Does chronomodulated radiotherapy improve pathological response in locally advanced rectal cancer?

The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and tumour distance from the anal verge. Females were less likely to exhibit several of the above responses. Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging. A prospective study in chronomodulated radiotherapy in this disease is warranted.     

Could preoperative short-course radiotherapy be the treatment of choice for localized advanced rectal carcinoma?

Short-course preoperative radiotherapy (RT) is widely used in northern Europe for locally advanced resectable rectal cancer, but its role in the era of advanced imaging techniques is uncertain. Here, we reviewed articles and abstracts on SCRT published from 1974 through 2013 with the goal of identifying patients who might be best suited for short-course RT. We included relevant articles comparing surgery with or without preoperative radiation published before and after the advent of total mesorectal excision. We also analyzed two randomized trials directly comparing short-course RT with conventionally fractionated chemoradiation (the Polish Colorectal Study Group and the Trans-Tasman Radiation Oncology Group) that compared short-course RT with conventional chemoradiotherapy. We conclude from our review that short-course RT can be generally applied for operable rectal cancer and produces high rates of pelvic control with acceptable toxicity; it reduces local recurrence rates but does not increase overall survival. SCRT seems to be best used for tumors considered “low risk,” i.e., those that are >5 cm from the anal margin, without circumferential margin involvement, and involvement of fewer than 4 lymph nodes. Whether sequential chemotherapy can further improve outcomes remains to be seen, as does the best time for surgery (immediately or 6–8 weeks after RT). We further recommend that selection of patients for short-course RT should be based on findings from magnetic resonance imaging or transrectal ultrasonography.     

Application of IMRT in adjuvant treatment of soft tissue sarcomas of the thigh—Preliminary results

Background

Fracture of the femur is the most frequent late complication in patients with soft tissue sarcomas (STS) who receive external beam radiotherapy after limb-sparing surgery.

Aim

To reduce the risk of bone fracture following radiotherapy of STS of the thigh, we minimized the dose to the femur and to surrounding normal tissues by applying intensity modulated radiation therapy (IMRT). We report preliminary results of post-surgery IMRT of the thigh in patients with STS in this extremity.

Materials and methods

10 adult patients undergoing post-operative radiotherapy of STS of the thigh were treated using IMRT. Clinical IMRT plans with simultaneous integrated boost (SIB) and 3-phase three-dimensional conformal radiotherapy (3D-CRT) were designed to adequately treat the planning target volume and to spare the femur to the largest extent possible. Dose distributions and dose-volume histograms were compared.

Results

For either technique, a comparable target coverage was achieved; however, target volume was better covered and critical structures were better spared in IMRT plans. Mean and maximum doses to OAR structures were also significantly reduced in the IMRT plans. On average, the mean dose to the femur in 3D-CRT plans was about two times higher than that in IMRT plans.

Conclusion

Compared with 3D-CRT, the application of IMRT improves the dose distribution within the concave target volumes and reduces dose to the OAR structures without compromising target coverage.     

Improving results of the surgical treatment of rectal cancer in the Surgical Department of County Hospital, Szekszárd

The authors present that 247 elective rectal operations were performed between 1 January, 1996 and 31 December, 2001 in their surgical department. The examined 6 years were divided into a 4-year and a 2-year period. 148 operations were performed in the first and 99 in the second period. Beside personal changes, methodical and technical modifications were introduced in the second period. Distribution of age and sex was similar, and the groups were comparable. The early postoperative mortality rate decreased from 9% to 4% during the examined time. Due to the double stapling technique, the rate of anterior rectal resections has increased from 40% to 69%, and the rate of abdomino-perineal rectal extirpation has decreased from 43% to 23%. Considerable difference was found in the rate of palliative stoma-creation operations, since the 16% decreased to 8% in the second period, so the quality of life of patients has improved. The operative time, the hospital stay of the patients and the rate of operations with blood transfusion decreased. The different types of postoperative infections decreased due to the new methods.     

Diagnostic value of intraoperative histopathological examination of the sentinel nodes in breast cancer and skin melanoma—Preliminary results of single centre retrospective study

Objective

Intraoperative histopatological examination of the sentinel nodes enables selection of patients who need dissection of the regional lymphatic system during the same operation. The aim of this study is to evaluate the diagnostic value of intraoperative histopathological examination of the sentinel nodes in breast cancer and skin melanoma. Intraoperative histopathology of the sentinel nodes as a diagnostic method is used in patients with melanoma and breast cancer. Recent studies have proved it to be an effective method for evaluating the nodes in the final histopathology. Intraoperative histopathological examination of the sentinel nodes is not performed routinely and there is no clear position on this issue. In this paper we try to prove that intraoperative test gives patients the simultaneous benefits of removal of regional lymph nodes metastases and earlier initiation of adjuvant therapy.

Methods

The study comprises 137 patients with breast cancer and 35 patients with malignant skin melanoma. Sentinel nodes were intraoperatively sectioned and examined by means of the imprint method and frozen section evaluation. The patients with positive sentinel nodes underwent immediate dissection of regional lymph nodes. Those with negative sentinel nodes diagnosed in the intraoperative examination, but positive in final pathologic results, underwent subsequent dissection of regional lymph nodes.

Results

60 sentinel lymph nodes were found in 35 patients with skin melanoma. In 3 patients, 3 sentinel lymph nodes were false negative in the intraoperative histopathological examination. No false positive sentinel lymph nodes were found. 249 sentinel lymph nodes were found in the intraoperative histopathological examination in 137 patients with breast cancer. There were no false positive sentinel nodes, but there were 7 false negative sentinel nodes. In this study, only 5 (3.6%) patients with breast cancer and 3 (8.5%) patients with skin melanoma required another regional operation.

Conclusion

The method of intraoperative histopathological evaluation of the sentinel nodes enables identification of metastases in these lymph nodes and gives a possibility to carry out a one-step regional lymphadenectomy and start the adjuvant therapy earlier.     

Morbidity dynamics in proton–photon or photon radiation therapy for locally advanced prostate cancer

Aim

This study evaluated the frequency and long-term dynamics of early and late post irradiation damage after proton–photon or photon therapy for locally advanced prostate cancer.

Continuous Multimodality Monitoring in Children after Traumatic Brain Injury—Preliminary Experience

Introduction

Multimodality monitoring is regularly employed in adult traumatic brain injury (TBI) patients where it provides physiologic and therapeutic insight into this heterogeneous condition. Pediatric studies are less frequent.

Methods

An analysis of data collected prospectively from 12 pediatric TBI patients admitted to Addenbrooke’s Hospital, Pediatric Intensive Care Unit (PICU) between August 2012 and December 2014 was performed. Patients’ intracranial pressure (ICP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were monitored continuously using brain monitoring software ICM+^®,) Pressure reactivity index (PRx) and ‘Optimal CPP’ (CPPopt) were calculated. Patient outcome was dichotomized into survivors and non-survivors.

Results

At 6 months 8/12 (66%) of the cohort survived the TBI. The median (±IQR) ICP was significantly lower in survivors 13.1±3.2 mm Hg compared to non-survivors 21.6±42.9 mm Hg (p = 0.003). The median time spent with ICP over 20 mm Hg was lower in survivors (9.7+9.8% vs 60.5+67.4% in non-survivors; p = 0.003). Although there was no evidence that CPP was different between survival groups, the time spent with a CPP close (within 10 mm Hg) to the optimal CPP was significantly longer in survivors (90.7±12.6%) compared with non-survivors (70.6±21.8%; p = 0.02). PRx provided significant outcome separation with median PRx in survivors being 0.02±0.19 compared to 0.39±0.62 in non-survivors (p = 0.02).

Conclusion

Our observations provide evidence that multi-modality monitoring may be useful in pediatric TBI with ICP, deviation of CPP from CPPopt, and PRx correlating with patient outcome.     

Application potential of chicken DNA chip in domestic pigeon species – Preliminary results

Introducing the SNP technology to pigeon breeding will enhance the competitiveness of a sector that produces one of the healthiest and best quality meats. The present study aimed to test the applicability of the Illumina Chicken_50K_CobbCons array on 24 domestic pigeon individuals from the Mirthys hybrids and Racing pigeon breeds. A total of 53,313 SNPs were genotyped. Principal component analysis shows a significant overlap between the two groups. The chip performed poorly in this data set, with a call rate per sample of 0.474 (49%). The low call rate was likely due to an increase in the evolutionary distance. A total of 356 SNPs were retained after a relatively strict quality control. We have demonstrated that it is technically feasible to use a chicken microarray chip on pigeon samples. Presumably, with a larger sample size and by assigning phenotypic data, efficiency would be improved, allowing more thorough analyses, such as genome-wide association studies.     

Immunological regression of metastatic cancer in the liver as a result of “in vivo xenogenization”

We attempted to induce the regression of liver metastatic tumor cellsin vivo by the administration to rats of Friend leukemia virus (FV) (in vivo xenogenization). The virus which was used in this experiment, FV, is highly immunogenic and does not normally cause disease in an adult rat. At first, we induced a FV viremia in tumor bearing rats in order to deliver the virus to the site of the tumor cells. FV viremia was induced by injecting 60 mg/kg cyclophosphamide (CY) i.v. after the administration of FV, and by transferring syngeneic bone marrow cells so that FV would be able to infect them and then replicate.In order that the tumor cells which were infected with virus should regress, it was necessary to break down their tolerance to FV antigens. As adoptive immunotherapy we therefore, transferred syngeneic spleen cells from rats which had been immunized with FV to tumor bearing rats. The result of this experiment was that these tumor bearing rats infected with FV which had received either normal syngeneic spleen cells or no spleen cells as controls died from liver metastasis (8 out of 9 rats (89%) and 15 out of 17 (88%) respectively). On the other hand, only 4 out of the 15 (27%) tumor bearing rats which were infected with FV and which received FV-immune spleen cells died from liver metastasis.These sets of data indicate that thein vivo xenogenization of tumor cells are indeed able to induce the regression of metastic tumor cells.     

Immune competence in breast cancer — Relationship of pretreatment immunologic tests to diagnosis and tumor stage

Summary The immune competence of a group of 276 patients with suspected breast cancer has been assessed using a spectrum of tests: the peripheral lymphocyte count, serum immunoglobulin levels, lymphocyte response to phytohemagglutinin (PHA), Mantoux test, and dinitrochlorobenzene (DNCB) skin test. All tests were completed prior to any form of treatment as the initial part of an ongoing, long-term assessment which will ultimately relate immune competence to prognosis. 225 patients with breast cancer were allocated into stages based on their TNM status. The remaining 51 patients proved to have benign breast disease and made up the control group. In analysis, control patients were compared with early breast cancer patients, while the effect of advancing disease was assessed by betweenstage comparisons in the cancer group.There were no significant differences between early breast cancer and control patients or between cancer stages in peripheral lymphocyte count, serum immunoglobulin levels, lymphocyte response to PHA, or Mantoux responses. Age was found to have a crucial effect on some of these parameters and some apparent differences between the various groups lost significance after appropriate allowances were made for age.Important differences seen with the DNCB test persisted after allowing for age effects. Responses to DNCB were significantly depressed in patients with early breast cancer compared to controls. Patients with disseminated cancer showed greater depression than early breast cancer patients, but surprisingly, patients with locally advanced tumors had good responses to DNCB. Possible reasons for the paradoxical preservation of DNCB reactivity in patients with locally advanced cancer are discussed.The DNCB test is the most discriminating of the five tests of immune function studied.     

Immunogenicity of “viable” tumor cells after storage in liquid nitrogen

Summary Injection of vaccines containing BCG and irradiated L10 hepatoma cells into strain 2 guinea pigs led to arrest and regression of viable L10 cells injected contralateral to and simultaneous with the vaccine. If the tumor cells in the vaccine had been stored in LN2, the vaccine was significantly less effective. The diminished immunogenicity of the stored cells could not be attributed to the sequence of freezing and irradiation, nor to the presence of dead cells which had been killed during cryopreservation. We concluded that cells which had been stored in LN2 had undergone changes which decreased their immunogenicity but which did not alter permeability to trypan blue.     

Phase I study of recombinant human tumor necrosis factor α in advanced malignant disease

Summary A phase I study with recombinant human tumor necrosis factor (rhuTNF-; Knoll AG, Ludwigshafen, FRG) in patients with advanced malignant disease was undertaken to evaluate drug toxicity (organ specifity, time course, predictability, reversibility, maximal tolerated dose), effectiveness, antigenicity and pharmacokinetics. TNF was administered as a test dose followed by daily i.v. infusions for 5 days, every 3 weeks (single i.v. infusion lasting 10 min, TNF dissolved in 50 ml 5% human albumin). Dosage was increased in groups of 3 or 4 patients from 0.04 mg/m² to 0.28 mg/m². A total of 19 patients with different cancers, including seven large-bowel carcinomas, three chronic myelogenous leukemias, three hypernephromas, two small-cell lung cancers, one malignant melanoma, one malignant lymphoma, one rhabdomyosarcoma and one fibrosarcoma were treated. Major side-effects were chills and fever (maximum 40.4°C, median 38.7°C, 19/19), headache (12/19), nausea and vomiting (12/19) and pronounced (>20%) hypotension (4/19). Acute side-effects could be diminished by paracetamol or indomethacin pretreatment, and with one possible exception no tachyphylaxis to TNF was noted. Mild renal toxicity was seen during TNF treatment. Pharmacokinetic studies showed a serum half-life (t _1/2) ranging from 11 min to 17 min for doses from 0.04 mg/m² to 0.16 mg/m² and prolonged clearance with t _1/2 ranging from 54 min to 70 min in the 0.20–0.28 mg/m² dose range. No objective antitumor effects were observed in this phase I study.     

Characterisation of disseminated tumor cells in the bone marrow of breast cancer patients by the Thomsen–Friedenreich tumor antigen

The detection of disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients has proved prognostic significance in all stages of the disease. Further characterisation of those cells could help to improve the biological understanding of metastases, develop targeted therapies and define surface markers for enrichment techniques. The Thomsen–Friedenreich (TF) antigen has been shown to be a tumor specific antigen in breast cancer. The aim of this study was to investigate the expression of TF on DTC-BM in 25 patients. Bone marrow samples were first double-stained by a Cy3 conjugated cytokeratin (CK) antibody (ab) A45 B/B3 (IgG) and anti-TF ab Nemod 2 (IgM), followed by Cy2 conjugated goat anti-mouse IgM ab. For further characterisation samples were also double-stained with anti-TF ab Nemod 2 (IgM), followed by Cy2 conjugated goat anti-mouse IgM ab, and anti MUC1 ab A76-A/C7 IgG, followed by Cy3 conjugated goat anti-mouse IgG. CK positive DTC-BM showed co-expression of TF antigen in 22/23 patients (96%) and 61 of 62 detected cells (98%). Mononuclear BM cells without CK expression were also negative for TF. All of the TF positive cells showed strong MUC1 expression. This is the first study showing co-expression of CK and TF as markers of DTC-BM. Double staining experiments of TF and MUC1 expression showed that MUC1 is the carrier protein of TF in these cells. As TF is a specific marker of DTC-BM, it could be used as a target for antibody based therapy and immunomagnetic enrichment techniques for the isolation of DTC-BM.     

Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer

Transforming growth factor-β (TGF-β) is a secreted polypeptide that signals via receptor serine/threonine kinases and intracellular Smad effectors. TGF-β inhibits proliferation and induces apoptosis in various cell types, and accumulation of loss-of-function mutations in the TGF-β receptor or Smad genes classify the pathway as a tumor suppressor in humans. In addition, various oncogenic pathways directly inactivate the TGF-β receptor-Smad pathway, thus favoring tumor growth. On the other hand, all human tumors overproduce TGF-β whose autocrine and paracrine actions promote tumor cell invasiveness and metastasis. Accordingly, TGF-β induces epithelial–mesenchymal transition, a differentiation switch that is required for transitory invasiveness of carcinoma cells. Tumor-derived TGF-β acting on stromal fibroblasts remodels the tumor matrix and induces expression of mitogenic signals towards the carcinoma cells, and upon acting on endothelial cells and pericytes, TGF-β regulates angiogenesis. Finally, TGF-β suppresses proliferation and differentiation of lymphocytes including cytolytic T cells, natural killer cells and macrophages, thus preventing immune surveillance of the developing tumor. Current clinical approaches aim at establishing novel cancer drugs whose mechanisms target the TGF-β pathway. In conclusion, TGF-β signaling is intimately implicated in tumor development and contributes to all cardinal features of tumor cell biology.     

In situ expression of IFN-γ-inducible T cell α chemoattractant in breast cancer mounts an enhanced specific anti-tumor immunity which leads to tumor regression

Increased evidence indicates that chemokines are involved in tumor growth. ITAC, a key member of chemokines, possesses the ability to recruit T cells and enhance immune responses. Therefore, ITAC might contribute to antitumor immunity. In this study, we evaluated the relationship between the expression of ITAC and human breast cancer advancement. We further investigated whether forced expression of ITAC in tumor sites could mediate enhanced antitumor immunity in a murine breast cancer model. Results showed that ITAC expression level was down-regulated in 31 breast cancer specimens compared to normal mammary tissues, and associated negatively with the stages of breast cancer. Contrarily, forced expression of ITAC in murine 4T1 tumor cells resulted in tumor regression after initial growth upon injection into naïve Balb/c mice. More lymphocytes were recruited to the site of tumor inoculated by 4T1-ITAC and more than 80% of these T cells expressed the ITAC receptor, CXCR3. ITAC-recruited TILs exhibited 4T1-specific proliferation and cytotoxicity, and an increased IFN-γ but decreased IL-4 production. Importantly, forced expression of ITAC in 4T1 tumor nodules inhibited tumor growth. These findings demonstrated that the decreased expression of ITAC is associated with the advancement of breast cancer in patients. Forced expression of ITAC in tumor site not only induces increased T cell-recruitment and elicits a specific antitumor immunity, but also mediates regression of established 4T1 tumors, indicating the potential application of ITAC-expressing tumor cells in cancer immunotherapy and vaccine designing.     

PD-L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non-small cell lung cancer?

PD-L1 and tumor mutation burden (TMB) are the most widely used immunotherapy biomarkers to identify populations who would attain clinical benefit, with the higher values predicting better therapeutic efficacy. This review addresses the predictive values and unresolved challenges of these two biomarkers. PD-1 and PD-L1 inhibitors have induced durable and effective responses in patients with advanced non-small cell lung cancer, confirmed by multiple clinical trials and real-world studies. Different clinical trials, involving both PD-1/PD-L1 inhibitors alone and combination regimens, adopted either PD-L1 or TMB to stratify the patients, although the predictive capabilities of these two biomarkers are different. In the first-line setting, PD-L1 of 50% or more as a cut-off value can help select candidates for pembrolizumab or atezolizumab monotherapy; however, these two biomarkers poorly predict the efficacy of immunotherapy combination regimens as first-line treatments. In the second-line setting, although patients can benefit from nivolumab regardless of PD-L1 expression, both PD-L1 and blood TMB can be used as biomarkers to find patients suitable for atezolizumab. Except for inaccurate predictiveness, there are many unresolved problems with regard to the two biomarkers, such as the lack of standard detection methods, and their susceptibilities to other dynamic changes. The predictive values of TMB and PD-L1 were low in most circumstances; however, PD-L1 expression greater than ≥ 50% can help select appropriate patients for pembrolizumab and atezolizumab, respectively, as first-line monotherapies. Higher PD-L1 or TMB was associated with greater efficacy for atezolizumab as a second-line monotherapy.