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MTS assays on cell lines after treatment with ADCT-301, Non-binding ADC and naked antibody, HuMax-TAC

Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody–drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug–antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G2–M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors. Mol Cancer Ther; 15(11); 2709–21. ©2016 AACR.

In vivo efficacy in Karpas disseminated models. Kaplan Meier survival plots of disseminated Karpas 299 models

Comet assay on CD25-negative Daudi cells after ADCT-301 and SG3199 treatment

In vivo PBMC DNA cross-linking. DNA cross-linking as measured in CD25-negative PBMCs from SCID mice treated with ADCT-301

DAR determination by SEC, RPLC and HIC

In vivo efficacy in Karpas 299 subcutaneous models. Kaplan Meier survival plots of subcutaneous models in Figures 5A and 5B

In vivo efficacy in Ramos disseminated model. Kaplan Meier survival plots of disseminated CD25-negative Ramos model

This essay explores the use of the notions of grammar and governmentality in the work of Michel Foucault and Noam Chomsky. The goal is to exhibit the contrast but also mutual influence of these thinkers. Chomsky places his own linguistic theory in what he calls a tradition of Cartesian linguistics. Foucault’s presents an archaeology of general grammar in the French Classical Era. Chomsky and Foucault equally posit principles of governmentality. Both differ in terms of what they think the study of language brings to our understanding of ethical and political freedom. Governmental structure and grammatical structure, for Foucault, are always conventional, rather than essential – merely expressions of power dynamics. For Chomsky, the innate and natural human universality implied by underlying structures, in contrast, intimates a path to freedom from governmental coercion and oppression.

Introduction Preoperative testing for COVID‐19 has become widely established to avoid inadvertent surgery on patients with COVID‐19 and prevent hospital outbreaks. Methods A prospective cross sectional study was carried out in two university hospitals examining the pre‐operative protocols for patients undergoing otolaryngology surgery and the incidence of COVID‐19 within 30 days of surgery in patients and the otolaryngologists performing surgery. Results One hundred and seventy‐three patients were recruited. One hundred and twenty‐three (71%) patients “cocooned” for 14 days prior to surgery. All completed a questionnaire prior to admission. One hundred and fifty‐six patients (90%) had reverse transcriptase‐polymerase chain reaction (RT‐PCR) nasopharyngeal swabs, 14 patients (8%) had CT thorax. No cases of COVID‐19 were detected among patients followed up at 30 days. Two surgeons developed COVID‐19 early during the study period. Conclusion Current pre‐operative testing protocols consisting primarily of questionnaires and RT‐PCR resulted in zero cases of COVID in this cohort. It is possible that COVID‐19 restrictions and high proportion of patients cocooning preoperatively were factors in ensuring a low rate of COVID‐19 post‐operatively.

Personalised medicine aims to optimise patient outcomes by tailoring treatments and interventions to the individual. While this approach can offer a number of benefits, it can be accompanied by significant overheads in terms of resources. Prostheses exist in order to restore and replicate the normal functions and appearance of the body but if these are not individually tailored to the patient’s needs then a true restoration cannot be fully achieved. Traditionally a labour intensive process, the fabrication of craniofacial prostheses, involves taking a plaster cast of the area to be treated, hand carving wax models of the restoration and multiple meetings with the patient to alter this wax restoration before making a final prosthesis in silicone. Utilising the patient’s pre-existing computed tomography (CT) images and 3D printing technology, a patient-specific prosthesis can be created with improved efficiency and accuracy. This study demonstrates methods used to create a patient-specific orbital prosthesis using CT images. These images were manipulated in a way which allowed for the intact orbit to be mirrored and used to develop a 3D printed model which acted as the starting point to create a silicone prosthesis. The benefits of using this method include reduced manufacturing time, decreased outpatient appointments, improved personalised outcomes and a repeatable process allowing multiple prostheses to be made. 3D printing is a valuable tool which can provide significant savings in time and improve patient outcomes by offering a tailored approach to each individual’s treatment.

Objective: Preoperative testing for COVID-19 has become widely established to avoid inadvertent surgery on patients with COVID-19 and prevent hospital outbreaks, however, there is limited evidence underpinning new protocols. We wished to study the effectiveness of preoperative COVID-19 testing during and after the first wave of the pandemic in Ireland. Design Prospective cohort study. Setting: 2 university hospitals in the Republic of Ireland. Participants: Patients undergoing otolaryngology surgery and the otolaryngologists performing surgery. Main outcome measure: Incidence of COVID-19 within 30 days of surgery. Results: 173 patients (56% male) were recruited. 123 (71%) patients “cocooned” for 14 days prior to surgery. All patients completed a questionnaire prior to hospital admission. 156 patients (90%) had reverse transcriptase-polymerase chain reaction (RTPCR) nasopharyngeal swabs, 14 patients (8%) had CT thorax. No cases of COVID-19 were detected among patients followed up at 30 days. Two surgeons developed COVID-19 early during the study period not considered to be related directly to contact within the hospital. Conclusion: Current pre-operative testing protocols consisting primarily of questionnaires and RT-PCR resulted in zero cases of COVID reported in this cohort. It is possible that COVID-19 restrictions and high proportion of patients cocooning preoperatively were factors in ensuring a low rate of COVID-19 postoperatively. Ongoing data collection is required to confirm these findings in the setting of further disease surges.

Background Tracheal stoma recurrence following oral cavity surgery is exceedingly rare. Although several different mechanisms for this have been described, the pathogenesis still remains uncertain. Methods We present the case of a gentleman who presented 6-months following oral cavity SCC resection with a large fungating mass at his previous tracheostomy site, and also review the reported literature on this rare phenomenon. Results Four weeks after diagnosis of his recurrence he underwent a total laryngectomy, wide-local skin excision and reconstruction with a pectoralis major pedicled flap. He recovered well initially following his operation, however unfortunately contracted nosocomial SARS-Cov2 and succumbed from respiratory complications during his post-operative recovery. Conclusion Stomal recurrence after temporary tracheostomy for oral cavity malignancies are very rare. Previously reported management of these can vary from surgical to palliative treatment. Methods to prevent these include delaying tracheostomy until after surgical resection, packing the pharynx during resection and adjuvant radiotherapy.

The purpose of this study was to investigate whether the time delay between 'out of house' proprietary virtual surgical planning (OH-VSP) of the mandibular resection for oral cancer and the actual surgery results in compromised margins and oncological disadvantage for the patient. Outcomes of patients who had OH-VSP of their mandibular resection and reconstruction were compared with those of patients who had the same surgery using a conventional non-VSP approach. The groups were similar in patient demographics, tumour stage and size, nodal status, and reconstruction complexity. VSP resulted in a significant reduction in operating time (P

This paper presents the results of a retrospective case-controlled cohort study to investigate the effectiveness of a donor-site local anaesthetic infusion protocol to reduce opioid requirements, length of intensive therapy unit (ITU) stay, and incidence of postoperative delirium. Adult free flap head and neck patients were identified from a prospective database (n = 86). There was a significant reduction in mean opioid requirements (p0.001). Postoperative delirium was observed in 12 of 35 patients before introduction of the protocol, and in 10 of 51 patients after its introduction (p = 0.139). Donor-site local anaesthetic infusion reduces opioid requirements for patients undergoing head and neck free flap reconstruction, and is a valuable adjunct to an enhanced recovery protocol.

Ameloblastoma is a locally aggressive tumor that most commonly arises in the mandible. It has a high rate of recurrence if inadequately excised. We report a case of a patient who developed recurrence of his ameloblastoma in his fibula flap mandibular reconstruction despite clear resection margins 23 years after resection. This is the first reported case of recurrent ameloblastoma in a neo-mandible reconstruction in the setting of negative margins. We discuss its surgical management using digital planning and reconstruction using a contralateral free fibula flap. Ameloblastoma is a locally aggressive entity that requires complete excision. Recurrence can even occur in the reconstruction, which can present a challenge to manage. Consideration should be given to repeat excision and second osseous flap reconstruction.

BACKGROUND The purpose of this study was to compare outcomes for segmental reconstruction of the mandible between patients who underwent reconstruction with a fibula flap (group 1), and those with an alternative osseous free flap in which the fibula flap was unsuitable either for defect reasons (group 2) or in which the fibula flap could not safely be harvested because of compromised leg vessels (group 3). METHODS One hundred fifty-two patients who underwent osseous free flap reconstruction of a mandibular segmental defect between January 2008 and June 2014 were identified from operating records. Outcomes between groups was compared. RESULTS The flap success rate was 97% and the late recipient-site complication rate was 19%. There was no difference in flap success or complication rates between groups. CONCLUSION Bony reconstruction of the mandible can be achieved with no compromise in flap success even where preoperative vascular studies or the nature of the defect deem the fibula unsuitable. © 2017 Wiley Periodicals, Inc. Head Neck 39: 916-920, 2017.

The reporting of the outcomes of flap reconstruction is often based on numerical success rates. Whilst this remains a useful variable with which to measure success, it is limited in its ability to reflect the complex processes involved. The lack of consistency in the categorisation of outcomes of flap reconstruction in the head and neck could potentially lead us to lose the opportunity to fully capture the implications of its success or failure, or both. We propose a classification that moves away from primarily reporting the results of its binary nature, and focuses more on the process of reconstruction, particularly in the head and neck.

Previously, the engulfment and cell motility 3 (ELMO3) protein has been reported to be involved in cell migration and cytoskeletal remodeling. As of yet, nothing is known about the role of ELMO3 in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to asses ELMO3 expression in postoperatively irradiated HNSCC patients and to evaluate a possible correlation between this expression and patient survival. 125 postoperatively irradiated HNSCC patients were included in this study. ELMO3 expression was assessed using immunohistochemistry (IHC). The expression of ELMO3 in the respective HNSCC tumor tissues and its lymph node metastases was correlated with patient survival using Kaplan-Meier curve analyses. Through IHC, ELMO3 expression was detected in 71.2% of the HNSCC cases tested. We found significantly increased overall and disease-free survival rates and decreased recurrence rates in patients with no detectable ELMO3 expression. In reverse, we found that ELMO3 expression served as an independent marker for a decreased overall and disease-free survival. Our data indicate that in the surgically treated and postoperatively irradiated patients tested, ELMO3 expression serves as a predictive marker for reduced survival.

Background The purpose of this study was to determine the effect of postoperative radiotherapy (PORT) on recurrence and survival in patients with oral squamous cell carcinoma (OSCC) of intermediate recurrence risk. Methods Intermediate risk patients, defined as pT1, pT2, pN0, or pN1 with at least one adverse pathological feature (eg, lymphovascular/perineural invasion), were identified from the head and neck databases of the Liverpool Head and Neck Cancer Unit and the Sydney Head and Neck Cancer Institute. Patients who received surgery and PORT were case matched with patients treated by surgery alone based on pN, pT, margins, and pathological features. Results Ninety patients were matched into 45 pairs. There was significant improvement (P = .039) in locoregional control with PORT (84%) compared with surgery alone (60%), which was concentrated in the pN1 subgroup (P = .036), but not the pN0 subgroup (P = .331). Conclusion PORT significantly improves locoregional control for intermediate risk OSCC.

Background The purpose of this study was to explore the significance of resection margin status on local recurrence and survival for early (T1/T2) oral cancer and to determine if the significance of the resection margin varies with the biological aggression of the tumor as determined by pN status. Methods The influence of resection margin size and local recurrence for 295 patients with pT1/T2 oral cavity squamous cell carcinomas (SCCs) treated by primary surgery, including neck dissection, between 1998 and 2010 was analyzed. Results Overall, there was a trend toward increased local recurrence with close or involved margins. When stratified according to nodal status, there was no relationship between margin size and local recurrence for the pN0 group. Conclusion The size of the resection margin does not seem to influence local control in stage I/II oral cancer. With future advances in preoperative neck staging, this data may help plan personalized therapy in head and neck cancer. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1176–1180, 2015

This study is a review of practice for patients with T1 or T2 squamous cell carcinoma (SCC) of the anterior tongue and floor of the mouth who presented to the regional maxillofacial unit in Liverpool between 1992 and 2007. We examined trends in management and analysed their effects on resection margins, recurrence, and survival. The Liverpool head and neck oncology database was used to identify patients, and to retrieve their clinical, surgical, and pathological data. When data were missing the case notes and pathology records were reviewed. Follow up was taken to January 2011. A total of 382 patients were included. Despite more conservative treatment with closer resection margins (27% in 1992-1995 and 60% in 2004-2007), fewer free flaps (79% in 1992-1995 and 38% in 2004-2007), and less adjuvant radiotherapy (37% in 1992-1995 and 22% in 2004-2007), there has been no significant increase in local recurrence (14% in 1992-1996 and 8% in 2004-2007), and overall survival has not been adversely affected. This is most striking when T1 tumours are considered in isolation with a consistent trend towards fewer clear margins (95% in 1992-1995 and 28% in 2004-2007) and fewer free flaps (53% in 1992-1995 and 11% in 2004-2007). The case mix was similar over the study period. These data support a more conservative approach to the management of early oral cancer.

Purpose To determine the complication rate for patients presenting with isolated mandibular angle fractures treated by open reduction and internal fixation using a single superior border miniplate technique. Patients and Methods This is a retrospective study of consecutive patients with isolated mandibular angle fractures treated using a specific protocol at a Regional Oral and Maxillofacial Department between January 1998 and December 2004. Patient demographics, fracture etiology, length of hospital stay, removal of third molar, and postoperative complications were recorded. Preoperative and postoperative inferior alveolar nerve function was recorded. Objective sensory testing and patient interviews were conducted to determine the incidence of postoperative sensory deficit. Results The study population included 50 patients presenting with isolated mandibular angle fractures, 6 patients (12%) experienced complications requiring bone plate removal. These complications were minor and occurred after fracture healing as follows: 4 patients (8%) experienced superficial soft tissue infection associated with the bone plate, treated with oral antibiotics, 1 patient (2%) experienced bone plate exposure, and a further patient (2%) presented with a fractured bone plate. All 6 patients (12%) were treated by bone plate removal under general anesthesia as elective day case surgery. Thirty-nine (78%) patients had long-term sensory follow-up, mean 37 months (2 to 84 months). Permanent inferior alveolar sensory deficit (>12 months) was present in 4 (8%). Five of 26 (19%) patients with normal postinjury/preoperative sensory function had a postoperative sensory deficit. All patients in this group reported recovery of normal sensation within 6 months. Conclusions The results of this study suggest that the complication rates associated with the treatment of isolated mandibular angle fractures using a superior border plating technique, in this patient population, is relatively low (12%). The complications were all minor in nature. There was a permanent (>12 months) inferior alveolar sensory deficit in 4 (8%) patients.

Summary No universally accepted classification system exists for mandibular defects after oncological resection. Here, we discuss the scientific literature on classifications for mandibular defects that are sufficiently presented either pictorially or descriptively, and propose a new classification system based on these findings. Of 167 studies included in the data analysis, 49 of these reports sufficiently described the defect for analysis. These reports were analysed for classification, reconstruction, size of defect, number of osteotomies needed, and complications. On the basis of these findings, a new classification is proposed based on the four corners of the mandible (two angles and two canines): class I (lateral), class II (hemimandibulectomy), class III (anterior), and class IV (extensive). Further classes (Ic, IIc, and IVc) include condylectomy. The increasing defect class relates to the size of the defect, osteotomy rate, and functional and aesthetic outcome, and could guide the method of reconstruction.

Meeting Programme Prof David O'Hagan [University of St Andrews, UK]—Enzymatic C–18F Bond Synthesis: A New Strategy for PET Synthesis. Dr Michael Carroll [University of Newcastle, UK]—Studies Towards 6-[18F]Fluoro-m-tyramine using Iodonium Salts. Dr John Gardiner [University of Manchester, UK]—Methods Towards Isotopomer-Versatile Synthesis of 13C-Labelled Carbohydrates. Prof William Lockley [University of Surrey, UK]—Some New Catalytic Systems for Isotope-Exchange Labelling. Dr David Rustidge [Scynexis Europe, UK]—14C-Synthesis—Not Always as Easy as it Looks. Dr Richard Hartley [University of Glasgow, UK]—The Potential for using Titanium Alkylidene Chemistry in Solid-Phase Radiochemical Synthesis. Dr Ian Wilson [Turku Imanet, Finland]—Transition of PET Tracers from Clinical Research Tools to Commercial Diagnostics. Dr Simon Harwood [GlaxoSmithKline, UK]—The Synthesis of Stable Labelled Ketamine. Dr John Herbert [Sanofi-Aventis, UK]—Towards Robust Conditions for Iridium-mediated Exchange. Dr Conor Barry [University of Bristol, UK]—Total Synthesis of Clavosolide A.

Osteomyelitis of the maxilla is extremely rare. When it occurs, there is invariably an underlying predisposing condition. We describe a 28-year-old woman whose presentation with osteomyelitis of the maxilla led to a diagnosis of generalized osteopetrosis.

As a result of theoretical concerns about the use of GDP as the main policy indicator, and the implications this may have for the achievement of other policy goals, the UN proposed a system of integrated environmental and economic accounting (SEEA). Part of their guidelines recommends the collection of data regarding environmental protection expenditure (EPE). Both EUROSTAT and the OECD have designed and implemented methodologies with the aim of producing EPE accounts for international comparison. While much effort has been employed in examining and refining the design and implementation, to date little has been said regarding the policy relevance of such accounts. We have applied the Eurostat and OECD methodologies to produce the first ever EPE dataset for Ireland. This work involved a detailed examination of both public and private sector environmental expenditure and estimated that EPE in Ireland was equal to just under 1% of GDP in 1998. We conclude that the main policy relevance lies in the assessment of the potential for industries involved in the supply and operation of environmental abatement services in Ireland. To the extent that expenditure can be disaggregated to sectoral level in those sectors exposed to international competition, it can also inform a discussion about the relation between environmental compliance costs and sectoral competitiveness. Copyright © 2002 John Wiley & Sons, Ltd. and ERP Environment.

Purpose To evaluate the incidence of ocular injuries and clinical ocular signs in patients with orbitozygomatic fractures of varying severity, presenting to a regional oral and maxillofacial surgery service. Patients and Methods This is a retrospective study of patients presenting to Limerick Regional Hospital (Limerick, Ireland) with orbitozygomatic fractures from January 1998 to December 2004. Patients with panfacial fractures and those with isolated zygomatic arch fractures were excluded. All patients were examined by the ophthalmology service preoperatively and reviewed postoperatively as indicated. The study population was divided into 3 subgroups based on the extent of the bony injury (confirmed by clinical, plain radiographic, and CT examination) as follows: group 1: “simple” noncomminuted orbitozygomatic complex fractures; group 2: comminuted orbitozygomatic complex fractures; group 3: “pure” orbital blowout fractures. Patient demographics, fracture etiology, and ocular findings were recorded. Results The study population included 148 patients (130 males, 18 females). All fractures were unilateral. Ocular findings were present in 29 (20%) patients, consisting of 8 of 85 patients (9%) in group 1; 15 of 53 patients (28%) in group 2; and in 6 of 10 patients (60%) in group 3. Conclusions Clinical ocular findings and injuries are a relatively common complication of orbitozygomatic fractures, occurring in 29 (20%) patients in this study. These injuries occur more often in patients with orbital blowout fractures compared with comminuted orbitozygomatic complex fractures or simple orbitozygomatic complex fractures. Ophthalmology consultation is recommended for all patients presenting with orbitozygomatic fractures, and is essential for patients with orbital blowout fractures, based on the high incidence of clinical ocular findings and injuries in this subgroup of patients.

Background: Stable reduction of fractures of the zygomatic complex is essential to avoid long-term aesthetic, sensory, and ocular consequences. Delayed collapse or relapse after reduction of fractures of the zygomatic complex is attributed to muscle forces, when there has been no additional trauma. A number of studies have identified the masseter muscle as a contributor, but none has described the role of the temporalis muscle. Methods: The origins of the temporalis muscle were examined in six cadaveric dissections. The temporal and zygomatic regions were exposed through a temporoparietal flap. Bone cuts were made above and below the frontozygomatic suture in the lateral orbital margin. The lateral orbital margin was then fractured and reflected laterally on its periosteum so that muscle attachments could be seen clearly. Results: In all six dissections, the authors found that the temporalis muscle took origin not only from the floor of the temporal fossa and temporalis fascia but also from the lateral margin of the orbit and the frontal process of the zygomatic bone as far down as the body of the zygoma. Conclusions: The authors postulate that the functional forces exerted by this muscle on the zygomatic complex cause postoperative distraction at the frontozygomatic suture. The authors' findings provide further anatomical evidence to support internal fixation of all fractures of the zygomatic complex, even those that are considered clinically stable, if permanent flattening of the cheekbone is to be avoided.

The restoration of the edentulous atrophic anterior maxillary ridge has proved difficult. The absence of both gingival and bony alveolar tissue contributes to these problems. Numerous techniques to address these issues have been described. We report a case of a patient who sustained multiple facial injuries as a consequence of an accident, including the loss of the maxillary incisor teeth and associated alveolus. This patient underwent fixed implant supported prosthetic rehabilitation, following the use of distraction osteogenesis in the reconstruction of the edentulous atrophic anterior maxillary ridge.

The incidence of osteomyelitis has dramatically reduced since the introduction of antibiotics. When it now occurs in Western society, the possibility of predisposing immunosuppressive conditions or underlying bony pathology should be considered. Osteomyelitis is a complication in 10% of cases of osteopetrosis. Osteopetrosis (marble bone disease, Albers-Schonberg disease, osteosclerosis fragilis generalisata) is a congenital sclerosing disease of bone caused by aberrant osteoclast mediated bone resorption. There is normal production of bone with lack of physiological resorption. The disease represents a spectrum of clinical variants because of the heterogeneity of genetic defects resulting in osteoclast dysfunction. Three clinically distinct forms are recognized: an infantile malignant autosomal recessive form, an intermediate autosomal recessive form, and an adult benign autosomal dominant form. Infantile malignant autosomal recessive osteopetrosis is diagnosed within the first year of life. Patients typically present with pathologic fracture or failure to thrive with frequent respiratory, head and neck, or bony infections. Physical examination shows lethargy, small stature, marked hepatosplenomegaly, and dysmorphic features including macrocephaly, frontal bossing, and hypertelorism. Neural palsies may occur, particularly affecting the optic, oculomotor, and facial nerves because of progressive thickening of bone at the expense of the neural canals. Intermediate autosomal recessive osteopetrosis is usually diagnosed toward the end of the first decade of life. Patients often present with pathological fracture. Clinical characteristics include delayed motor and cognitive development, mild disproportionate short stature, mild hepatosplenomegaly, and dysmorphic features such as macrocephaly and frontal bossing. Cranial nerve compression and mandibular osteomyelitis are common features. This form of osteopetrosis is rare. Most patients survive into adulthood but with significant disability. Autosomal dominant osteopetrosis (adult benign osteopetrosis) is a much milder condition. Patients have a normal life expectancy and many are asymptomatic. Patients may present in adulthood with recurrent fractures, back pain, bone pain, or osteomyelitis, particularly of the mandible. Cranial nerve palsies and osteoarthritis of the hips and knees are other potential features. Autosomal dominant osteopetrosis is divided into 2 radiological subtypes. In type I, cranial sclerosis and thickening affects mainly the calvarium. The calvarium is almost normal in type II, but the cranial base is sclerotic. Although both types involve generalized skeletal sclerosis, patients with the type II subtype have a higher risk for fractures.