Management of immune-related adverse events in anti-PD-1-treated patients with advanced cutaneous squamous cell carcinoma.

Immune checkpoint inhibitors (ICI) have shown very promising results in the management of patients with inoperable or metastatic cutaneous squamous cell carcinoma (cSCC). However, ICI can cause a range of immune-related adverse events (irAEs) affecting a multitude of organs including skin, gastrointestinal tract, endocrine system, heart, lung, kidneys and the nervous system. In principle, clinical management irAEs does not change significantly with respect to the kind of cancer treated with ICI. However, advanced cSCC typically occurs in a clinically challenging patient population typically presenting with advanced age and/or significant comorbidities such as immunosuppression due to haematological malignancies and their respective treatment. Moreover, many patients with advanced cSCC are organ transplant patients taking immunosuppressants. As a consequence use of ICI per se and management of ICI-induced irAEs generates more complexity and difficulties in patients with cSCC compared to other entities. Here, we provide a brief review on the management of anti-programmed cell death protein 1-induced irAEs in patients with cSCC focusing on the characteristic clinical challenges present in this population.

Relevance of the Heisenberg-Kitaev model for the honeycomb lattice iridates A2IrO3.

Combining thermodynamic measurements with theoretical calculations we demonstrate that the iridates A2IrO3 (A=Na, Li) are magnetically ordered Mott insulators where the magnetism of the effective spin-orbital S=1/2 moments can be captured by a Heisenberg-Kitaev (HK) model with interactions beyond nearest-neighbor exchange. Experimentally, we observe an increase of the Curie-Weiss temperature from θ≈-125 K for Na2IrO3 to θ≈-33 K for Li2IrO3, while the ordering temperature remains roughly the same T(N)≈15 K. Using functional renormalization group calculations we show that this evolution of θ and T(N) as well as the low temperature zigzag magnetic order can be captured within this extended HK model. We estimate that Na2IrO3 is deep in a magnetically ordered regime, while Li2IrO3 appears to be close to a spin-liquid regime.

A population-based study examining the influence of a specialized rapid-access cancer clinic on initial treatment choice in localized prostate cancer.

INTRODUCTION: Treatment decisions in localized prostate cancer are complicated by the available choices. A rapid-access cancer clinic (RAC) has been unique to Calgary, AB, since 2007. This RAC offers multidisciplinary prostate cancer education by a urologist, medical oncologist, and radiation oncologist. It is hypothesized that treatment utilization data from decisions taken at RAC may serve to benchmark the appropriateness of treatment decisions on a population level. METHODS: Records of patients with clinically localized prostate cancer in Alberta between October 1, 2007 and September 30, 2009 were reviewed with ethics approval. Records were linked to the Alberta Cancer Registry database. Clinical, treatment, and health services characteristics pertaining to patients attending RAC were compared to the general population. The primary endpoint was utilization rates of each initial treatment. RESULTS: During this two-year period, 2838 patients were diagnosed with localized prostate cancer; 375 attended RAC. The utilization rates among RAC patients vs. the whole Alberta population were: prostatectomy 60.3% (95% confidence interval [CI] 55.3-65.2) vs. 48.0% (95% CI 47.1-50.7; χ2 p<0.001); active surveillance 16.0% (95% CI 12.3-19.7%) vs. 13.5% (95% CI 12.2-15.8; χ2 p=0.214); radiotherapy 11.7% (95% CI 8.5-15.0) vs. 18.0% (95% CI 16.9-20.5; χ2 p=0.002); and hormone therapy 8.0% (95% CI 5.2-10.8) vs. 17.4% (95% CI 16.1-18.9; χ2 p<0.001). CONCLUSIONS: A specialized clinic for localized prostate cancer may be associated with a higher likelihood of receiving surgery or active surveillance as initial treatment compared to the prostate cancer population in Alberta.

NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1.

Accumulating evidence implicates the transcription factor NF-kappaB as a positive mediator of cell growth, but the molecular mechanism(s) involved in this process remains largely unknown. Here we use both a skeletal muscle differentiation model and normal diploid fibroblasts to gain insight into how NF-kappaB regulates cell growth and differentiation. Results obtained with the C2C12 myoblast cell line demonstrate that NF-kappaB functions as an inhibitor of myogenic differentiation. Myoblasts generated to lack NF-kappaB activity displayed defects in cellular proliferation and cell cycle exit upon differentiation. An analysis of cell cycle markers revealed that NF-kappaB activates cyclin D1 expression, and the results showed that this regulatory pathway is one mechanism by which NF-kappaB inhibits myogenesis. NF-kappaB regulation of cyclin D1 occurs at the transcriptional level and is mediated by direct binding of NF-kappaB to multiple sites in the cyclin D1 promoter. Using diploid fibroblasts, we demonstrate that NF-kappaB is required to induce cyclin D1 expression and pRb hyperphosphorylation and promote G(1)-to-S progression. Consistent with results obtained with the C2C12 differentiation model, we show that NF-kappaB also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1. These data therefore identify cyclin D1 as an important transcriptional target of NF-kappaB and reveal a mechanism to explain how NF-kappaB is involved in the early phases of the cell cycle to regulate cell growth and differentiation.

p53 and Ki-67 as predictive markers for radiosensitivity in squamous cell carcinoma of the oral cavity? an immunohistochemical and clinicopathologic study.

PURPOSE: Previously published data relating the expression of p53 and Ki-67 to radiation response in head and neck cancer are conflicting. This may be due to differences in patient selection and treatment modalities. In this study of a homogenous population of patients with oral cavity cancer, Ki-67 and p53 indices were correlated with histopathologically assessed tumor regression after preoperative radiochemotherapy and longterm outcome. METHODS AND MATERIALS: Eighty-eight patients with squamous cell carcinoma of the oral cavity and treated between September 1985 and November 1995 by preoperative radiochemotherapy and definitive surgery were included in this analysis. By immunohistochemistry (IHC) the pre-irradiation expression of p53 and of Ki-67 were analyzed and correlated with the histopathologically proven tumor regression, overall survival and local control. RESULTS: The overall 2- and 5-year survival rates were 76.5% and 63%, the locoregional control rates were 84% and 79%, respectively. After preoperative radiochemotherapy 29 patients (33%) showed complete tumor regression (ypT(0) classification). Survival and local control rates were significantly higher for patients showing ypT(0) classification than ypT(1-4) classification (p < 0.01). This effect was independent of pretreatment tumor classification in multivariate analysis. Pre-irradiation p53 status and Ki-67 index had no influence on tumor regression and clinical outcome in these patients. CONCLUSION: Complete tumor regression after preoperative treatment is related to an improved outcome in combined modality treatment of oral cavity cancer. The presented study could not demonstrate an influence of p53 and Ki-67 status as detected by immunohistochemical staining on survival, local control, or tumor regression after radiochemotherapy.

Poly(L-lactide): a long-term degradation study in vivo. I. Biological results.

Three poly(L-lactides) with different molecular weights were synthesized. Small blocks (3 x 3 x 2 mm) and rods (25 x 3 x 2 mm) were produced either by injection moulding (amorphous parts, Mvis 200,000 and 120,000, respectively) or machined out of a solid aspolymerized polylactide block (crystalline parts, Mvis 429,000) and implanted into the dorsal muscle of rats. After 1 to 116 wk the rats were killed and the implants were recovered. Histological preparation was carried out using the cutting-grinding technique. All three polylactides had incorporated well, forming a collagenous fibrous layer. Crystalline block polylactide remained stable in form and structure over the whole observation period. Amorphous injection-moulded specimens developed a rough surface within weeks, then deep resorptive lacunae after ca. 1 yr and became totally degraded (Mvis 120,000) or nearly totally degraded (Mvis 200,000) after 2 yr. This velocity of biodegradation seems to meet the requirements for an absorbable material for osteosynthesis. Long-term implantation into rodents brings the problem of foreign-body tumorigenesis independent of the chemical nature of implants (the Oppenheimer effect). Observations in this study and in the literature are discussed.

Poly(L-lactide): a long-term degradation study in vivo. Part III. Analytical characterization.

Three poly(L-lactides) with different molecular weights were synthesized as solid blocks from the melt. Two batches were ground and small specimens were produced by injection moulding. The third block was processed by machining, yielding crystalline parts. All were implanted as small rods into the dorsal muscle of rats. The implants were recovered, weight loss was determined, and the samples analysed. The samples degraded very fast, reaching the same molecular weight level after 20 wk, then degraded simultaneously. Analysis showed differences depending on the solid state of the polymer. The differences in the degradation behaviour of the amorphous and crystalline samples can be explained by assuming a simple hydrolysis as the main degradation mechanism, affecting the whole polymer, if in an amorphous state, but only the amorphous domains in a crystalline polymer.

Poly(L-lactide): a long-term degradation study in vivo. Part II: Physico-mechanical behaviour of implants.

Three different poly(L-lactide) rods (25 x 3 x 2 mm) were produced either by injection moulding or machined out of a solid as-polymerized polylactide block and were implanted for 1-116 months into the dorsal muscle of rats. After recovery, the polylactide specimens were carefully cleaned, dried, photographed and weighed. Bending strength and Young's modulus of elasticity were determined. The surfaces of the broken rods were examined by scanning electron microscopy. Block polylactide samples initially looked milky. They became friable and broke into white or brownish fragments during the implantation period, whereas total disintegration could not be observed. Electron scanning microscopy revealed a porous surface with crystalline elements persisting for the whole time. Mechanical stability fell from 127 +/- 3 MPa at implantation time to about half after 3 wk (61 +/- 4 MPa) and about a quarter (32 +/- 4 MPa) after 6 wk. Both injection-moulded polyactides (A1 and A2) were clear and transparent initially. After implantation they gradually became whitish, fragmented after about 64 wk and disintegrated 90 wk later into small parts and powder. Electron scanning microscopy at first showed a homogeneous surface. A kind of cortex developed after about 4 wk and deep cracks ran through the rod after 32 wk. Round pores of 1.5-10 microns diameter developed after 1 yr of implantation. Bending strengths were 130 +/- 8 MPa (A1) and 115 +/- 14 MPa (A2); these remained nearly stable over about 12 wk, then declined linearly. Although a higher initial mechanical strength is desirable for use in osteosynthetic devices, mechanical stability of amorphous injection-moulded polylactides over the first 12 wk and total disintegration thereafter approaches the requirements for their use as a material for osteosynthesis.

A simplified system for the identification of staphylococci by multipoint inoculation of test media.

Most hospital bacteriologists have divided staphylococci into two groups: Staphylococcus aureus and the coagulase-negative staphylococci of which the novobiocin-resistant varieties are termed S. saprophyticus. The identification of S. aureus has been easy but that of the other staphylococci has provided some difficulties and most currently available methods are expensive or time consuming. Multipoint inoculation of a set of test media provides a convenient way of identifying large numbers of staphylococcal isolates. In tests with 118 isolates, mainly clinical but including some environmental isolates and some from the National Collection of Type Cultures, there was 90.7% agreement between identifications by the API-Staph system and by the multipoint system. The remaining 9.3% of strains was identified by the multipoint system but could not be identified by use of the data supplied in the API-Staph kit.

Long-term maintenance of alveolar bone gain after implantation of autolyzed, antigen-extracted, allogenic bone in periodontal intraosseous defects.

This randomized controlled trial assessed the long-term maintenance of alveolar bone gain after implantation of autolyzed, antigen-extracted, allogenic (AAA) bone. AAA bone is a demineralized freeze-dried bone allograft processed after previously described methods. In each of 14 patients, AAA bone was implanted into the intraosseous defect of 1 tooth (test); a second tooth with an intraosseous defect was treated by modified Widman flap surgery alone (control). All patients were offered supportive periodontal therapy at 3- to 6-month intervals following treatment. Clinical measurements were taken prior to surgery, 6 months, and 3 years following surgery. Of the 14 patients enrolled, 11 patients completed the 6-month and 8 patients the 3-year examination. In test teeth, bone gain was significantly greater compared to control teeth at 6 months (2.2+/-0.5 mm and 1.2+/-0.5 mm, respectively) and 3 years (2.3+/-0.7 mm and 1.1+/-0.8 mm, respectively) (P < 0.05). Also, more probing attachment was gained in test compared to control teeth at 3 years (2.0+/-0.7 mm and 0.8+/-0.5 mm, respectively; P < 0.05). At 3 years, Porphyromonas gingivalis was detected in 3 test and 2 control teeth by polymerase chain reaction, whereas no Actinobacillus actinomycetemcomitans was found. Due to the low detection frequency, there was no clear correlation between the maintenance of alveolar bone during supportive periodontal therapy and subgingival infection with P. gingivalis. The data indicated that alveolar bone gain after implantation of AAA bone may be maintained over a minimum of 3 years in patients receiving periodontal supportive therapy.

The use of the 'de-epithelialized' scapular flap for soft tissue augmentation--a case report.

For the augmentation of maxillo-facial soft tissue deficiencies, microsurgical 'pure' fat transplants have proven effective. In this paper, we present the 'de-epithelialized' scapular flap and discuss its significance in comparison with other microvascular fat transfers. Consistency of transplant vessels and minimal dependence of volume on the overall nutritional condition are its specific advantages. The transplant can be securely fixed at the retained corium.

Reconstruction of large defects in the oropharynx with a revascularized intestinal graft: an experimental and clinical report.

Our experimental investigation in six mongrel dogs with free revascularized jejunal loop for intraoral lining shows functional adaptation of the small bowel mucosa clinically and histologically. Although 1 year after transplantation 70 percent or more of the graft's surface remains small bowel mucosa, the flattening and widening of the villi produces an epithelial layer that satisfies the conditions of the oropharynx. In 30 clinical cases with a follow-up period of over 4 years our experimental experience is confirmed. After extensive ablative surgery in the oropharynx, primary reconstruction with free revascularized jejunal loop in combination with mandibular replacement has some significant advantages: There is no cicatricial induration of the graft. Mucus production occurs. Flexibility of the grafts and almost unlimited transplant supply lead to satisfying reconstruction even in difficult anatomic sites. Mesenteric fat tissue serves as good transplant material for extended soft-tissue loss. There is good wound healing, owing to abundant blood supply and prompt agglutination of the serosa. The long vascular pedicle provides revascularization apart from the resection area, which is important in irradiated cases. Decreased mucus production after 2 hours of normothermic ischemia and the anatomic reconstruction of mandibular replacement make tracheostomy not necessary.

Repair of human skull defects using osteoinductive bone alloimplants.

To estimate the efficacy of cranioplasty in clinical practice, autolyzed, antigen-extracted, allogenic (AAA) bone was prepared from cortical bones of human organ donors. AAA bone implants consisted of completely demineralized bone powder, completely demineralized pliable bone chips, surface-demineralized bone chips with pliable crevices, surface-demineralized rigid bone chips, or combinations thereof. 21 patients received AAA bone cranioplasties and were followed-up for between 12 and 58 months (average: 29 months). No infection or rejection of any of the AAA bone implants occurred. X-ray assessments as well as bone scintigraphies revealed osseous integration and remodelling of the AAA bone implants with minimal resorption, with the exception of completely demineralized AAA bone chips which showed partial resorption (2 cases). However, the partial resorption of completely demineralized AAA bone chips ceased after the implants had been remodelled. In 4 cases, the osteosynthesis material was removed between 10 and 18 months after the cranioplasty. In another case, a re-entry was necessary because of recurrence of an intracranial tumor. All of these five AAA bone reconstructions showed bleeding surfaces and osseous consolidations at the time of re-entry. A bone biopsy taken from one of these cranioplasties showed osteoinduction on the surface of the AAA bone implants. This first clinical review of cranial reconstructions using osteoinductive AAA bone implants emphasizes the therapeutical application of AAA bone for cranioplasty. Large AAA bone chips from human skull bones facilitate the reproduction of the skull's convexity especially when combined with preoperative stereolithography-based planning.

IgG monoclonal antibodies that inhibit osteoinductivity of human bone matrix-derived proteins (hBMP/NCP).

Monoclonal hBMP/NCP (human bone morphogenetic protein and associated noncollagenous proteins) antibodies of the IgG class were produced. In vitro, 12 of 19 hBMP/NCP antibodies showed functional inhibition of hBMP/NCP-induced chondroneogenesis in a neonatal muscle tissue assay. Inducing factors were characterized by their inhibiting antibodies with immunoblotting. Several peptide factors seem to be involved in the cascade of induced chondro- and osteogenesis.

Inductive properties of recombinant human BMP-2 produced in a bacterial expression system.

Recombinant human BMP-2, produced in E. coli, refolded and concentrated to a purity of more than 98%, has been demonstrated to be biologically active. In vitro, amounts of 0.4 microg BMP-2 or more induced new cartilage formation in 27 out of 47 samples of a neonatal muscle tissue assay, with chondroneogenesis occurring 14 days after a four-hour contact between BMP-2 and the muscle tissue. In vivo, BMP-2 was implanted in the thigh muscle of ICR mice for a period of three weeks. Amounts of 4 microg BMP-2 and more showed heterotopic bone formation in 15 out of 17 samples. When BMP-2 was combined with a collagen carrier, amounts of 0.4 microg protein or more induced heterotopic bone formation in 30 out of 33 samples four weeks after the implantation in the abdominal wall of Sprague-Dawley rats. The results show that the E. coli-derived BMP-2 was active in different assay systems in concentrations equal to those required with mammalian cell-expressed BMP-2. It could also be demonstrated that a single morphogen (BMP-2) is enough to initiate the differentiation process associated with bone induction. The presented bacterial expression system also offers the opportunity to produce large quantities of recombinant BMP-2 for clinical applications.

Stereolithography in oral and maxillofacial operation planning.

Stereolithography (STL) is a method of organ-model-production based on computed tomography scans which enables the representation of complex 3-dimensional anatomical structures. Surfaces and internal structures of organs can be produced by polymerization of UV-sensitive liquid resin using a laserbeam. In oral and maxillofacial surgery this technique is advantageous for reconstruction of severe skull defects because a more accurate preoperative planning is possible. Using recently developed software we are able to reconstruct unilateral bony defects by virtual mirror imaging of the contralateral side and production of a STL mirror model as well as the reconstruction of non-mirrorable defects by superposition. Advantages of STL are the representation of complex anatomical structures, high precision and accuracy, and the option to sterilize the models for intraoperative use. More accurate planning using this method improves postoperative results, decreases risks and shortens treatment time.

Preoperative radiochemotherapy and radical surgery in comparison with radical surgery alone. A prospective, multicentric, randomized DOSAK study of advanced squamous cell carcinoma of the oral cavity and the oropharynx (a 3-year follow-up).

A multicentric, randomized study of squamous cell carcinoma (SCC) of the oral cavity and the oropharynx has been undertaken by DOSAK. The results after radical surgery alone have been compared with the results of combined preoperative radiochemotherapy followed by radical surgery. Patients with primary (biopsy proven) SCC of the oral cavity or the oropharynx with tumor nodes metastasis (TNM) stages T2-4, N0-3, M0 were included in the study. A total of 141 patients were treated by radical surgery alone, whereas 127 patients were treated by radical surgery preceded by preoperative radiochemotherapy. The preoperative treatment consisted of conventionally fractioned irradiation on the primary and the regional lymph nodes with a total dose of 36 Gy (5 x 2 Gy per week) and low-dose cisplatin chemotherapy with 5 x 12.5 mg cisplatin per m2 of body surface during the first week of treatment. Radical surgery according to the DOSAK definitions (DOSAK, 1982) was performed after a delay of 10-14 days. During the follow-up period, 28.2% of all patients suffered from locoregional recurrence, and 27.2% of the patients died. The percentages were higher after radical surgery alone for locoregional recurrence (31% and 15.6%) and for death (28% and 18.6%). The life-table analysis showed improved survival rates of 4.5% after 1 year and 8.3% after 2 years in the group of patients treated with combined therapy. The demonstrated improvement appeared to be significant with the Gehan-Wilcoxon test as well as with the log rank test below a P value of 5%.

Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in patients with multiple sclerosis (MS). A subject is considered CCSVI positive if ≥ 2 venous hemodynamic (VH) criteria are fulfilled. OBJECTIVE: To determine prevalence of CCSVI in a large cohort of patients with MS, clinically isolated syndrome (CIS), other neurologic diseases (OND), and healthy controls (HC), using specific proposed echo-color Doppler (ECD) criteria. METHODS: Transcranial and extracranial ECD were carried out in 499 enrolled subjects (289 MS, 163 HC, 26 OND, 21 CIS). Prevalence rates for CCSVI were calculated in 3 ways: first, using only the subjects for whom diagnosis was certain (i.e., borderline subjects were excluded); secondly, including the borderline subjects in the "no CCSVI" group; and finally, taking into account subjects who presented any of the VH criteria. RESULTS: CCSVI prevalence with borderline cases included in the "no CCSVI" group was 56.1% in MS, 42.3% in OND, 38.1% in CIS, and 22.7% in HC (p < 0.001). The CCSVI prevalence figures were 62.5% for MS, 45.8% for OND, 42.1% for CIS, and 25.5% for HC when borderline cases were excluded (p < 0.001). The prevalence of one or more positive VH criteria was the highest in MS (81.3%), followed by CIS (76.2%), OND (65.4%), and HC (55.2%) (p < 0.001). CCSVI prevalence was higher in patients with progressive than in nonprogressive MS (p = 0.004). CONCLUSIONS: Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS.