Arthritis augments breast cancer metastasis: role of mast cells and SCF/c-Kit signaling

Introduction

Breast cancer remains the second leading cause of cancer-related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis.

Methods

We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and another that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored.

Results

First, we confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs, which may be the underlying cause for the enhanced lung and bone metastases observed in the arthritic mice. Next, we showed that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis.

Conclusion

This is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.     

Risk factors for early sepsis in very low birth weight neonates with respiratory distress syndrome

AIM: To identify maternal and neonatal factors that increase suspicion of early sepsis in Very Low Birth Weight neonates with respiratory distress syndrome. METHODS: The cohort included 282 neonates born at Soroka Medical Centre 1996-2000. Definitions of 'high' and 'low'-suspicion groups for early sepsis were based on comparison between neonates with early sepsis and the remaining cohort. Univariate analysis and logistic regression were used to compare between groups. RESULTS: The incidence of early sepsis in the cohort was 1.8%, and 94% received antibiotics following delivery. Comparing with the remaining cohort, the five neonates with early sepsis had increased incidence of positive maternal cultures, use of antenatal antibiotics, lower 1 min Apgar scores and tendency to leucopenia. A 'low-suspicion' group comprised 38% of the cohort and did not include any neonates with early sepsis. This group were more frequently treated with antenatal steroids and delivered by Caesarean section compared to the 'high-suspicion' group, but otherwise there were no clinical and laboratory differences. CONCLUSION: Although the incidence of early sepsis is low almost all neonates received antibiotics. A 'low-suspicion' group was defined and the role of antibiotic treatment in this group needs to be determined.     

Management of Acute Cholecystitis: Prevalence of Percutaneous Cholecystostomy and Delayed Cholecystectomy in the Elderly

Background

Published guidelines recommend early cholecystectomy for acute cholecystitis in the elderly. Alternatively, percutaneous cholecystostomy can be used in compromised patients.

Methods

We reviewed 806 elderly patients diagnosed with biliary disease retrospectively identified through billing and diagnosis codes. Two hundred sixty-five patients with histologically documented acute cholecystitis were selected.

Results

Initially, 75 patients had percutaneous cholecystostomy (Group 1), 64 (24 % underwent interval cholecystectomy, 74 (28 %) early (Group 2), and 127 (48 %) delayed cholecystectomy (Group 3). Group 1 was more likely to have American Society of Anesthesiologists (ASA) scores of 4 when compared to those in Groups 2 and 3 (p?=?0.04). No difference existed among the groups when patients with an ASA of 4 were excluded: conversion rates (11 %), biliary leak, bowel injury, need for reoperation, or 30 days mortality. Patients in Group 1 and in Group 3 were five times (p?=?0.04) and four times (p?=?0.06) more likely, respectively, than those in Group 2 to have recurrent episodes of pancreatitis, cholecystitis, and cholangitis.

Conclusion

Patients were more likely to have delayed cholecystectomy after initial antibiotic therapy or cholecystostomy without the benefit of a lower conversion rate when compared to the early group, but they had higher recurrent episodes of cholecystitis/pancreatitis or cholangitis.     

Tracheotomy and inhalation injury

Indications for tracheotomy in patients with respiratory burns have been unclear. Much of the literature is inconclusive or misleading. A thorough understanding of the pathogenesis, diagnosis, and therapy of inhalation injury is necessary to understand the role of tracheotomy. A critical review reveals relatively clearcut indications for the use of tracheotomy in inhalation injury, but many unanswered questions. Increased participation by otolaryngologists in burn management is recommended.     

Left and Right Intelligence: Case Studies of Raven's Progressive Matrices Following Brain Bisection and Hemidecortication

Each hemisphere of two commissurotomy and two hemispherectomy patients was tested separately on the book form of Raven's Standard Progressive Matrice test (RSPM) and on the book, board and tactile forms of Raven's Coloured Progressive Matrices test (RCPM). The two patients who had undergone complete cerebral commissurotomy were tested unilaterally with the aid of a contact lens technique which permits free unilateral ocular scanning and visual guidance. The two other patients had undergone dominant (right) and non-dominant (left) hemispherectomy for post-infantile lesions and were tested in free vision. IQ estimates for the left hemispheres based on RSPM scores ranged from 74 to 103 (mean 87) and right hemisphere IQ estimates ranged from 74 to 93 (mean 83).Whereas a small and insignificant trend for left hemisphere dominance was observed on the RSPM, an insignificant trend of right hemisphere superiority appeared on the RCPM. The same trend of right hemisphere advantage had been observed on a tactile-visual modification of the RCPM (D. Zaidel and Sperry, 1973). Thus, the suggested laterality pattern seems to be modality nonspecific. In contrast to the small difference in lateral preference for each of the two tests as a whole, the individual problem sets in both tests yielded different laterality indices. Further, bigger laterality effects were observed on more difficult items. The right hemispheres also seemed more labile and less sensitive to item difficulty than either the corresponding left hemispheres or normal subjects with comparable scores.Instructions to use an overt trial-and-error solution method with the board form of the RCPM resulted in a change of strategy in both hemispheres. But only the left hemisphere of patient N.G., who did not have a ceiling effect, seemed to benefit from the opportunity for error correction to become superior on this version of the RCPM. The right hemisphere seems unable to utilize partial information as if its solution strategy is non-constructive.Neither the isolated nor the disconnected hemisphere has the dramatic focal deficits, such as unilateral neglect of space or dramatically reduced RPM scores, which often accompany unilateral cerebral insult.To the extent that RSPM measures general intelligence (“g”), our data suggest that “g” is bilaterally represented though in unequal amounts for different parts of the test. Thus, the data better support the primary abilities model of intelligence with localized and neurologically dissociable cerebral organization, than they support a hierarchical model incorporating a concept of “g” that enters into all intellectual functions and is homogeneously represented in the cerebral cortex. It is suggested that “g” may contain at least two independent factors, 9_L and g_R.