The development of musculoskeletal radiology for 100 years as presented in the pages of Acta Radiologica.

During the last 100 years, musculoskeletal radiology has developed from bone-only radiography performed by everyone to a dedicated subspecialty, still secure in its origins in radiography but having expanded into all modalities of imaging. Like other subspecialties in radiology, it has become heavily dependent on cross-sectional and functional imaging, and musculoskeletal interventions play an important role in tumor diagnosis and treatment and in joint diseases. All these developments are reflected in the pages in Acta Radiologica, as shown in this review.

Paleopathological study of a podal osteochondroma from the prehistoric Hypogeum of Calaforno (Sicily).

In this article, we report a case of isolated podal osteochondroma from the prehistoric Hypogeum of Calaforno (Giarratana, Ragusa, Sicily). Although the phalanx exhibiting the benign tumoral mass comes from a context featuring several commingled remains, the very good state of preservation of this bone allowed us to perform a comprehensive study of the neoplasm by applying a multidisciplinary approach encompassing archeology, morphology, stereomicroscopy, and radiology. The results from this very ancient specimen have been assessed in the light of the available paleopathological literature and clinical implications currently encountered in modern patients.

Ewing Sarcoma and the History of Similar and Possibly Related Small Round Cell Tumors: From Whence Have We Come and Where are We Going?

The diagnosis of small round cell tumors always has been extremely difficult, and our current classification systems continue to evolve. Since its initial discovery by Dr James Ewing, the historical context of what is acceptably included under the designation "Ewing sarcoma" has changed. Although Ewing sarcoma and primitive neuroectodermal tumor were both initially described in the early 20th century, these tumors were considered likely distinct entities until the end of that same century, almost 75 years later. With modern immunohistochemistry and more recent advances in molecular techniques, the understanding of Ewing sarcoma and Ewing-like tumors has improved dramatically but also raises new questions and challenges. We now know that this category of tumors is remarkably more heterogenous than initially thought, especially in regards to its cytogenetics and molecular properties, and some of these differences likely have prognostic relevance. Whether we are now expanding the spectrum of Ewing sarcoma or simply recognizing new entities is controversial. Therapeutic approaches to address these new categories and/or entities need further focus and attention. Herein, we provide a comprehensive historical perspective on Ewing sarcoma, Ewing-like tumors (CIC and BCOR-rearranged sarcomas), and related and/or similar small round cell tumors, often included in the differential diagnosis, including mesenchymal chondrosarcoma, desmoplastic small round cell tumor, and small cell osteosarcoma. We also seek to provide updates and insights into the evolving classification and clinical relevance of the Ewing family of tumors.

Skeletal metastatic carcinomas from the Roman period (1st to 5th Century AD) in Hungary.

OBJECTIVES: According to paleopathological records, tumors have a great antiquity. The prevalence of cancer in ancient populations might have differed from that in modern humans because of substantial differences in environmental factors, life expectancy and the availability of treatment. This study presents 3 cases of probable skeletal metastatic carcinoma from the Roman period (1st-5th century AD) in Hungary, showing the development of bone metastases of cancer without chemo- and radiotherapy. METHODS: All skeletons were subjected to a careful macroscopic investigation, which was extended by radiological, stereo- and scanning electron microscopic analyses. RESULTS: In 1 case, the mixed nature and localization of the lesions, as well as the sex and age of the individual, suggested breast cancer as the primary focus. In the other 2 cases, based on the mostly osteoblastic nature and the localization of the lesions as well as on the sex and age of the individuals, the most probable diagnostic option is prostate carcinoma with skeletal metastases. CONCLUSIONS: In view of the scarcity of cancer metastases that have been diagnosed in archeological specimens in general, identification of all examples of cancer in antiquity represents an important contribution both to paleopathology and to modern medicine.

Present at the beginning: a personal reminiscence on the history of teriparatide.

The ability of parathyroid glandular extracts to stimulate bone acquisition in rodents was established in the 1920s, but interest in this action lay dormant for almost 50 years until application of contemporary laboratory methods permitted the large-scale production of an amino-terminal fragment of PTH, (1-34) hPTH (teriparatide), which was capable of carrying out all known actions of the full-length (1-84) PTH molecule. In the 1970s, largely stimulated by the efforts of a British pharmacologist, Dr. John Parsons, the scientific community began to revisit these anabolic actions and showed that single daily injections of teriparatide dramatically increased bone mass in several mammalian species and restored bone in oöphorectomized rats. Shortly thereafter, human studies confirmed a striking increase in trabecular bone mass and showed also that an important part of teriparatide's action is to increase cortical bone. Eli Lilly and Company conducted a formal registration trial in postmenopausal women with osteoporosis. The unexpected occurrence of osteosarcomas in Fisher 344 rats treated long-term with teriparatide provoked an abrupt cessation of that trial, but ambiguity concerning the relevance of this rat finding to human disease, combined with significant anti-fracture efficacy, led to FDA approval of teriparatide for men and postmenopausal women with osteoporosis "at high risk for fracture" in 2002. Subsequently, teriparatide has been approved also for treatment of patients with glucocorticoid-associated osteoporosis, and papers indicating utility of this agent for dental and orthopedic applications have begun to appear.

Osseous mass in a maxillary sinus of an adult male from the 16th-17th-century Spain: Differential diagnosis.

OBJECTIVE: To undertake a differential diagnosis of a large mass found in the left maxillary sinus of a cranium dated to the 16th-17th-century, and to expand knowledge of the diagnosis of osseous tissue formation in osteoarchaeological studies. MATERIAL: A cranium recovered from the cemetery of San Salvador de Palat de Rey church, León (Spain). METHODS: Macroscopic analysis, CT scanning. RESULTS: Macroscopic analysis indicated that the individual was probably a male over 30 years old with an ossified mass in the left maxillary sinus, measuring 24 × 19 × 24 mm, occupying approximately 27 % of the maxillary antrum. Computed tomography revealed a well-demarcated radiolucent unilocular mass with some radiopaque areas, with no communication with the alveoli of the premolars or molars. No erosive lesions or signs of inflammation were found. CONCLUSIONS: Neither the macroscopic, nor the radiological characteristics are compatible with inflammatory or malignant pathology, favoring a diagnosis of ossifying fibroma. SIGNIFICANCE: This case adds to the few reported cases in the osteoarchaeological literature, especially since there is limited relevant reference data to assist diagnosis. The CT scans and 3D reconstruction presented here facilitate differential diagnosis in future paleopathological studies. LIMITATIONS: Destructive methods were not authorized. SUGGESTIONS FOR FURTHER RESEARCH: In the future, micro-CT analysis, which was not performed in the current study, may add new and valuable information.

History of orthopedic oncology in the United States: progress from the past, prospects for the future.

Orthopedic oncology in the United States has its roots in European medicine of the 1800s in which sarcomas were first classified on the basis of their gross characteristics (1804) and amended on the basis of their histologic features (1867). Surgical management, local excision, with unacceptable mortality gave way to amputation in the 1870s and remained so, until limb-sparing resection was cautiously embarked upon in the mid 1900s. Nonsurgical adjuvant was first devised in the 1880s (as Coley's toxins) but remained largely ineffective until the advent of chemotherapy in the 1970s. The combination of these in the last 30 years, together with vastly improved staging and reconstructive techniques has led to the current preponderance of limb-salvaging surgery and greatly improved survival rates. Their application has been greatly enhanced by the development of Orthopedic oncology fellowships, formation of Orthopedic oncology societies, and the institution of federally funded regional cancer centers with the formation of multidisciplinary sarcoma treatment teams.

Ernest Amory Codman, MD, 1869-1940.

This biographical sketch on Ernest Amory Codman corresponds to the historic text, The Classic: The Registry of Bone Sarcomas as an Example of the End-Result Idea in Hospital Organization, available at DOI 10.1007/s11999-009-1048-7 and The Classic: Registry of Bone Sarcoma: Part I.-Twenty-Five Criteria for Establishing the Diagnosis of Osteogenic Sarcoma. Part II.-Thirteen Registered Cases of "Five Year Cures" Analyzed According to These Criteria, available at DOI 10.1007/s11999-009-1049-6 .

The Intriguing History of Cancer Immunotherapy.

Immunotherapy is often perceived as a relatively recent advance. In reality, however, one should be looking for the beginnings of cancer immunotherapy under different names as far as in the Antiquity. The first scientific attempts to modulate patients' immune systems to cure cancer can be attributed to two German physicians, Fehleisen and Busch, who independently noticed significant tumor regression after erysipelas infection. The next significant advances came from William Bradley Coley who is known today as the Father of Immunotherapy. It was Coley who first attempted to harness the immune system for treating bone cancer in 1891. His achievements were largely unnoticed for over fifty years, and several seminal discoveries in the field of Immunology, such as the existence of T cells and their crucial role in immunity in 1967, stepped up the research toward cancer immunotherapy known today. The following paper tracks cancer immunotherapy from its known beginnings up until recent events, including the 2018 Nobel Prize award to James Allison and Tasuku Honjo for their meticulous work on checkpoint molecules as potential therapeutic targets. That work has led to the successful development of new checkpoint inhibitors, CAR T-cells and oncolytic viruses and the pace of such advances brings the highest hope for the future of cancer treatment.

The overlooked primary: bladder cancer metastases on dry bone. A study of the 20th century CAL Milano Cemetery Skeletal Collection.

OBJECTIVE: The aim of this article is to provide additional documentation of bone metastases to help anthropologists recognize the condition and potentially suggest the diagnosis of bladder carcinoma in differential diagnosis. MATERIALS AND METHODS: Thirteen individuals clinically diagnosed with bladder carcinoma from the 20th century Milano Cemetery Skeletal Collection were macroscopically studied to document bone metastases in bladder cancer. RESULTS: Bone metastases were found through macroscopic observation in three individuals or 23% of the study sample. Metastases were mostly of a mixed nature (45%), although both osteoblastic (13%) and osteolytic (9%) also occurred. In particular, mixed and osteoblastic metastases exhibited different distribution patterns, even when affecting the same bones. The vertebrae (24.7%), skull (12.9%), ribs (11.7%), proximal humeri (7.8%), pelvis (5.2%), proximal femora (2.6%), sacrum (1.3%) and sternum (1.3%) were the most commonly affected. Osteolytic lesions included coalescing superficial pits or lesions perforating the bone cortex. Proliferative lesions manifested as spongiosclerosis or periosteal new bone. Mixed metastases were osteolytic lesions exposing a thickened trabecular bone or coalescent porosity with reactive new bone. CONCLUSIONS: Bladder carcinoma metastases were mostly mixed, exhibiting periosteal reactions, perforations of bone cortex, spongiosclerosis and coalescing porosity. SIGNIFICANCE: Bladder carcinoma is rarely considered in the differential diagnosis of the primary organ. This study reports the macroscopic aspect of bone metastases in bladder carcinoma and may help anthropologists diagnose the condition in skeletons. LIMITATIONS: Absence of evidence is not evidence of absence; some lesions may have been hidden from macroscopic observation and therefore missed. FURTHER RESEARCH: Radiographic analysis and comparison with other neoplasms should provide additional details for the diagnosis of bladder cancer bone metastases.

Multiple osteomata from medieval Tuscany, Italy (ca. 10th-12th AD).

OBJECTIVE: To explore the possible etiology of multiple osteomata on a skull and long bones from an individual from a medieval site in Tuscany, Italy. MATERIALS: Human skeletal remains dating to the 10th-12th century AD from the parish church of S. Pietro in Pava, in the province of Siena (Tuscany, Central Italy). METHODS: Macroscopic and imaging analyses (Cone Beam Computed Tomography). RESULTS: Nine round-shaped new bone formations are observed on a female individual aged 40-50 years. The lesions have a smooth surface and range from 2.2-6 mm in diameter. CONCLUSIONS: Cone Beam Computed Tomography confirmed that the lesions were composed of compact bone. Macroscopic and radiological features suggest the presence of nonsyndromic multiple osteomata. SIGNIFICANCE: Single cranial osteomata are commonly observed in osteoarchaeological remains, but multiple osteomata are rare and might assist in our understanding of neoplastic conditions in the past. LIMITATIONS: The lack of soft tissues prevents the diagnosis of complex disorders, such as the Gardner syndrome, which is characterised by multiple osteomata and polyposis of the colon. SUGGESTIONS FOR FURTHER RESEARCH: Careful investigation and reporting of all neoplastic lesions in ancient human remains in order to increase our knowledge about the etiology in past human populations.

[The role of medical imaging in paleoanthropology]. / Apports de l'imagerie médicale en paléoanthropologie.

Study of the health status of ancient populations relies on the detection and analysis of bone or dental lesions from skeletons. In the absence of clinical or biological data, the identification of a pathology relies on anatomic and radiographic findings. Three paleopathological cases are presented and macroscopic and imaging findings are discussed. These include one case of eosinophilic granuloma, one case of Ewing sarcoma, and one case of secondary hypertrophic osteoarthropathy. Each case illustrates the value and limitations of retrospective diagnosis; an etiologic diagnosis can either be possible, suggested or unknown. Multiple biases, related to specimen preservation and the frequent non-specific nature of bony changes, make paleopathological diagnosis challenging. As such, the use of medical imaging seems valuable in the evaluation of such lesions. It allows non-invasive evaluation of the bone, underlying pathology, and lesion comparison to finally narrow the differential diagnosis.

A probable primary malignant bone tumor in a pre-Columbian human humerus from Cerro Brujo, Bocas del Toro, Panamá.

We present a rare case of primary bone cancer principally affecting the right humerus of a skeleton from the pre-Columbian site of Cerro Brujo (1265-1380 CE) in Bocas del Toro, on the Caribbean coast of Panamá, excavated in the early 1970s. The humerus contains a dense, calcified sclerotic mass with associated lytic lesions localized around the midshaft of the diaphysis. Evidence of systemic inflammation and anemia, likely caused by the cancer, are visible in the form of severe porotic hyperostosis of the cranial vault and bilateral periosteal reactions in the tibiae. Differential diagnosis and future probes of the tumor are discussed. A tooth from the individual yielded a radiocarbon date 150 years later than those of the domestic occupation at the site. Given that it was the only formal burial recovered from the site, and as the individual had such a visible, painful, and rare pathology, this likely constitutes a ritual burial.

Differential diagnosis of a neoplastic condition in a prehistoric juvenile individual from La Falda site, Northwest Argentina.

Bone neoplasms or tumors are of great interest for paleopathological studies due to their close relationship with health and survivorship as well as for their epidemiologic and demographic relevance. However, the identification of these lesions in archaeological specimens is very uncommon. The aim of this paper is to report the case of skeleton R5 E#1 from the prehistoric cemetery La Falda, in the Northwest region of Argentina. During the osteopathological analysis of the skeletal series, proliferative lesions in several bones of the skeleton of a 7-10-year-old juvenile were observed (i.e., both scapulae; left clavicle, humerus, and ulna, both os coxae, femora, and fibulae, and right foot bones). Age-at-death estimation, location and distribution pattern, and morphological appearances of the lesions indicated that this juvenile suffered from a neoplastic condition. A comprehensive differential diagnosis was carried out, suggesting that these lesions were compatible with hereditary multiple osteochondromas. However, Ewing's sarcoma was not definitively ruled out as a probable diagnosis. Thus, this work adds new evidence to the existence of neoplastic conditions in the prehistoric populations of the Americas, and it contributes original data to perform a differential diagnosis for multiple proliferative lesions.

A probable case of metastatic carcinoma in the medieval Netherlands.

Despite recent considerable gains, our knowledge of cancer in antiquity is still limited. This paper discusses an adult individual from a Dutch medieval hospital site who demonstrates osteoblastic and osteolytic lesions on the ribs, scapula, clavicle, and vertebrae. The morphology, radiographic appearance, and distribution of the skeletal lesions suggest that this individual was affected by metastatic carcinoma. This case increases the number of publications that present an osteoblastic and osteolytic response to cancer and contributes to the body of evidence for archaeological neoplastic disease. For the Netherlands, this individual presents the first published case of probable metastatic carcinoma with mixed skeletal lesions.