Transvaginal Polytetrafluoroethylene Mesh Surgery for Pelvic Organ Prolapse: One-Year Safety and Efficacy Results.

OBJECTIVE: To evaluate the efficacy and safety of the polytetrafluoroethylene (PTFE) mesh by comparing conventionally used polypropylene (PP) mesh in tension-free vaginal mesh (TVM) surgery for pelvic organ prolapse (POP). METHODS: We conducted an observational cohort study of patients who underwent TVM using a PTFE or PP mesh. PTFE was used from June 2019 to May 2021, and PP mesh from January 2018 to May 2019. Outcomes included POP recurrence, perioperative complications, and patient satisfaction. Restricted mean survival time was used to analyze POP recurrence, comparing the time to recurrence between the two groups at 1year after TVM. RESULTS: Of 171 patients, 104 underwent PP mesh placement (PP group) and 67 underwent PTFE mesh placement (PTFE group). POP recurrence was observed in 10 and nine patients in the PP and PTFE groups, respectively. The mean time until the recurrence in the PTFE group was significantly shorter than that in the PP group (restricted mean survival time difference: -20.3days; 95% CI, -40.1 to -0.5; P = .044). Subgroup analysis revealed the meantime until recurrence was significantly shorter in the PTFE group for postoperative periods 3months or less, ages >70years, and POP stage ≥3. There were no intervention cases in either group and no significant differences in the perioperative complications. Patient satisfaction was greater in the PTFE group after 3months postoperatively. CONCLUSION: TVM surgery with a PTFE mesh is more prone to recurrence than that with a PP mesh, but with higher patient satisfaction. Within 3months of surgery, elderly patients and those with advanced-stage POP require care to prevent recurrence.

[A Case of IgG4-Related Disease Arising in Female Periurethra].

A 67-year-old female, with a past medical history of IgG4-related Mikulicz disease, was referred to our department for a periurethral mass revealed by contrast-enhanced computed tomography. She presented with weak urine flow a half year before the first consultation. Magnetic resonance imaging (MRI) revealed a periurethral mass, 39×39×29 mm, extending from the bladder neck to the urethral meatus. Serum IgG4 level was elevated to 580 mg/dl. Histological examination by the transvasinal biopsy revealed a lymphocytic infiltrate with IgG4-positive plasmacytoid predominance, leading to the diagnosis of IgG4-related disease arising in the periurethra. She was treated with prednisolone for 4 months, and urinary disturbance disappeared. MRI showed that the periurethral mass decreased in size.

[A Case of Ipsilateral Multifocal Renal Cell Carcinoma Treated with Robot-Assisted Partial Nephrectomy].

A 55-year-old male was referred to our hospital for left lower back pain. Computer tomography suggested a left ureteral stone and two left renal tumors at ventral and lateral sites. The ventral tumor measured 7 mm, and it showed intense early enhancement. On the other hand, the lateral tumor measured 22 mm, and it was enhanced weakly. We performed a single-stage robot-assisted partial nephrectomy, because he had chronic renal insufficiency and the two tumors appeared to be different types of renal cell carcinoma. Pathological examination revealed the ventral tumor was clear cell renal cell carcinoma, while the lateral tumor was papillary renal cell carcinoma. He is free of recurrence 1 year and 2 months after operation.

[A Case of Retroperitoneal Primary Castleman's Disease which was Difficult to Differentiate from Liposarcoma].

A 38-year-old man had a right lower retroperitoneal mass found by abdominal echography in a medical examination, and he consulted the internal medicine of Sumitomo Hospital. On the suspicion of malignant lymphoma, he received a laparotomy with biopsy. Pathological examination revealed that the tumor was either benign lymphadenopathy or low-grade malignant lymphoma, and he was follow-up. Two years later, he was introduced to our department because the follow-up computed tomography revealed signs of a tumor and a mass of adjunctive adipose tissue that increased markedly. Thus, we suspected that the tumor was liposarcoma before the operation, and performed retroperitoneal tumor resection. However, we found that the tumor was pathologically a hyaline vascular type of Castleman's disease and the pathological examination showed no malignant cells in the peritumoral adipose tissue. Since Castleman's disease lacks the characteristic symptoms or image findings, the preoperative diagnosis is generally difficult. Cases with growth of the peritumoral adipose tissue are rare, and the differentiation from the liposarcoma is usually difficult. We discussed how to perform the differential diagnosis of Castleman's disease, and especially about the differential diagnosis of liposarcoma.

[A Case of Androgen Insensivity Syndrome with a Seminoma in the Abdominal Undescended Testis].

A 48-year-old female was referred to our hospital for further urological examination of primary amenorrhea. She had been suffering from amenorrhea since 12 years old. Although she had normal female external genitalia, she had a blind-ended vagina with complete absence of the uterus.Laboratory tests showed high testosterone level and the 46 XY karyotype. Thus, our diagnosis was androgen insensivity syndrome. Magnetic resonance imaging showed bilateral intra-abdominal testes. We performed laparoscopic bilateral gonadalectomy. Pathological diagnosis was seminoma in the right gonad. She is free of recurrence 6 months after operation.

Hyperthermic Effect of Ginger (Zingiber officinale) Extract-Containing Beverage on Peripheral Skin Surface Temperature in Women.

Ginger is known to warm the body. Therefore, we conducted a placebo-controlled crossover trial to investigate the hyperthermic effect of a palatable ginger-containing beverage in healthy women with cold-sensitive extremities. Six women drank 280 mL of 0.07% ginger extract-containing or placebo beverage in a temperature-controlled room (21°C). Their palm temperatures were measured as measure of surface body temperature using a thermographic camera before intake and every 10 min after intake for 60 min. Palm temperature increased immediately following intake of the ginger and placebo beverages. However, palm temperature following intake of the ginger beverage increased for 20 min, while palm temperature following placebo intake decreased again after 10 min. The increased palm temperature following ginger intake was maintained significantly longer than after placebo intake (p < 0.05). In response to a questionnaire, some subjects answered that their increased body temperature was maintained after drinking the ginger beverage. Ginger extract-containing beverage may thus improve cold sensitivity.

Serum heat shock protein 47 levels are elevated in acute interstitial pneumonia.

BACKGROUND: Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. We hypothesized that HSP47 could be a useful marker for fibrotic lung disease. The aim of this study was to evaluate serum levels of HSP47 in patients with various idiopathic interstitial pneumonias (IIPs). METHODS: Subjects comprised 9 patients with acute interstitial pneumonia (AIP), 12 with cryptogenic organizing pneumonia (COP), 16 with nonspecific interstitial pneumonia (NSIP), 19 with idiopathic pulmonary fibrosis (IPF), and 19 healthy adult volunteers. RESULTS: Patients with AIP had serum HSP47 levels that were significantly higher than those of COP, NSIP or IPF patients and those of healthy volunteers. In contrast, serum levels of HSP47 among patients with COP, NSIP, IPF, and healthy volunteers did not differ significantly. Receiver operating characteristic curves revealed that the cut-off level for HSP47 that resulted in the highest diagnostic accuracy for discriminating between AIP and COP, NSIP, IPF, and healthy controls was 859.3 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 100.0%, 98.5%, and 98.7%, respectively. CONCLUSION: The present results demonstrate that, among patients with various IIPs, serum levels of HSP47 were elevated specifically in patients with AIP.

Serum heat shock protein 47 levels in patients with drug-induced lung disease.

BACKGROUND: Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone that is required for molecular maturation of various types of collagens. We recently reported that HSP47 serum levels were markedly higher in patients with acute exacerbations of idiopathic pulmonary fibrosis (IPF) when compared with patients with stable IPF, suggesting that serum HSP47 levels correlate with interstitial pneumonia activity. The aim of this study was to evaluate serum HSP47 levels in patients with drug-induced lung disease (DILD). METHODS: Findings from high-resolution computed tomographic chest scans of 47 patients with DILD were classified into one of four predominant patterns: organizing pneumonia (OP) (n = 4), nonspecific interstitial pneumonia (NSIP) (n = 24), hypersensitivity pneumonitis (HP) (n = 11), and diffuse alveolar damage (DAD) (n = 8). Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, and SP-D were measured in these patients. RESULTS: The PaO2/fraction of inspired oxygen (FiO2) (P/F) ratios were significantly lower and the alveolar-arterial difference of oxygen (A-a DO2) was significantly higher in the DAD group than in the other groups. Patients with DAD had the worst outcomes among the different subgroups. Patients in the DAD group had significantly higher serum HSP47 levels than those in other groups. Receiver operating characteristic curves revealed that HSP47 was superior to KL-6, SP-A, and SP-D for discriminating between the DAD group and the other groups. The cut-off level for HSP47 that resulted in the highest diagnostic accuracy was 1711.5 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 87.5%, 97.4%, and 95.7%, respectively. Serum levels of HSP47 in the group of patients requiring glucocorticoids were significantly higher than those in patients who experienced clinical improvement without glucocorticoid administration. Serum HSP47 levels also significantly correlated with various respiratory parameters. CONCLUSION: This study demonstrated that serum HSP47 levels were elevated in patients with DILD with a DAD pattern who had the worst outcomes among the different subgroups, and that this was correlated with P/F ratio and A-a DO2.

Standardized diagram improves diagnostic accuracy and variability in the identification of testicular cells prepared for testicular sperm extraction and intracytoplasmic sperm injection.

OBJECTIVE: To examine the accuracy and variability of identification of human germ cells and validate the previously reported diagram referable to identifying human testicular cells, which was made to improve the identification. METHODS: Eighty-seven testicular cells obtained from azoospermic patients were stained with MitoTracker, and observed under phase contrast, fluorescent, and differential interference microscopy. The recorded image and movie data of phase contrast microscopy were assessed by 10 reviewers comprising embryologists and reproductive physicians 2 times, once without the diagram and 1 year later with use of it. True cell type identifications were determined as referenced by morphologic characteristics and MitoTracker staining. Variability between reviewers was assessed using multirater κ statistics, and changes of the concordance rates to the reference were examined. RESULTS: Multirater κ coefficients changed from 0.14 to 0.49 overall, from 0.10 to 0.34 for sperm-like cells, and from 0.044 to 0.46 in round-shaped cells before and after using the diagram, which represents a change from fair to substantial agreement overall for round-shaped cells and to moderate agreement for sperm-like cells. The concordance rates to the reference before and after the use of the diagram also significantly improved from 28.4% to 59.1% overall, from 38.9% to 54.6% for sperm-like cells, and from 19.4% to 59.1% for round-shaped cells, respectively. CONCLUSION: Identification of human germ cells by embryologists and reproductive physicians was not uniform or satisfactory. However, the diagram significantly improved identification such that it may be useful as an efficient checklist for the identification of germ cells.

Inhibition of ß2-microglobulin/hemochromatosis enhances radiation sensitivity by induction of iron overload in prostate cancer cells.

BACKGROUND: Bone metastasis is the most lethal form of several cancers. The ß2-microglobulin (ß2-M)/hemochromatosis (HFE) complex plays an important role in cancer development and bone metastasis. We demonstrated previously that overexpression of ß2-M in prostate, breast, lung and renal cancer leads to increased bone metastasis in mouse models. Therefore, we hypothesized that ß2-M is a rational target to treat prostate cancer bone metastasis. RESULTS: In this study, we demonstrate the role of ß2-M and its binding partner, HFE, in modulating radiation sensitivity and chemo-sensitivity of prostate cancer. By genetic deletion of ß2-M or HFE or using an anti-ß2-M antibody (Ab), we demonstrate that prostate cancer cells are sensitive to radiation in vitro and in vivo. Inhibition of ß2-M or HFE sensitized prostate cancer cells to radiation by increasing iron and reactive oxygen species and decreasing DNA repair and stress response proteins. Using xenograft mouse model, we demonstrate that anti-ß2-M Ab sensitizes prostate cancer cells to radiation treatment. Additionally, anti-ß2-M Ab was able to prevent tumor growth in an immunocompetent spontaneous prostate cancer mouse model. Since bone metastasis is lethal, we used a bone xenograft model to test the ability of anti-ß2-M Ab and radiation to block tumor growth in the bone. Combination treatment significantly prevented tumor growth in the bone xenograft model by inhibiting ß2-M and inducing iron overload. In addition to radiation sensitive effects, inhibition of ß2-M sensitized prostate cancer cells to chemotherapeutic agents. CONCLUSION: Since prostate cancer bone metastatic patients have high ß2-M in the tumor tissue and in the secreted form, targeting ß2-M with anti-ß2-M Ab is a promising therapeutic agent. Additionally, inhibition of ß2-M sensitizes cancer cells to clinically used therapies such as radiation by inducing iron overload and decreasing DNA repair enzymes.

Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis.

Little is known about the pathophysiology of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is essential for biosynthesis and secretion of collagen molecules. Previous studies in experimental animal fibrosis models have shown that downregulation of HSP47 expression reduces collagen production and diminishes fibrosis progression. In this study, serum HSP47 levels were evaluated to elucidate pathogenic differences involving HSP47 between AE-IPF and stable (S)-IPF. Subjects comprised 20 AE-IPF and 33 S-IPF patients. Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, SP-D, and lactate dehydrogenase (LDH) were measured. Immunohistochemical analysis of lung HSP47 expression was determined in biopsy and autopsy tissues diagnosed as diffuse alveolar damage (DAD) and usual interstitial pneumonia (UIP). Serum levels of HSP47 were significantly higher in AE-IPF than in S-IPF patients, whereas serum levels of KL-6, SP-A, and SP-D did not differ significantly. Receiver operating characteristic curves revealed that HSP47 was superior for discriminating AE-IPF and S-IPF. The cutoff for HSP47 resulting in the highest diagnostic accuracy was 559.4 pg/mL; sensitivity, specificity, and diagnostic accuracy were 100.0%, 93.9%, and 96.2%, respectively. Immunohistochemical analysis revealed that pulmonary HSP47 expression was greater in DAD than UIP tissues. Serum HSP47 was significantly higher in AE-IPF than in S-IPF patients, suggesting that underlying fibrogenic mechanisms involving HSP47 differ in the two conditions.

A single nucleotide polymorphism within the novel sex-linked testis-specific retrotransposed PGAM4 gene influences human male fertility.

BACKGROUND: The development of novel fertilization treatments, including in vitro fertilization and intracytoplasmic injection, has made pregnancy possible regardless of the level of activity of the spermatozoa; however, the etiology of male-factor infertility is poorly understood. Multiple studies, primarily through the use of transgenic animals, have contributed to a list of candidate genes that may affect male infertility in humans. We examined single nucleotide polymorphisms (SNPs) as a cause of male infertility in an analysis of spermatogenesis-specific genes. METHODS AND FINDING: We carried out the prevalence of SNPs in the coding region of phosphoglycerate mutase 4 (PGAM4) on the X chromosome by the direct sequencing of PCR-amplified DNA from male patients. Using RT-PCR and western blot analyses, we identified that PGAM4 is a functional retrogene that is expressed predominantly in the testes and is associated with male infertility. PGAM4 is expressed in post-meiotic stages, including spermatids and spermatozoa in the testes, and the principal piece of the flagellum and acrosome in ejaculated spermatozoa. A case-control study revealed that 4.5% of infertile patients carry the G75C polymorphism, which causes an amino acid substitution in the encoded protein. Furthermore, an assay for enzymatic activity demonstrated that this polymorphism decreases the enzyme's activity both in vitro and in vivo. CONCLUSION: These results suggest that PGAM4, an X-linked retrogene, is a fundamental gene in human male reproduction and may escape meiotic sex chromosome inactivation. These findings provide fresh insight into elucidating the mechanisms of male infertility.

Water avoidance stress induces frequency through cyclooxygenase-2 expression: a bladder rat model.

OBJECTIVES: Water avoidance stress is a potent psychological stressor and it is associated with visceral hyperalgesia, which shows degeneration of the urothelial layer mimicking interstitial cystitis. Cyclooxygenase-2 inhibitors have been recognized to ameliorate frequency both in clinical and experimental settings. We investigated the voiding pattern and cyclooxygenase-2 expression in a rat bladder model of water avoidance stress. METHODS: After being subjected to water avoidance stress or a sham procedure, rats underwent metabolic cage analysis and cystometrography. Real time reverse transcription polymerase chain reaction was carried out to examine cyclooxygenase-2 messenger ribonucleic acid in bladders of rats. Protein expression of cyclooxygenase-2 was analyzed with immunohistochemistry and western blotting. Furthermore, the effects of the cyclooxygenase-2 inhibitor, etodolac, were investigated by carrying out cystometrography, immunohistochemistry and western blotting. RESULTS: Metabolic cage analysis and cystometrography showed significantly shorter intervals and less volume of voiding in water avoidance stress rats. Significantly higher expression of cyclooxygenase-2 messenger ribonucleic acid was verified by reverse transcription polymerase chain reaction. Immunohistochemistry and western blotting showed significantly higher cyclooxygenase-2 protein levels in water avoidance stress bladders. Furthermore, immunohistochemistry showed high cyclooxygenase-2 expression exclusively in smooth muscle cells. All water avoidance stress-induced changes were reduced by cyclooxygenase-2 inhibitor pretreatment. CONCLUSIONS: Chronic stress might cause frequency through cyclooxygenase-2 gene upregulation in bladder smooth muscle cells. Further study of cyclooxygenase-2 in the water avoidance stress bladder might provide novel therapeutic modalities for interstitial cystitis.

HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats.

Thrombin activates immunocompetent microglia and increases release of inflammatory cytokines under intracerebral hemorrhage (ICH) insults. Also, thrombin injection into the striatum evokes acute necrosis and delayed apoptosis of neurons. A nucleoprotein high-mobility group box 1 (HMGB1) that is released from necrotic cells has been suggested to behave like a cytokine and cause over-facilitation of immune functions. Here we examined the effect of glycyrrhizin, known as an inhibitor of HMGB1, on thrombin-induced injury in rat cortico-striatal slice cultures and in vivo rat ICH model. In slice cultures, thrombin-induced a drastic increase in propidium iodide fluorescence indicating necrotic cell death in the cortical region, and robust shrinkage of the striatal tissue. Glycyrrhizin (10-100 µM) attenuated thrombin-induced cortical injury in a concentration-dependent manner. The protective effect of glycyrrhizin was not mediated by glucocorticoid receptors or modulation of nitric oxide production, but was reversed by exogenous HMGB1 application. The injury induced by a high concentration of HMGB1 was suppressed by glycyrrhizin. In vivo, unilateral injection of type IV collagenase into rat striatum induced ICH associated with brain edema formation, contralateral paralysis and neuron death. Once daily intraperitoneal administration of glycyrrhizin attenuated ICH-induced edema in both the cortex and the basal ganglia, and improved behavioral performance of rats in forelimb placing. Moreover, glycyrrhizin partially but significantly ameliorated ICH-induced neuron loss inside hematoma. These findings suggest that an HMGB1 inhibitor glycyrrhizin is a potential candidate for a remedy for ICH.

Solifenacin may improve sleep quality in patients with overactive bladder and sleep disturbance.

OBJECTIVE: To examine the effect of solifenacin for not only overactive bladder symptoms but also sleep disturbance. Nocturia and urgency are independent factors for sleep disturbance. METHODS: Fifteen male patients with overactive bladder symptoms and sleep disturbance were enrolled in this study. The overactive bladder symptoms score (OABSS) and Athens insomnia scale (AIS) were used as a subjective questionnaire for overactive bladder symptoms and insomnia. The Actiwatch-16 (Mini-Mitter-Respironics, Inc., Bend, OR) was used as an objective measurement tool for insomnia. Total sleep time, sleep efficiency, sleep latency, wake-after-sleep onset, and number of awakenings were measured by the Actiwatch. We evaluated the changes of each parameter before and 8 weeks after the administration of solifenacin. Statistical comparisons before and after the administration were made using the Wilcoxon signed-rank test. To examine the relation between OABSS and AIS, Spearman's testing was used for correlations between independent variables and P<.05 was considered statistically significant. RESULTS: Total OABSS and total AIS were significantly improved after administration of solifenacin. The categories of urgency and nocturia in OABSS and the categories of awakening during the night and sleep quality in AIS were also significantly improved. The Actiwatch study showed that total sleep time and sleep efficiency were significantly improved. The decrease of AIS was significantly correlated with the decrease of urgency (ρ=0.635, P=.0175) but not with nocturia. CONCLUSION: The treatment of urgency by solifenacin may improve not only overactive bladder symptoms but also sleep disturbance.

Dietary glucosylceramide enhances cornified envelope formation via transglutaminase expression and involucrin production.

In this study, we investigated whether dietary glucosylceramide (GlcCer) and its metabolite sphingoid bases, sphingosine (SS), phytosphingosine (PS), sphingadienine (SD) and 4-hydroxysphingenine (4HS), influence cornified envelope (CE) formation. CE is formed during terminal differentiation of the epidermis through crosslinking of specific precursor proteins by transglutaminases (TGases), and is essential for the skin's barrier function. Oral administration of GlcCer (0.25 mg/day) for 14 consecutive days dramatically reduced transepidermal water loss, an indicator of the skin barrier condition, in hairless mice with barrier perturbation induced by single-dose ultraviolet B (UVB) irradiation. The GlcCer treatment also increased the level of TGase-1 mRNA in UVB-irradiated murine epidermis approximately 1.6-fold compared with the control. Further, all four sphingoid bases at 1 µM concentration enhanced CE formation of cultured normal human keratinocyte cells. Among them, SS, PS and SD, but not 4HS, stimulated production of involucrin, one of the CE major precursor proteins. SD increased the expression of TGase-1 mRNA, while SS increased the expression of TGase-3 mRNA. These results indicate that the skin barrier improvement induced by oral GlcCer treatment might be at least partly due to a reinforcement of CE formation in the epidermis mediated by sphingoid bases metabolically derived from GlcCer.

Lower urinary tract symptoms and erectile dysfunction associated with depression among Japanese patients with late-onset hypogonadism symptoms.

The aim of this study was to investigate the relation between lower urinary tract symptoms (LUTS), erectile dysfunction (ED) and depression in Japanese patients with late-onset hypogonadism (LOH) symptoms. The study comprised 87 Japanese patients with LOH symptoms (>27 points on the Aging Males Symptoms Scale). Thirty-four patients were diagnosed as having depression and the remaining 53 patients were diagnosed as not having depression by the Mini International Neuropsychiatric Interview. We compared the International Index of Erectile Function (IIEF) 5, International Prostate Symptom Score (IPSS), IPSS quality-of-life (QOL) index, King's Health Questionnaire (KHQ), endocrinological data, and free uroflow study between depression and non-depression patients and performed multiple logistic regression analysis. IIEF5 scores of depression patients were significantly lower than those of non-depression patients. In KHQ, only the category of general health perceptions was significantly higher in depression patients than non-depression patients. However, IPSS, QOL index, and endocrinological and uroflowmetric data showed no significant difference between the groups. Multiple logistic regression analysis revealed moderate and severe ED to be risk factors for depression. However, LUTS are not related to depression. Moderate and severe ED is correlated with depression, whereas LUTS are not related to depression in Japanese LOH patients.

Tumor-stroma co-evolution in prostate cancer progression and metastasis.

Cancer development is complex and involves several layers of interactions and pleotropic signaling mechanisms leading to progression. Cancer cells associate with resident stromal fibroblasts, smooth muscle cells, macrophages, endothelium, neurons and migrating cells at metastatic sites and phenotypically and genotypically activate them. These become an integral part of the cancer cell community through activated cell signaling mechanisms. During this process, the cancer cells and cells in the cancer microenvironment "co-evolve" in part due to oxidative stress, and acquire the ability to mimic other cell types (which can be termed osteomimicry, vasculomimicry, neuromimicry and stem cell mimicry), and undergo transition from epithelium to mesenchyme with definitive morphologic and behavioral modifications. In our laboratory, we demonstrated that prostate cancer cells co-evolve in their genotypic and phenotypic characters with stroma and acquire osteomimetic properties allowing them to proliferate and survive in the skeleton as bone metastasis. Several signaling interactions in the bone microenvironment, mediated by reactive oxygen species, soluble and membrane bound factors, such as superoxide, beta2-microglobulin and RANKL have been described. Targeting the signaling pathways in the cancer-associated stromal microenvironment in combination with known conventional therapeutic modalities could have a synergistic effect on cancer treatment. Since cancer cells are constantly interacting and acquiring adaptive and survival changes primarily directed by their microenvironment, it is imperative to delineate these interactions and co-target both cancer and stroma to improve the treatment and overall survival of cancer patients.