal plane was assessed using the computer-assisted postural assessment system with Moiré fringe analysis. No statistically significant differences were observed in pre-operational postural parameters of interest. Exam II revealed highly significant differences in SLA values; results suggesting more pronounced dysfunction were observed in the MAS group. Exam III revealed highly significant differences in PIA, SH, SD and SLA values; results suggesting more pronounced dysfunction were observed in the MAS group. Undesirable postural changes occur both in women who were treated with radical mastectomy and in those who underwent breast-conserving surgery; breast-conserving surgery is associated with decreased severity in postural abnormalities;