Tumor-induced osteomalacia: An overview.

Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field.

Uterine Inflammatory Myofibroblastic Neoplasms With Aggressive Behavior, Including an Epithelioid Inflammatory Myofibroblastic Sarcoma: A Clinicopathologic Study of 9 Cases.

The experience with uterine inflammatory myofibroblastic neoplasms with an unfavorable outcome is limited. We present the clinicopathologic features of 9 such cases, including 8 inflammatory myofibroblastic tumors (IMTs) and 1 epithelioid inflammatory myofibroblastic sarcoma (EIMS). Median patient age for the IMT group was 50.5 years; the patient with EIMS was 43 years old. Patients presented with abnormal uterine bleeding, presumed fibroids, pelvic pain, arthralgia and low-grade fever, as well as an incidental finding. Median tumor size for the IMTs was 8.5 cm. The borders were either infiltrative or well-circumscribed. Histologically, IMTs were purely fascicular or myxoid or showed predominance of one or the other pattern. Seven tumors were spindled, and 1 was both spindled and epithelioid. Tumors had variable nuclear atypia, ranging from grade 1 to 3. All tumors had an inflammatory infiltrate-predominantly lymphocytic, majority had necrosis (62.5%) and none had lymphovascular invasion. 7/8 (87.5%) tumors were positive for ALK-1 by immunohistochemistry (IHC). One tumor was negative for ALK-1 by IHC but was positive for ALK fusion by fluorescence in situ hybridization and had TNS1-ALK fusion by next-generation sequencing (NGS). Three other tumors with NGS testing showed one of the following ALK-fusion partners: FN1, DCTN1, and IGFBP5. The EIMS had infiltrative borders, myxoid and hyalinized patterns, epithelioid cells, and no lymphovascular invasion. This tumor was ALK-1 positive by IHC, had ALK rearrangement by fluorescence in situ hybridization and RANBP2-ALK fusion by NGS. Extrauterine disease at time of diagnosis was noted in 2/8 (25%) of IMTs, and in the single case of EIMS. Seven patients had surgery as primary treatment, 1 patient had neoadjuvant chemotherapy and 1 patient declined treatment. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, radiotherapy or hormonal therapy. Most patients (71.4%) recurred within 24 months (mos). Two thirds of patients were alive with disease at last follow up (mean 43.6 mos). The patient with EIMS was alive with disease at 22 mos. IMT referral cases were initially diagnosed as smooth muscle tumors in 87.5% of cases; while the EIMS was diagnosed as high-grade endometrial stromal sarcoma. Lack of consideration of IMT in the differential diagnosis of smooth muscle tumors with myxoid features can result in misdiagnosis and under-utilization of targeted therapy in these patients.

Emerging roles of ECM remodeling processes in cancer.

Extracellular matrix (ECM) plays a central and dynamic role in the creation of tumor microenvironment. Herein we discuss the emerging biophysical and biochemical aspects of ECM buildup and proteolysis in cancer niche formation. Dysregulated ECM remodeling by cancer cells facilitate irreversible proteolysis and crosslinking, which in turn influence cell signaling, micro environmental cues, angiogenesis and tissue biomechanics. Further, we introduce the emerging roles of cancer microbiome in aberrant tumor ECM remodeling and membrane bound nano-sized vesicles called exosomes in creation of distant pre-metastatic niches. A detailed molecular and biophysical understanding of the ECM morphologies and its components such as key enzymes, structural and signaling molecules are critical in identifying the next generation of therapeutic and diagnostic targets in cancer.

Worsening of unrecognized tumour-induced osteomalacia with inadvertent use of recombinant human parathyroid hormone.

Not required for Clinical Vignette.

Combination therapy comprising irreversible electroporation and hydroxycamptothecin loaded electrospun membranes to treat rabbit VX2 subcutaneous cancer.

Irreversible electroporation (IRE) is a kind of promising cancer treatment technology. However, local recurrence still occurs because of incomplete ablation. The aim of this study was to investigate the combined therapy of IRE and a hydroxycamptothecin loaded electrospun membrane (EM/HCPT) to treat rabbit VX2 subcutaneous cancer. HCPT loaded membranes were developed by electrospinning. Mechanical test and in vitro drug release study of EM/HCPT were performed. 24 rabbits with subcutaneous VX2 tumor were randomly divided into four groups: the control group, the EM/HCPT group, the IRE ablation group, and the IRE + EM/HCPT group. The tumor cells were ablated by IRE first, followed by subcutaneous implantation of EM/HCPT to release HCPT constantly in order to damage the residual cancer cells. The tumor inhibition efficacy was assessed by the tumor real-time monitoring, histological and immunofluorescent analyses, and transmission electron microscopy (TEM) examination. Assessment of the release from EM/HCPT showed that HCPT release lasted for about 7 days. The in vivo antitumor efficacy assessment, histological and immunofluorescent analyses, and TEM examination showed that IRE + EM/HCPT had the best tumor inhibition ability. In addition, the biochemical analyses and hematoxylin and eosin (H&E) staining of normal organs indicated that IRE + EM/HCPT treatment was safe. Our study provided a new concept in cancer treatment and might promote the application of IRE.

Using biology to guide the treatment of sarcomas and aggressive connective-tissue tumours.

Sarcomas are a heterogeneous group of malignancies that arise from cells of a mesenchymal origin. Surgery forms the mainstay of the treatment of most patients with localized sarcoma and might be followed or preceded by chemotherapy and/or radiotherapy. In the metastatic setting, systemic treatments tend to improve survival and control symptoms. However, the adverse events and sometimes disappointing outcomes associated with these empirical approaches to treatment indicate a need for new approaches. The advent of next-generation sequencing (NGS) has enabled more targeted treatment of many malignancies based on the presence of specific alterations. NGS analyses of sarcomas have revealed the presence of many alterations that can be targeted using therapies that are already used in patients with other forms of cancer. In this Review, we describe the genomic alterations considered to define specific nosological subgroups of sarcoma and whose contribution to oncogenesis provides a biological rationale for the use of a specific targeted therapy. We also report several less successful examples that should guide researchers and clinicians to better define the extent to which the identification of driver molecular alterations should influence the development of novel treatments.

Locally Aggressive Connective Tissue Tumors.

In this review, we highlight the complexities of the natural history, biology, and clinical management of three intermediate connective tissue tumors: desmoid tumor (DT) or aggressive fibromatosis, tenosynovial giant cell tumor (TGCT) or diffuse-type pigmented villonodular synovitis (dtPVNS), and giant cell tumor of bone (GCTB). Intermediate histologies include tumors of both soft tissue and bone origin and are locally aggressive and rarely metastatic. Some common aspects to these tumors are that they can be locally infiltrative and/or impinge on critical organs, which leads to disfigurement, pain, loss of function and mobility, neurovascular compromise, and occasionally life-threatening consequences, such as mesenteric, bowel, ureteral, and/or bladder obstruction. DT, PVNS, and GCTB have few and recurrent molecular aberrations but, paradoxically, can have variable natural histories. A multidisciplinary approach is recommended for optimal management. In DT and PVNS, a course of observation may be appropriate, and any intervention should be guided by symptoms and/or disease progression. A surgical approach should take into consideration the infiltrative nature, difficulty in obtaining wide margins, high recurrence rates, acute and chronic surgical morbidities, and impact on quality of life. There are similar concerns with radiation, which especially relate to optimal field and transformation to high-grade radiation-associated sarcomas. Systemic therapies must be considered carefully in light of acute and chronic toxicities. Although standard and novel therapies are promising, many unanswered questions, such as duration of therapy and optimal end points to evaluate efficacy of drugs in clinical practice and trials, exist. Predictive biomarkers and novel clinical trial end points, such as volumetric measurement, magnetic resonance imaging T2 weighted mapping, nuclear imaging, and patient-reported outcomes, are in development and will require validation in prospective trials.

Localized pigmented villonodular synovitis of posterior compartment of the knee.

Pigmented villonodular synovitis (PVNS) is an uncommon entity involving articular or extra-articular tissues and maybe localized or diffuse in extent. The knee is by far the commonest joint to get involved. Localized PVNS of the knee can occur in any location but its confinement to the posterior compartment is infrequent. We present our experience of managing localized posterior compartment PVNS of the knee. There were 10 patients (7 males and 3 females) with average age of 33 years. These patients had symptoms of pain, locking, or swelling for a mean of 13.9 years before diagnosis. All the patients underwent arthroscopic synovectomy without adjuvant therapy, and PVNS was proven on histopathology. At an average follow-up of 23 months, no patient had recurrence of symptoms. The average International Knee Documentation Committee (IKDC) score at last follow-up was 85.21. Magnetic resonance imaging evaluation at final follow-up did not reveal any residual disease or recurrence in any patient.

Malignant phosphaturic mesenchymal tumor with pulmonary metastasis: A case report.

RATIONALE: Phosphaturic mesenchymal tumor (PMT) is a new tumor entity of soft tissue and bone tumor recently accepted by the World Health Organization, which typically causes the paraneoplastic syndrome of tumor-induced osteomalacia (TIO). The majority of PMTs follow a benign clinical course and local recurrence occurs in < 10% of cases, malignant PMTs with distant organ metastasis are extremely uncommon. PATIENT CONCERNS: We reported a 41-year-old woman who was diagnosed with PMT 10 years ago with a repeated recurrence and pulmonary metastasis. DIAGNOSES: Based on clinical manifestations, MRI scan, serum biochemical indicators evaluation, followed by histopathological examination, the patient was diagnosed as malignant PMT with pulmonary metastasis. INTERVENTIONS: The patient was treated with calcium, phosphorus, and vitamin D after surgical resection and measured the serum ion concentrations every 3 months. OUTCOMES: The patient had a favorable outcome for 10 months without recurrence. LESSONS: PMTs lack of characteristic histological morphology, some recurrence cases may appear benign morphologically; the malignant PMTs are easily overlooked. Patients with PMT should be carefully evaluated and monitored, in order to early identify its malignant potential.

Oncogenic osteomalacia: role of Ga-68 DOTANOC PET/CT scan in identifying the culprit lesion and its management.

OBJECTIVE: The aim of this study was to evaluate the role of 68Ga-DOTANOC positron emission tomography (PET)/CT scan in localization of culprit lesion for biopsy and required intervention [surgical excision/radiofrequency ablation (RFA)] in patients with long-standing oncogenic osteomalacia (OOM)/tumour-induced osteomalacia. METHODS: 17 patients (8 males and 9 females) underwent 68Ga-DOTANOC PET/CT scan. The patients referred with clinical and biochemical evidence of hypophosphatemia and raised fibroblast growth factor-23. Qualitative and semi-quantitative parameters were used to identify culprit lesions. RESULTS: 68Ga-DOTANOC PET/CT scan revealed 52 lesions in 17 patients, and 37/52 of these lesions were tracer avid. 26/37 lesions were non-specific focal tracer-avid skeletal lesions (fractures or degenerative changes). 11/37 tracer-avid skeletal lesions present in 9 patients (3 lesions in 1 patient and 1 each in rest of the 8 patients) were highly suspicious for culprit lesions in view of high maximum standardized uptake value (SUVmax) (range 1.5-15.4; mean 7.0 ± 4.6), lesion size (0.9-5.0 cm; mean 3.3 ± 1.5) and associated soft-tissue component. During subsequent imaging with CT/MRI, 7/9 patients showed concordant lesions which were excised or biopsied and histopathologically verified as phosphaturic mesenchymal tumours. Surgical excision was resorted to in most of the detected lesions, and RFA was performed in one patient. CONCLUSION: There is some overlap in SUVmax between fracture-/bone-associated lesions and culprit lesions with a tendency of most non-culprit lesions to have lower SUVmax and no associated soft-tissue component. In such scenario, intensely tracer-avid, larger non-fracture lesions with soft-tissue component may lead to identification of culprit lesion among multiple lesions. Following detection of culprit lesion, surgical removal is the best treatment. RFA is alternative to surgery in cases where surgery is not possible owing to osteopenia/poor bone health. Advances in knowledge: The main challenge in patients of long-standing OOM is the presence of multiple skeletal lesions (both tumour- or tracer-avid fractures), and it is confusing to identify culprit lesion. This was noted in our study with 68Ga-DOTANOC and has not been mentioned in studies performed with 68Ga-DOTATATE/TOC PET/CT. In such scenario, 68Ga-DOTANOC PET/CT needs to be reviewed and read thoroughly to localize the culprit lesion out of the multiple tracer-avid lesions.

Tumor-Induced Osteomalacia: an Up-to-Date Review.

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome resulting in renal phosphate wasting and decreased bone mineralization. TIO is usually induced by small, slowly growing tumors of mesenchymal origin (phosphaturic mesenchymal tumor mixed connective tissue variant [PMTMCT]). Nonspecific symptoms including fatigue, bone pain, and musculoskeletal weakness make the diagnosis elusive and often lead to a delay in treatment. The prognosis of TIO is excellent following complete resection of the neoplasm, which leads to the rapid and complete reversal of all symptoms. If the tumor cannot be detected, treatment relies on supplementation with phosphate and active vitamin D compounds. Subsequent radiotherapy in case of incompletely resected tumors or definitive radiotherapy in unresectable tumors is an important treatment option to avoid recurrence or metastasis even though this occurs rarely. Due to the risk of recurrence or late metastases, long-term monitoring is required even in TIO patients diagnosed with a benign tumor.

Murine xenograft model demonstrates significant radio-sensitising effect of liposomal doxorubicin in a combination therapy for Feline Injection Site Sarcoma.

Therapy of cats suffering from feline injection site sarcomas (FISS) is still a challenging problem, as the recurrence rate after surgery is up to 70%. Four FISS-derived primary tumour cell lines and corresponding xenograft tumour mouse models were established to evaluate the efficacy of a concomitant chemo-/radiation therapy with doxorubicin. In vitro, strongly depending upon the timing of administration, pre-treatment with 0.25 µmol doxorubicin resulted in a significant enhancement of radiation-induced (3.5 Gy) tumour cell death. This result was confirmed in vivo, where only the combined chemo-/radiation therapy resulted in a significant reduction in tumour growth compared to the respective mono-therapies with either doxorubicin or radiation. These results support the use of the concomitant chemo-/radiation therapy for adjuvant treatment of FISS, particularly in advanced or recurrent disease where surgery alone is no longer feasible.

Oncogenic osteomalacia caused by phosphaturic mesenchymal tumours in the proximal and shaft of the tibia: a case report.

Oncogenic osteomalacia is caused by a small mesenchymal tumour characterised by phosphaturia, hypophosphatemia, decreased serum vitamin D3 level, and osteomalacia. Phosphaturic mesenchymal tumour of the mixed connective tissue type (PMTMCT) is the commonest subtype and usually involves a single site. We report a case of PMTMCT involving the left proximal and shaft of the tibia in a 42-year-old man.

[Anti-FGF23 antibody therapy for patients with tumor-induced osteomalacia].

Tumor-induced osteomalacia (TIO) is a disease caused by fibroblast growth factor 23 (FGF23) secreted from the causative tumor. This disease is cured by complete surgical removal of the tumor. However, there are several difficult cases in which the responsible tumors cannot be found, are incompletely removed, or relapse after the surgery. Anti-FGF23 antibody is being studied as a novel therapy for FGF23-related hypophosphatemic diseases. The efficacy of anti-FGF23 antibodies were confirmed using a murine model of X-linked hypophosphatemic rickets (XLHR) , which is the most common heritable form of FGF23-related hypophosphatemic disease. In addition, results of phase I study of single injection of humanized anti-FGF23 antibody for adult patients with XLHR were recently published and the safety and effectiveness of this antibody was shown. This antibody therapy may be useful for patients with TIO with similar pathogenesis to that of XLHR.