Clinical results and immunologic effects of a mixed bacterial vaccine in cancer patients

A biological response modifier, mixed bacterial vaccine (MBV), derived fromStreptococcus pyogenes andSerratia marcescens was used as a single agent in the treatment of 11 patients with refractory malignancies. MBV’s effect on interleukin-2 (IL-2) production, plasma interferon (IFN) and tumor necrosis factor (TNF) levels was monitored. Most patients’ peripheral blood mononuclear cells continued to produce baseline to elevated levels of IL-2, in spite of age and disease status. Several patients maintained moderate to high IFN levels. In general there was little correlation between IL-2 and IFN levels or with the response to therapy. One of 11 patients had minor response, 1 of 11 had partial response, 4 of 11 had temporary stabilization of disease, and 5 of 11 had progressive disease. A patient with AIDS and Kaposi’s sarcoma experienced a dramatic improvement in performance status and disease stabilization. In all patients side effects occurred only following i. v. and not i. m. administration and included fever and chills. No adverse hepatic, renal or hematolgic effects were observed. MBV is a well-tolerated biological response modifier with modest activity in advanced human tumors.     

Activation and clinical significance of the unfolded protein response in breast cancer

Introduction:

The tumour microenvironment is hypoglycaemic, hypoxic and acidotic. This activates a stress signalling pathway: the unfolded protein response (UPR). The UPR is cytoprotective if the stressor is mild, but may initiate apoptosis if severe.Activation of the UPR in breast carcinoma is induced by microenvironmental stress such as glucose and oxygen deprivation, but may also be linked to oestrogen stimulation. It may be clinically significant as it may alter chemosensitivity to doxorubicin.

Methods:

395 human breast adenocarcinomas were immunohistochemically stained for UPR activation markers (glucose-regulated protein (GRP-78 and XBP-1). A model of UPR activation in vitro by glucose deprivation of T47D breast cancer cells was developed to determine how the UPR affects cellular sensitivity to doxorubicin and 5-fluorouracil. Cytotoxicity was assessed using a colorimetric cytotoxicity assay (MTT). The effect of oestrogen stimulation and tamoxifen exposure on UPR activation by T47D cells was determined by western blotting measurement of the key UPR protein, GRP-78.

Results:

Expression of GRP78 and XBP-1 was demonstrated in 76% and 90% of the breast cancers, respectively, and correlated with oestrogen receptor positivity (P=0.045 and 0.017, respectively). In vitro UPR activation induced resistance to both doxorubicin and 5-flurouracil, (P<0.05). Oestrogen stimulation induced GRP78 and XBP1 over-expression on western blotting. Tamoxifen did not block this response and may induce UPR activation in its own right.

Conclusions:

The UPR is activated in the majority of breast cancers and confers resistance to chemotherapy. In vitro oestrogen stimulates UPR induction. UPR activation may contribute to breast cancer chemoresistance and interact with oestrogen response elements.     

Correlative Significance of Tumor Regression Grade and ypT Category in Patients Undergoing Preoperative Chemoradiotherapy for Locally Advanced Rectal Cancer

Background: In patients with locally advanced rectal cancer, the treatment response to preoperative chemoradiotherapy (PRCRT) varies, and the ypT stage may change as a result of tumor shrinkage. The purpose of this study was to evaluate the correlative significance and determine the prognostic value of tumor regression grade and ypT category staging systems.Materials and Methods: This retrospective observational study was conducted in a tertiary center. A total of 1240 patients with rectal cancer who underwent curative resection after PRCRT between January 2007 and December 2016 were consecutively included.Results: A significant association was found between the American Joint Committee on Cancer/College of American Pathology tumor regression grading system and ypT category, indicating a potential correlation between worse tumor regression grade and more advanced T stage (Cramer's V = 0.255, P < .001). The ypT stage and tumor regression grade were independent predictors of each other (P < .001). The good response group (tumor regression grades 0-1) had significantly higher 5-year disease-free survival (85.5% vs. 68.2%, P < .001) and overall survival (92.1% vs. 81.0%, P < .001) rates than the poor response group (tumor regression grades 2-3). However, the ypT and ypN categories were the most important independent prognostic factors for disease-free and overall survival.Conclusions: Tumor regression grade and ypT category were significantly correlated. Although tumor regression grade alone is not definitive, it is closely related to the ypT stage and impacts oncologic outcomes. These findings should be taken into consideration when stratifying the prognosis of patients undergoing PRCRT.     

Response of the murine gastrointestinal epithelium to cis-dichlorodiammineplatinum. II: radiation combinations

Single doses of cis-dichlorodiammineplatinum II (cis DDP) up to 8 mg/kg produced a dose-dependent inhibition of proliferative activity with a subsequent period of compensatory hyperplasia in the colon. The stomach was less responsive to cis DDP. Cis DDP-radiation combinations produced a dimunition in the proliferative response of the colon when compared to that following radiation only. This response was only seen in the stomach following 8 mg/kg of cis DDP and radiation. Cytokinetic analysis of the jejunal response to 8 mg/kg of cis DDP showed a gradual reduction in LN and MF/crypt with a reduction in the rate of DNA synthesis of S-phase cells through 8 hours post-treatment. By 24 hours the cellular DNA synthetic rate had recovered, although the number of S-phase cells was further reduced. The previously reported jejunal response to cis DDP-radiation combinations involved a reduction in crypt survival, coupled with a reduced proliferative capacity of surviving cells. Further investigation has revealed a possible inhibition of radiation damage repair by cis DDP, leading to increased levels of cell kill with the combination and reduced recovery of DNA synthetic rates in surviving cells.     

Radiographic and metabolic response rates following image-guided stereotactic radiotherapy for lung tumors

Purpose

To evaluate radiographic and metabolic response after stereotactic body radiotherapy (SBRT) for early lung tumors.

Materials and methods

Thirty-nine tumors were treated prospectively with SBRT (dose = 48-60 Gy, 4-5 Fx). Thirty-six cases were primary NSCLC (T1N0 = 67%; T2N0 = 25%); three cases were solitary metastases. Patients were followed using CT and PET at 6, 16, and 52 weeks post-SBRT, with CT follow-up thereafter. RECIST and EORTC criteria were used to evaluate CT and PET responses.

Results

At median follow-up of 9 months (0.4-26), RECIST complete response (CR), partial response (PR), and stable disease (SD) rates were 3%, 43%, 54% at 6 weeks; 15%, 38%, 46% at 16 weeks; 27%, 64%, 9% at 52 weeks. Mean baseline tumor volume was reduced by 46%, 70%, 87%, and 96%, respectively at 6, 16, 52, and 72 weeks. Mean baseline maximum standardized uptake value (SUV) was 8.3 (1.1-20.3) and reduced to 3.4, 3.0, and 3.7 at 6, 16, and 52 weeks after SBRT. EORTC metabolic CR/PR, SD, and progressive disease rates were 67%, 22%, 11% at 6 weeks; 86%, 10%, 3% at 16 weeks; 95%, 5%, 0% at 52 weeks.

Conclusions

SBRT yields excellent RECIST and EORTC based response. Metabolic response is rapid however radiographic response occurs even after 1-year post treatment.     

Endpoints for damage to normal tissues.

The response of normal tissues is vital in assessing any cancer treatment. Reasons are discussed why the response of normal structures in small animals is thought to be relevant to that in man. Endpoints for damage to a variety of normal tissues are considered and examples of dose response curves for many of these systems, taken from the published literature, are used as illustrations.     

Clinical Outcomes of Single Versus Double Hormone Receptor–Positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy

Purpose

To compare tumor response rates and survival outcomes between single and double hormone receptor (HR)-positive breast cancer (BC) patients treated with neoadjuvant chemotherapy.

Cancer Stem Cells and Response to Therapy

The cancer stem cell (CSC) model states that cancers are organized in cellular hierarchies, which explains the functional heterogeneity often seen in tumors. Like normal tissue stem cells, CSCs are capable of self-renewal,either by symmetric or asymmetric cell division, and have the exclusive ability to reproduce malignant tumors indefinitely. Current systemic cancer therapies frequently fail to eliminate advanced tumors, which may be dueto their inability to effectively target CSC populations. It has been shown that embryonic pathways such as Wnt, Hedgehog, and Notch control self-renewal and cell fate decisions of stem cells and progenitor cells. These are evolutionary conserved pathways, involved in CSC maintenance. Targeting these pathways may be effective in eradicating CSCs and preventing chemotherapy or radiotherapy resistance.     

Can the Neutrophil to Lymphocyte Ratio Predict Complete Pathologic Response to Neoadjuvant Breast Cancer Treatment? A Systematic Review and Meta-analysis

The systemic inflammatory response plays a role in tumor progression and development. The neutrophil to lymphocyte ratio (NLR) is a biochemical marker of systemic inflammation and is increasingly gaining appreciation for its prognostic role in predicting breast cancer outcomes. Previous research has demonstrated that patients who achieve a complete pathologic response (pCR) to neoadjuvant breast cancer treatment have a more favorable disease-free survival. This study aimed to assess whether the NLR can predict pCR to neoadjuvant therapy in breast cancer. A meta-analysis of 8 relevant studies was performed. The primary endpoint included pCR. Secondary endpoint included 5-year disease-free survival. Eight studies were included, reporting on 1586 patients. A total of 363 (22.88%) patients achieved pCR post neoadjuvant therapy. A lower NLR was associated with a greater rate of pCR (odds ratio, 1.83; 95% confidence interval, 1.15-2.91; P = .0003). Only 4 studies produced data on disease-free survival. A lower NLR was associated with a higher 5-year disease-free survival; however, this did not achieve statistical significance (hazard ratio, 1.38; 95% confidence interval, 0.82-2.31; P = .02). Sub-group analysis of sample size, NLR value, and geographic location proved statistically significant in determining an association between NLR and pCR. This meta-analysis found NLR to be a predictor for pCR in patients with breast cancer. All of the studies reviewed were retrospective cohort studies. Adequately sized, prospective clinical trials are needed to understand if NLR could become an important prognostic indicator of pCR.     

Preliminary results of a phase III trial of spontaneous animal tumors to heat and/or radiation: early normal tissue response and tumor volume influence on initial response

A Phase III randomized trial was initiated to test the relative efficacies of heat alone, radiation alone and heat plus radiation using spontaneous malignancies in pet animals. Heat alone was inferior to the other two treatment arms as demonstrated by a significantly higher non-response rate and shorter response duration. The ratio of complete response rates (CR) for heat plus radiation to radiation alone or the thermal relative risk (TRR) was greater for tumors greater than 10 cm3 as compared to those less than 10 cm3 (TRR = 4.8 and 1.4, respectively). The overall TRR for complete responses was 2.3. The CR data for the combined therapy arm indicate at least an additive effect between heat and radiation for small tumors but most likely a synergistic effect in the larger tumor group. Based on the data currently available, no significant difference in response duration is observed between the two radiation arms, although a nonsignificant advantage to the combination therapy exists. Normal tissue effects were evaluated by incidence of full moist desquamation within the irradiated volume, late fibrosis and bone necrosis. Since the radiation skin dose depended upon the technique being used it was possible to estimate the dose to achieve moist desquamation in 50% of the animals (DD50) by a logistic regression model as being 3728 +/- 344 rad for radiation alone. Significant lowering of the DD50 was not observed for the addition of heat to radiation. Low patient numbers where intact skin was heated prevented an accurate analysis of the effect, however.     

The pathology of breast cancer in Japanese women compared to other ethnic groups: A review

Review of comparative pathology studies of breast cancer among Japanese women and other ethnic groups reveals consistent differences in tumor morphology and host response. Japanese women show lower rates of breast cancer than Caucasian women, a difference that is accounted for by increased rates of this cancer in postmenopausal Caucasian women. Postmenopausal breast cancer is also less common among Japanese who migrated to a western environment. Autopsy studies of Japanese women without breast cancer indicate a lower prevalence of ductal hyperplasia, a breast cancer precursor, among indigenous Japanese women and first generation migrants than among second generation Japanese women in Hawaii who have higher rates of breast cancer. Postmenopausal breast cancers in Caucasian women are more likely to have estrogen receptors than cancers in postmenopausal Japanese women or premenopausal women of either race. Postmenopausal Japanese women are more likely to havein situ tumors than Caucasian women, even after adjusting for tumor size. A more vigorous host response to breast cancer among Japanese women, as compared to Caucasians, is suggested by more intense lymphocytic infiltration, greater degrees of lymph node sinus histiocytosis and fewer lymph node metastases in the Japanese.     

Impact of senescence‐associated secretory phenotype and its potential as a therapeutic target for senescence‐associated diseases

“Cellular senescence” is a state in which cells undergo irreversible cell cycle arrest in response to a variety of cellular stresses. Once cells senesce, they are strongly resistant to any mitogens, including oncogenic stimuli. Therefore, cellular senescence has been assumed to be a potent anticancer mechanism. Although irreversible cell‐cycle arrest is traditionally considered the major characteristic of senescent cells, recent studies have revealed some additional functions. Most noteworthy is the increased secretion of various secretory proteins, such as inflammatory cytokines, chemokines, growth factors, and MMPs, into the surrounding extracellular fluid. These newly recognized senescent phenotypes, termed senescence‐associated secretory phenotypes (SASPs), reportedly contribute to tumor suppression, wound healing, embryonic development, and even tumorigenesis promotion. Thus, SASPs appear to be beneficial or deleterious, depending on the biological context. As senescent cells are known to accumulate during the aging process in vivo, it is quite possible that their accumulation in aged tissues promotes age‐associated functional decline and various diseases, including cancers, at least to some extent. Here, we focus on and discuss the functional and regulatory network of SASPs toward opening up new possibilities for controlling aging and aging‐associated diseases.     

Effects of enteral and parenteral nutrition on tumor response to chemotherapy in experimental animals

The effects of oral and intravenous nutrition on host and tumor responses to graded doses of methotrexate (MTX) were evaluated in 150 adult Sprague-Dawley rats. All animals were inoculated with Walker-256 carcinosarcoma and were fed a regular diet for ten days before assigning them to three dietary groups. Group I (n = 64) received a constant intravenous infusion of 30% dextrose-5% amino acids (IVH), group II (n = 64) received an identical solution orally ad libitum, and group III (n = 22) received a regular diet ad libitum. Animals in groups I and II were then divided into three subgroups each that received either 20 mg/kg, 40 mg/kg, or 60 mg/kg of MTX intramuscularly. Ten days later, all surviving animals were killed. Animals fed the 30% dextrose-5% amino acid diet orally and given 20 mg/kg and 40 mg/kg of MTX lost slightly less body weight when compared with their IVH counterparts. In the 60 mg/kg treatment group, orally fed animals lost 52 gm of body weight compared with 23 gm in IVH animals. IVH rats given 20 mg/kg and 40 mg/kg of MTX demonstrated significant inhibition of tumor growth and decreased tumor weight/body weight ratios when compared with orally fed rats. No improvement in tumor response to 60 mg/kg of MTX was observed, however, when IVH animals were compared with orally fed rats. In a second study, nutrient intake was maintained at a constant level by intravenous infusion in one group and intrajejunal infusion in another group of tumor-bearing rats. Host and tumor responses to 20 mg/kg of MTX were similar in both groups of animals.     

Nuclear Accumulation of p53 in Normal Human Fibroblasts Is Induced by Various Cellular Stresses which Evoke the Heat Shock Response, Independently of the Cell Cycle

Nuclear accumulation of p53 is induced by various DNA damaging agents (the p53 response). Induction of nuclear accumulation of p53 after various cellular stresses, mostly other than DNA damage, including heat shock, was examined in normal human fibroblasts by immunostaining and flow cytometry using a mouse anti-p53 monoclonal antibody. Immunostaining revealed nuclear accumulation of p53 within 6 h after various stresses [heat shock, osmotic shock, heavy metal (Cd), blockers of the cellular respiratory system (NaN₃), amino acid analogues (azetidine and canavanine), an inhibitor of protein synthesis (puromycin), and oxygen free radicals (H₂O₂)]. Heat shock proved to be one of the most effective inducers among these stresses. FACScan analysis revealed that this induction of p53 occurred regardless of the stage in the cell cycle and that accumulation of cells in G2/M occurred. As all of these stresses are known to induce the heat shock response, the mechanism of p53 induction after stresses and that of heat shock response may share, at least partly, some common signaling pathway(s).     

Tumor response after long interval comparing 5x5Gy radiation therapy with chemoradiation therapy in rectal cancer patients

Background

In the era of organ preserving strategies in rectal cancer, insight into the efficacy of preoperative therapies is crucial. The goal of the current study was to evaluate and compare tumor response in rectal cancer patients according to their type of preoperative therapy.