Abnormal tumor vasculatures and bone marrow-derived pro-angiogenic cells in cancer

Tumor-derived factors affect the stroma of cancer tissue by activating pro-angiogenic signals. One of the key components of this response is the mobilization of the pro-angiogenic cells from bone marrow (BM), which contribute to the development of abnormal tumor vasculature. Evidence is accumulating that the pro-angiogenic cells derived from BM are involved in the physiological processes of tissue repair and wound healing. However, vascular structure in cancer tissue is impaired, resulting in the formation of chaotic neo-vessels and hypoxic microenvironments. Ultimately, these structural and functional abnormalities result in the limited delivery of chemotherapeutic agents and create regions of metabolic derangement, both of which enhance resistance to chemotherapy. In spite of recent advances in targeted therapy using anti-vascular agents, clinical results from studies using individual agents have unsatisfactory, necessitating the combinatorial use of anti-cancer drugs and a targeting agent. We suggest the possibility of a new therapeutic approach in which aberrant tumor vessels are normalized by BM-derived pro-angiogenic cells, and the delivery of anti-cancer drugs is maximized. In this review, we focus on the current understanding of the structure and function of tumor vessels, and an alternative approach to the repair of abnormal tumor vasculature by the use of BM-derived pro-angiogenic cells. This approach may improve both the delivery and the efficacy of anti-cancer drugs by restoring aberrant tumor vascularization and hypoxia.     

The clinical manifestations of lumbar disease are correlated with self-rating depression scale scores

Background

Depression can exacerbate symptoms of chronic pain and worsen disability. The symptoms of lumbar disease may be particularly sensitive to psychological state, but statistical associations between low back pain (LBP) severity and mental health status have not been established.

Methods

Of the 151 patients with LBP, 122 completed questionnaires probing depressive symptoms, LBP severity, and degree of disability. In addition to completing self-report questionnaires, patients provided demographic and clinical information. A self-rating depression scale (SDS) was used to screen for depression. Pain and disability were assessed by the visual analog scale (VAS) and the Roland–Morris disability questionnaire (RDQ), respectively. Overall clinical severity was assessed using the Japanese Orthopaedic Association (JOA) score. Kendall’s tau correlation coefficients were calculated to examine the relationships among these variables.

Results

Ninety-four patients (77 %) were in a depressive state as indicated by SDS score ≥40, including mild depression group (47 patients, SDS score from 40 to 49) and depression group (47 patients, SDS score ≥50). There were only 28 patients in the no depression group (SDS score ≤39). There was no significant difference in both age and pain duration among the three groups. The mean VAS score in the depression group (70 ± 19 mm) was higher than both no depression (41 ± 24 mm) and mild depression groups (52 ± 21 mm). The mean JOA score in the no depression group (14 ± 5.0 points) was higher than both mild depression (12 ± 4.0 points) and depression groups (10 ± 6.0 points). The mean RDQ in the depression group (15.1 ± 6.0 points) was higher than both no depression (6.4 ± 5.0 points) and mild depression groups (10.9 ± 5.4 points). Factors significantly correlated with SDS score included VAS, JOA score, and RDQ score. In contrast, SDS did not correlate with patient age or pain duration.

Conclusions

The majority of chronic LBP patients examined were in a depressed state and the severity of depression correlated with pain severity, degree of self-rated disability, and clinical severity.     

Cervical Lymph Node Dissection for Clinically Submucosal Carcinoma of the Thoracic Esophagus

Background

The purposes of this study were to clarify the risk factors for supraclavicular lymph node (SCLN) metastasis and the survival benefit from cervical lymph node (LN) dissections in patients with clinically submucosal (cT1b) carcinoma of the thoracic esophagus.

Methods

A total of 86 patients with this disease who underwent esophagectomy with 3-field lymph node dissection were retrospectively reviewed. Multivariate logistic regression and Cox proportional hazard model were used to identify the independent risk factors for SCLN metastasis and prognostic factors, respectively. An index calculated by multiplying the frequency of metastasis at nodal basin and the 5-year overall survival rate of patients with metastasis at that basin were used to assess the therapeutic outcomes.

Results

A total of 40 patients (47 %) were found to have pathological LN metastasis. Also, 13 patients (15 %) had cervical LN metastasis: 6 and 7 with carcinoma of the upper and mid-thoracic esophagus, respectively. SCLN metastasis was found in 6 patients (7 %); however, there was no independent risk factor for SCLN metastasis. The 5-year overall survival rate was 72.5 %. Cervical LN metastasis was an independent prognostic factor (p = .04; odds ratio 2.55; 95 % confidence interval 1.03–6.31); however, there was no significant difference in survival between patients with SCLN metastasis and those without (p = .06). The calculated index of estimated benefit from cervical LN dissections was 6.9, following upper mediastinal LN of 15.6 and perigastric LN of 8.3.

Conclusions

We could not identify risk factors to predict SCLN metastasis. Cervical LN dissection should not be omitted in patients with cT1b carcinoma, especially of the upper and mid-thoracic esophagus.     

The essence of the Japan Radiological Society/Japanese College of Radiology Imaging Guideline

Diagnostic imaging is undoubtedly important in modern medicine, and final clinical decisions are often made based on it. Fortunately, Japan has the highest numbers of diagnostic imaging instruments, such as CT and MRI devices, and boasts easy access to them as well as a high level of diagnostic accuracy. In consequence, a very large number of imaging examinations are performed, but diagnostic instruments are installed in so many medical facilities that expert management of these examinations tends to be insufficient. Particularly, in order to avoid risks, clinicians have recently become indifferent to indications of imaging modalities and tend to rely on CT or MRI resulting in increasing the number of imaging examinations in Japan. This is a serious problem from the viewpoints of avoidance of unnecessary exposure and medical economy. Under these circumstances, the Japan Radiological Society and Japanese College of Radiology jointly initiated the preparation of new guidelines for diagnostic imaging. However, the field of diagnostic imaging is extremely wide, and it is impossible to cover all diseases. Therefore, in drafting the guidelines, we selected important diseases and focused on “showing evidence and suggestions in the form of clinical questions (CQs)” concerning clinically encountered questions and “describing routine imaging techniques presently considered to be standards to guarantee the quality of imaging examinations”. In so doing, we adhered to the basic principles of assuming the readers to be “radiologists specializing in diagnostic imaging”, “simultaneously respecting the global standards and attending to the situation in Japan”, and “making the guidelines consistent with those of other scientific societies related to imaging”. As a result, the guidelines became the largest ever, consisting of 152 CQs, nine areas of imaging techniques, and seven reviews, but no other guidelines in the world summarize problems concerning diagnostic imaging in the form of CQs. In this sense, the guidelines are considered to reflect the abilities of diagnostic radiologists in Japan. The contents of the guidelines are essential knowledge for radiologists, but we believe that they are also of use to general clinicians and clinical radiological technicians. While the number and contents of CQs are still insufficient, and while chapters such as those on imaging in children and emergency imaging need to be supplemented, the guidelines will be serially improved through future revisions. Lastly, we would like to extend our sincere thanks to the 153 members of the drafting committee who authored the guidelines, 12 committee chairpersons who coordinated their efforts, six members of the secretariat, and affiliates of related scientific societies who performed external evaluation.     

Carbon-ion radiotherapy of spinal osteosarcoma with long-term follow

Purpose

Primary spinal osteosarcoma is quite rare, and the 5-year survival rate is very low. Because of its rarity, successful treatment experience with spinal osteosarcoma is limited. The purpose of this study is to report the effect of therapy of primary osteosarcoma of spine by carbon-ion radiotherapy (CIRT) and long-term follow.

Methods

A 70-year-old with primary spinal osteosarcoma who received CIRT underwent combined anterior artificial vertebral body replacement and posterior lumbar fusion (L1–L5) 3 years later.

Results

According to the surgical resection of tumoral lesion, pathological results showed that the intertrabecular space previously filled with tumor cells on the initial biopsy sample now contained necrotic tissue without tumor cells. This means that primary osteosarcoma of the spine was completely eliminated and achieved local control with CIRT, with a 7-year follow-up after the initial treatment.

Conclusions

Carbon ion beam treatment is an effective local treatment for patients with spinal osteosarcoma for whom surgical resection is not a feasible option, especially for elderly patients. However, more patients need to be evaluated over a longer term to assess the curative effect of CIRT.

     

Characterization of R peptide of murine leukemia virus envelope glycoproteins in syncytium formation and entry

Summary The C-terminal R peptide of ecotropic murine leukemia virus (MLV) envelope protein (Env) negatively controls membrane fusion activity. The R peptide cleavage during virion maturation activates its fusogenicity and is required for viral entry. We analyzed fusogenicity and transduction efficiency of mutant Env proteins of ecotropic, amphotropic, polytropic, and xenotropic MLVs. As the result, we found that the hydrophobic amino acid residues around the R peptide cleavage site are important for membrane fusion inhibition by the R peptide. In addition, we found that Env complexes with R peptide-truncated and -containing Env proteins have lower fusogenicity and transduction efficiency than those with the R-peptide-truncated Env alone, suggesting that efficient R peptide cleavage is required for efficient MLV vector transduction. The role of R peptide cleavage in amphotropic, polytropic, and xenotropic MLV infection has not been investigated. We found in this study that the R peptide cleavage is required for amphotropic, xenotropic, and polytropic MLV vector transduction, like with ecotropic MLV. The R-peptide-truncated Env proteins of the xenotropic and polytropic MLVs, however, had much lower fusogenicity than those of the ecotropic and amphotropic MLVs. These results provide valuable information for construction of efficient MLV vectors and for understanding the retroviral entry mechanism.     

Fibrotic changes in the infrapatellar fat pad induce new vessel formation and sensory nerve fiber endings that associate prolonged pain

The infrapatellar fat pad (IFP) contains nerve fiber endings and is considered to play an important role in the perception of knee pain. However, it is unclear whether and to what degree prolonged pain influences the nociceptive role of the IFP. To answer this question, we established a novel rat model of knee pain in which inflammation is restricted to the IFP. Rats received a single intra-IFP injection of monoiodoacetic acid (MIA) (0.2 mg/10 µL or 1.0 mg/10 µL) in the left knee and a phosphate-buffered saline (10 µL) injection in the right knee as a control. Pain-avoidance behavior and histological changes of the knee joint were measured at multiple time points up to 28 days after MIA injection. Histological analysis showed a transient inflammatory response in the IFP body in the 0.2-mg model, whereas prolonged inflammation followed by fibrotic changes was observed in the 1.0-mg model. Subtle histological alterations were observed in the articular cartilage and IFP surface regardless of the dose. The pain-avoidance behavior test indicated the development of prolonged knee pain throughout the experimental period in the 1.0-mg group. Histological assessments showed a significant increase in calcitonin gene-related peptide (CGRP)-positive nerve fiber endings inside IFPs with fibrosis in newly vascularized surrounding regions. These data suggest that irreversible fibrotic changes in the IFP induce the formation of new vessels and CGRP-positive nerve fiber endings that associate prolonged pain in the joint.     

Treatment strategies for aortic and peripheral prosthetic graft infection

Purpose

The aim of this study was to investigate the outcomes correlated with our treatment strategy for prosthetic graft infection.

Methods

Seventeen patients were treated for prosthetic graft infections between 1997 and 2009. Initially, total graft excision was applied in five cases, partial graft excision was applied in six cases and graft preservation with drainage and irrigation was applied in six cases. Among the graft-preserved cases, four patients were infected with methicillin-resistant Staphylococcus aureus (MRSA) and treated with gentian violet (GV).

Results

The overall survival rate was 88 % at 30 days and 82 % at 1 year in this series. Of the excised cases, nine patients survived; however, two patients died. Among the cases in which MRSA-infected grafts were preserved, three patients survived; however, one patient died under a septicemic state. Infected graft preservation was applied at a high rate of 36 %, and the mortality rate remained at 16 %, without any signs of graft reinfection.

Conclusions

In the treatment of infected grafts, the patient’s condition should be considered in order to select the appropriate treatment in each case. Graft preservation should be considered as an alternative treatment option, especially in high-risk patients, and GV can be effective for conservative treatment of prosthetic graft infections, including MRSA infections.