Muscle strength characteristics following megaprosthetic knee reconstruction for bone sarcoma.

OBJECTIVE: To assess muscle strength characteristics in patients with resection and megaprosthetic reconstruction of the knee for bone sarcoma compared to age- and sex-matched controls. METHODS: This was a cross-sectional, case-control study. Muscle strength characteristics for knee extension and -flexion were assessed isokinetically at three different joint velocities: 60, 120 and 180°/s, and by the rate of force development (RDFmax) in knee extension. The Toronto Extremity Salvage Score (TESS) was used in patients. RESULTS: Eighteen patients (91.6 months postop.) and 18 controls were included. Relative to controls, patients generated maximal torques of 19%, 23% and 23% in knee extension at 60, 120 and 180°/s, respectively. For knee flexion, patients generated maximal torques of 58%, 53% and 60% at 60, 120, and 180°/s, relative to the controls. RDFmax of the operated leg was 2.75 ± 2.13 N/ms, 7.16 ± 4.78 N/ms for the non-operated leg, and 7.95 ± 4.29 N/ms for the controls. The mean TESS score was 84.0. CONCLUSION: Patients reached approximately 20% of the maximal knee extension torque. In isometric assessments, they used double the amount of time to generate one-third of the maximal force compared to the controls despite good TESS scores.

Megaprosthesis for Metastatic Bone Disease-A Comparative Analysis.

BACKGROUND: Megaprosthetic reconstruction is sometimes indicated in advanced metastatic bone disease (MBD) of the appendicular skeleton with large degrees of bone loss or need for oncological segmental resection. Outcome after megaprosthetic reconstruction was studied in the setting of primary bone sarcoma with high levels of complications, but it is not known if this applies to MBD. METHOD: We performed a comparative analysis of complications and revision surgery for MBD and bone sarcoma surgery in an institutional cohort from 2005-2019. Presented are the descriptive data of the cohort, with Kaplan-Meier (K-M) rates of revision at 1, 2 and 5 years together with a competing risk analysis by indication type. RESULTS: Rates of revision surgery are significantly lower for MBD (8% at 1 year, 12% at 2 years), in the intermediate term, compared to that of sarcoma (18% at 1 year, 24% at 2 years) (p = 0.04). At 5 years this is not significant by K-M analysis (25% for MBD, and 33% for sarcoma), but remains significant in a competing risk model (8% for MBD, and 20% for sarcoma) (p = 0.03), accounting for death as a competing event. CONCLUSION: Rates of revision surgery after megaprosthetic reconstruction of MBD are significantly lower than that for primary bone sarcoma in this cohort.

Chondrosarcoma local recurrence in the Cancer Registry of Norway cohort (1990-2013): Patterns and impact.

BACKGROUND: There appears to be an association between local recurrence (LR) and risk of metastasis and death in central conventional chondrosarcoma (CCCS) of bone, but this has not been quantified in modern cohorts at a subtype level. METHODS: We identified nonmetastatic cases of CCCS (N = 180) from the Cancer Registry of Norway. We present prognostic analysis of LR accounting for immortal time bias by descriptive statistics and multivariable Cox models. RESULTS: Of 40 LR, one case demonstrated upgrading while two dedifferentiation. LR was associated with increased risk of metastasis (hazard ratio [HR] = 4.1 [confidence interval, 1.5-10.7]) and death (HR = 9.3 [5.0-17.5]) overall. LR was associated with significant increased risk of metastasis for those with a soft tissue component, axial location, malignancy grade 2, but not atypical cartilaginous tumor's, appropriately treated curettage patients, intramedullary tumors, grade 1 histology, extremity location or "Oslo low risk" group status. We found an increased risk of death for all groups except for those treated by appropriate curettage or belonging to the "Oslo low risk" group. About 50% of LR CCCS were asymptomatic and revealed by routine follow-up. CONCLUSIONS: Upgrading of LR for CCCS was a seldom event. LR was associated with significant increased risk of metastasis and death overall, but not for appropriately treated curettage patients or "Oslo low risk" status.

Risk stratification for central conventional chondrosarcoma of bone: A novel system predicting risk of metastasis and death in the Cancer Registry of Norway cohort.

BACKGROUND AND OBJECTIVES: Interobserver variability in histological grading of central conventional chondrosarcoma (CCCS) limits the quality of patient information and research progression. We aim to quantify known and new prognostic variables and propose a risk stratification model. METHOD: We selected 149 cases from the Cancer Registry of Norway. Cox proportional hazard models were estimated. Based on these results a dichotomous risk classification was proposed and presented by Kaplan-Meier estimates for rates of local recurrence, metastasis, and disease-specific survival. RESULTS: The influence of axial skeletal location (Hazard ratio [HR] = 19.06), a soft tissue component ≥1 cm (HR = 13.45), and histological grade 3 (HR = 16.46) are all significant in predicting the rate of metastasis. The creation of a variable combining axial skeletal location and a soft tissue component ≥1 cm strongly predicts the risk of metastasis (HR = 14.02; P < .001) and death (HR = 2.74; P = .030) at multivariate analysis, making the histological grade insignificant. Together with metastasis at diagnosis (HR = 285.65; P < .001), this forms the basis of our proposed risk stratification, producing a small high-risk group (39 cases with 33% risk of metastasis) and a large low-risk group (103 cases with 2% risk of metastasis) without a histological grade. CONCLUSION: Axial skeletal location and a soft tissue component ≥1 cm combined divides a CCCS cohort into low- and high-risk groups without a histological grade.

Chondrosarcoma in Norway 1990-2013; an epidemiological and prognostic observational study of a complete national cohort.

BACKGROUND: Knowledge of chondrosarcoma (CS) of bone to date is based on institutional reports and registry publications with limits in reporting, detail and quality of data. METHOD: We have performed a retrospective search of CS of bone in the National Cancer Registry in Norway from 1990-2013, cross checked against local tumor databases with further quality control and supplementation of all data from clinical files. The time period is defined by the routine use of axial imaging in clinical practice. A total of 311 cases are included. We performed 108 pathological reviews and 223 radiological reviews. The manuscript was prepared according to the STROBE checklist for strengthening of observational studies. We performed uni-/multivariate cox analyses to define independent prognostic variables from the main cohort of central CS of bone. RESULTS: The incidence of CS of bone in Norway is 2.85/million/yr. for both sexes overall, rising to 3.45/million/yr. in the last 5-year period. There is an increase in the most common central CS subtype, stronger for women than for men. Central CS had, in general 10-15% local recurrence rates, all evident by 5 years while metastasis rate increases with location and grade. Exceptions are extremity grade 1 CS which displayed no metastatic events and axial grade-3 disease with high rates (50%) of both local and metastatic relapse. Peripheral CS had limited metastatic potential (2%), but rates of local relapse (13%) continue to appear towards 10 years of follow up. Malignancy grade 3 independently predicts rate of metastasis and presence of soft tissue component predicts local recurrence, metastasis and survival. CONCLUSION: Rates of local recurrence, metastasis and disease specific survival follow clear patterns depending on subtype, location and grade allowing better tailoring of follow-up regimes. Malignancy grade 3 and the presence of a soft tissue component independently predict behavior for central CS of bone.

APC mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15-20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.

Photochemical delivery of bleomycin induces T-cell activation of importance for curative effect and systemic anti-tumor immunity.

Photochemical internalization (PCI) is a technology to enhance intracellular drug delivery by light-induced translocation of endocytosed therapeutics into the cytosol. The aim of this study was to explore the efficacy of PCI-based delivery of bleomycin and the impact on systemic anti-tumor immunity. Mouse colon carcinoma cells (CT26.CL25), stably expressing the bacterial ß-galactosidase, were inoculated into the legs of athymic or immuno-competent BALB/c mice strains. The mice were injected with the photosensitizer AlPcS2a and bleomycin (BLM) prior to tumor light exposure from a 670nm diode laser. Photochemical activation of BLM was found to induce synergistic inhibition of tumor growth as compared to the sum of the individual treatments. However, a curative effect was not observed in the athymic mice exposed to 30J/cm2 of light while >90% of the thymic mice were cured after exposure to only 15J/cm2 light. Cured thymic mice, re-challenged with CT26.CL25 tumor cells on the contralateral leg, rejected 57-100% of the tumor cells inoculated immediately and up to 2months after the photochemical treatment. T-cells from the spleen of PCI-treated mice were found to inhibit the growth of CT26.CL25 cells in naïve thymic mice with a 60% rejection rate. The results show that treatment of CT26.CL25 tumors in thymic mice by PCI of BLM induces a systemic anti-tumor immunity.

Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules.

A successful cure of cancer by biopharmaceuticals with intracellular targets is dependent on both specific and sufficient delivery of the drug to the cytosol or nuclei of malignant cells. However, cytosolic delivery and efficacy of membrane-impermeable cancer therapeutics are often hampered by the sequestration and degradation of the drugs in the endolysosomal compartments. Hence, we developed photochemical internalization (PCI) as a site-specific drug delivery technology, which bursts the membrane of endocytic vesicles inducing release of entrapped drugs to the cytosol of light exposed cells. The principle of PCI has been demonstrated in >80 different cell lines and 10 different xenograft models of various cancers in different laboratories demonstrating its broad application potential. PCI-induced endosomal escape of protein- or nucleic acid-based therapeutics and some chemotherapeutics will be presented in this review. With a joint effort by life scientists the PCI technology is currently in a Phase I/II clinical trial with very promising initial results in the treatment of solid tumors.

Photochemical internalization of bleomycin before external-beam radiotherapy improves locoregional control in a human sarcoma model.

PURPOSE: The aim of this study was to explore the tumor growth response of the combination photochemical internalization and external-beam radiotherapy. Photochemical internalization is a technology to improve the utilization of therapeutic macromolecules in cancer therapy by photochemical release of endocytosed macromolecules into the cytosol. METHODS AND MATERIALS: A human sarcoma xenograft TAX-1 was inoculated subcutaneously into nude mice. The photosensitizer AlPcS(2a) and bleomycin were intraperitoneally administrated 48 h and 30 min, respectively, before diode laser light exposure at 670 nm (20 J/cm(2)). Thirty minutes or 7 days after photochemical treatment, the animals were subjected to 4 Gy of ionizing radiation. RESULTS: Using photochemical internalization of bleomycin as an adjunct to ionizing radiation increased the time to progression for the tumors from 17 to 33 days as compared with that observed with photodynamic therapy combined with ionizing radiation as well as for radiochemotherapy with bleomycin. The side effects observed when photochemical internalization of bleomycin was given shortly before ionizing radiation were eliminated by separating the treatment modalities in time. CONCLUSION: Photochemical internalization of bleomycin combined with ionizing radiation increased the time to progression and showed minimal toxicity and may therefore reduce the total radiation dose necessary to obtain local tumor control while avoiding long-term sequelae from radiotherapy.

Photochemical internalization as an adjunct to marginal surgery in a human sarcoma model.

Local recurrences after inadequate surgery are a major challenge in many cancers. Photochemical internalization (PCI) is a new technology to release endocytosed macromolecules into the cytosol by a photochemical rupture of the endocytic vesicles. A recent study on an invasive human fibrosarcoma xenograft HT1080 indicated low sensitivity of the tumour periphery to disulfonated aluminium phthalocyanine (AlPcS(2a))-based photochemical treatment. The main goal of the present study was to evaluate the sensitivity of the remaining tumour after marginal resection of the HT1080 tumour to the photochemical treatment alone and PCI of bleomycin. AlPcS(2a) and bleomycin was systemically administrated 48 h and 30 min, respectively, prior to surgery and immediately followed by intra-operative light exposure at 670 nm (15 J cm(-2)). PCI of bleomycin as an adjunct to surgery did significantly delay tumour growth in contrast to the photochemical treatment alone. The results indicate that PCI of bleomycin may be an efficient intra-operative technique to eradicate cancer cells in the wound bed after inadequate surgery.

Photochemical internalization (PCI) in cancer therapy: from bench towards bedside medicine.

PDT in cancer therapy has been reviewed several times recently and many published reports have been showing promising results. The clinical approvals for PDT include curative treatment of early or superficial cancers and palliative treatment of more advanced disease. Still PDT has yet to become a widely used cancer treatment. This may partly be due to limitations in current PDT regimens and partly due to effective alternative treatment modalities. If the specificity and selectivity of PDT could be improved, PDT would probably make substantial progress and comprise an even more competitive alternative in cancer treatment. The PCI technology is based on the same principles as PDT, the activation of a photosensitizer by light and subsequently followed by formation of reactive oxygen species. Unlike PDT, the photosensitizer used in PCI has to be located in the endocytic vesicles of the targeted cells and will, upon activation of light, induce a release of endocytosed therapeutic agents after a photochemically induced rupture of the endocytic vesicles. The endocytosed therapeutic agent will then be released and may reach their intracellular target of action before being degraded in lysosomes. This site-specific drug delivery induced by PCI will take place in addition to the well described cytotoxic, vascular and immunostimulatory effects of PDT. PCI has been shown to facilitate intracellular delivery of a large variety of macromolecules that do not otherwise readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), RIP-based immunotoxins, genes and some chemotherapeutic agents. Several animal models have been used for in vivo documentation of the PCI principle and more animal models of clinical relevance have recently been utilized for addressing clinical issues. This review will focus on the possibilities and limitations offered by PCI to overcome some of the challenges recognized in current PDT regimens in cancer treatment.

Photochemical internalization of bleomycin is superior to photodynamic therapy due to the therapeutic effect in the tumor periphery.

Photochemical internalization (PCI) is under development for clinical use in treatment of soft tissue sarcomas and other solid tumors. PCI may release endocytosed bleomycin (BLM) into the cytosol by photochemical rupture of the endocytic vesicles. In this study, the human fibrosarcoma xenograft HT1080 was transplanted into the leg muscle of athymic mice. The photosensitizer disulfonated aluminum phthalocyanine (AlPcS(2a)) and BLM were systemically administrated 48 h and 30 min, respectively, prior to light exposure at 670 nm (30 J cm(-2)). The purposes of this study were to evaluate the treatment response to AlPcS(2a)-photodynamic therapy (PDT) and AlPcS(2a)-PDT in combination with BLM (i.e. PCI of BLM) in an orthotopic, invasive and clinically relevant tumor model and to explore the underlying response mechanisms caused by PDT and PCI of BLM. The treatment response was evaluated by measuring tumor growth, contrast-enhanced magnetic resonance imaging (CE-MRI), histology and fluorescence microscopy. The results show that PCI of BLM is superior to PDT in inducing tumor growth retardation and acts synergistically as compared to the individual treatment modalities. The CE-MRI analyses 2 h after AlPcS(2a)-PDT and PCI of BLM identified a treatment-induced nonperfused central zone of the tumor and a well-perfused peripheral zone. While there were no differences in the vascular response between PDT and PCI, the histological analyses showed that PDT caused necrosis in the tumor center and viable tumor cells were found in the tumor periphery. PCI caused larger necrotic areas and the regrowth in the peripheral zone was almost completely inhibited after PCI. The results indicate that PDT is less efficient in the tumor periphery than in the tumor center and that the treatment effect of PCI is superior to PDT in the tumor periphery.

Photochemical internalization: a new tool for drug delivery.

The utilisation of macromolecules in the therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve targeting and design of cytotoxic agents, DNA complexes and other macromolecules for clinical applications. In many cases the targets of macromolecular therapeutics are intracellular. However, degradation of macromolecules in endocytic vesicles after uptake by endocytosis is a major intracellular barrier for the therapeutic application of macromolecules having intracellular targets of action. Photochemical internalisation (PCI) is a novel technology for the release of endocytosed macromolecules into the cytosol. The technology is based on the activation by light of photosensitizers located in endocytic vesicles to induce the release of macromolecules from the endocytic vesicles. Thereby, endocytosed molecules can be released to reach their target of action before being degraded in lysosomes. PCI has been shown to stimulate intracellular delivery of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), DNA delivered as gene-encoding plasmids or by means of adenovirus or adeno-associated virus, peptide nucleic acids (PNAs) and chemotherapeutic agents such as bleomycin and in some cases doxorubicin. PCI of PNA may be of particular importance due to the low therapeutic efficacy of PNA in the absence of an efficient delivery technology and the 10-100-fold increased efficacy in combination with PCI. The efficacy and specificity of PCI of macromolecular therapeutics has been improved by combining the macromolecules with targeting moieties, such as the epidermal growth factor. In general, PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that it may have a variety of useful applications for site-specific drug delivery as for example in gene therapy, vaccination and cancer treatment.

Interprosthetic dislocations of the Charnley/Hastings hemiarthroplasty--report of 11 cases in 350 consecutive patients.

We report 11 cases of interprosthetic dislocation of the Charnley/Hastings hemiarthroplasty in a retrospective study of 350 consecutive patients treated for an acute femoral neck fracture. We found a total of 14 dislocations (4.0%), 11 were interprosthetic. The median age of the 350 patients was 79 (36-99) years and the median age of the 11 patients with an interprosthetic dislocation was 85 years (82-94). The median time from surgery to radiologically acknowledged dislocation was 18 (4-64) days. These interprosthetic dislocations may be caused by either an assembly mistake perioperatively, by maximum angulation and impingement between the components, or by trauma.