Oncontrol biopsy needle

The Oncontrol bone biopsy needle is a powered bone biopsy system used for bone marrow aspiration, but which can be used for biopsy of other bones. The driver runs at a single speed. Care should be taken to ensure the needle does not heat up when accessing hard bone.

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Mifamurtide (MTP-PE)

What is it?

Mifamurtide is the brand name for muramyl tripeptide phosphatidylethanolamine or MTP-PE for short. It is a synthetic derivative of muramyl dipeptide (MDP), which is an immune-stimulatory component of the bacterial cell wall. It’s advantage is that it has a longer half-life in plasma than MDP.

Mifamurtide is licensed for use as an adjunct in the treatment of high-grade resectable non- metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults. There has been much debate over the evidence to support it’s use but after much deliberation the National Institute for Health and Clinical Excellence (NICE) granted permission for it’s use in the UK in October 2011.  Read more about the NICE guidance.

How does it work?

Nucleotide-binding oligomerization domain-containing protein 2, or NOD2 for short, is a receptor found in monocytes and macrophages, which recognises bacterial peptidoglycan, stimulating an immune response. MTP-PE is recognised by NOD2 and thus simulates a bacterial infection, inducing an immune response and a cascade of cytokines including Tumour Necrosis Factor alpha (TNFα), which in turn generates a macrophage-mediated attack on the cancer cells.

The use of an immune stimulant like MTP-PE makes intuitive sense in the treatment of osteosarcoma, as post-resection infection has been shown to increase overall survival. Read more about infection in osteosarcoma.

The Evidence

There is one randomised controlled trial looking at the effect of Mifamurtide as an adjunct in the treatment of osteosarcoma. Meyers et al and the Children’s Oncology Group published the trial of 662 young people with localised, resectable osteosarcoma. They were randomly assigned to high-dose methotrexate, cisplatin, and doxorubicin plus or minus ifosfamide in a 2×2 factorial design, which also included a randomised evaluation of MTP. The study concluded that the addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P=0.03). The study has however generated much controversy. Read the paper for yourself in the Journal of Clinical Oncology.

Critics of the paper cite differences in the chemotherapy regimes in the different arms of the study, with cisplatin omitted from pre-operative chemotherapy in the ifosfamide-containing arm. Questions have also been raised about the apparent lack of effect of MTP on event-free survival (EFS) while at the same time overall survival (OS) is improved, as other studies suggest that EFS and OS are inextricably linked.

In defence of the paper it is pointed out that the trial was only powered to show a difference in effect from the MTP, which it does when the addition of MTP is looked at in isolation. It is also pointed out that MTP-containing arms of the trial had worse tumour necrosis at the time of resection, normally associated with a poorer prognosis, and yet those patients had the reported improvement in survival despite this.

You can read an eloquent commentary on some of the controversies in the Journal of Clinical Oncology.

You can read a riposte from the authors of the RCT of MTP, also in the Journal of Clinical Oncology.

  1. Meyers PA, Schwartz CL, Krailo MD, et al: Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival—A report from the Children’s Oncology Group. J Clin Oncol 26:633-638, 2008

The Cade Regime for Osteosarcoma

Sir Stanford Cade was one of the pioneers of radiotherapy and worked at the Westminster Hospital between 1924 and 1960. Amongst his extraordinary output he published a thoughtful paper on the treatment of osteogenic sarcoma in the prechemotherapy era (1).  He reasoned that early amputation had no impact on survival in osteosarcoma, and therefore that early metastasis was the norm. Furthermore he argued that to amputate the limbs of patients with such a poor prognosis was unreasonable and mutilating. The Cade regime therefore involved high dose radiotherapy to the primary tumour site, followed by secondary amputation if the patient survived long enough. He was able to demonstrate clinical, radiological and pathological responses to radiotherapy in this relatively radioresistant tumour.  His description defined treatment for osteosarcoma in the prechemotherapy era.

Reference:

Journal of the Royal College of Surgeons of Edinburgh. 1955 Dec ;1(2):79–111.

Primary lymphoma of bone in adults

Primary lymphoma of bone (PLB) is defined as malignant, lymphoid infiltrate within bone, without evidence of lymph nodes or other tissues at presentation. It arises from the medullary cavity and manifests as a localised, solitary lesion.

It is rare, accounting for only 3% of primary bone malignancies and 5% of extra nodal lymphomas(1). Bone lymphoma is not uncommon in advanced lymphoma originating from other sites, but PLB accounts for less than 2% of all lymphomas in adults (2).

To be defined as primary bone lymphoma there must be:

(i) a primary focus in a single bone

(ii) positive histological diagnosis

(iii) no evidence of distant soft tissue or distant lymph node involvement.

However this definition of PLB is controversial. Some studies have included patients with Ann Arbor stage 1 and 2 only, whereas others have also included patients with stage 4 disease (3).  Regional lymph node involvement at diagnosis is therefore accepted by some, as is involvement of multiple skeletal sites, as long as the other criteria are met (4).

The majority of PLB is Non-Hodgkin lymphoma, with large B-cell lymphoma being the most common subtype. Other types include follicular lymphoma and Burkitt lymphoma. Differential diagnosis includes Ewing’s sarcoma, neuroblastoma, and other round cell tumours. It can also be associated with AIDS, immunosuppression and Paget’s disease.

The most common presentations are bone pain not relieved by rest, a palpable mass, pathological fracture or cord compression. About 10% have systemic symptoms at presentation including night sweats, weight loss and fever. Common sites include the femur, humerus, tibia, spine, pelvis, sternum, ribs and skull.

PLB most often involves the diametaphysis of major long bones. Radiological findings are of an aggressive pattern of lytic bone destruction and associated soft tissue mass. CT or MRI will show a large soft tissue mass and abnormal marrow attenuation without extensive cortical destruction (5).

Because PLB is rare, there have been few randomised control trials to evaluate treatment. Traditionally radiotherapy has been used as treatment with or without chemotherapy. However more recently the standard treatment has consisted of chemotherapy (CHOP regime) with or without radiotherapy depending on the histological type and stage. Several studies have established that a combination of chemotherapy and radiotherapy is better than radiotherapy alone (6,7).

The evidence is conflicting as to which regimen produces the best survival rates. Most studies are of small sample size and are therefore limited in their value in identifying prognostic factors.

A study by Alencar et al recorded progression free survival at 83% at 4 years with no difference between treatment with chemotherapy and a combination of chemotherapy and radiotherapy (8).  Jawed et al, in a review of 1500 adults, estimated 5 year survival at 58% and 10 year survival at 45%, and the only positive prognostic indicators identified were localised disease and younger age (9).

Disease free and overall survival rates have also been reported to be 78% and 91% at 5 years and 73% and 87% at 10 years, respectively (10).

Surgical management is limited to biopsy, stabilisation of pathological fracture and decompression of spinal canal compromise. There is no clear role for debulking surgery or resection.

The introduction of rituximab in March 2001 for treatment of diffuse large cell lymphoma has shown increased survival rates compared to those treated without rituximab, for example 3 year progression free survival has been demonstrated at 88% verses 52% without rituximab (11).

Dr Ruth Blackwell MBBS

GPST1

Newcastle Upon Tyne

References:

1. Baar J, Burkes RL, Bell R, Blackstein ME, Fernandes B, Langer F. Primary non-Hodgkin’s lymphoma of bone. A clinicopathologic study. Cancer. Feb 15 1994;73(4):1194-9.
2 Ramadan KM, Shenkier T, Sehn LH, Gascoyne RD, Connors JM. A clinicopathological retrospective study of 131 patients with primary bone lymphoma: A population-based study of successively treated cohorts from the British Columbia Cancer Agency. Ann Oncol 2007;18:129-35.
3 Jawad et al. Primary Lymphoma of bone in adult patients. Cancer 2010;116(4):871
4 Singh T, Satheesh CT, Lakshmaiah KC, Suresh TM, Babu GK, Lokanatha D, Jacob LA, Halkud R. Primary bone lymphoma: A report of two cases and review of the literature. J Can Res Ther 2010;6:296-8
5 Mulligan ME, McRae GA, Murphey MD. Imaging features of primary lymphoma of bone AJR Am J Roentgenol 1999;173:1691-7.
6 Dubey P, Ha CS, Besa PC et al. Localized primary malignant lymphoma of bone. Int J Radiat Oncol Biol Phys 1997;37:1087-1093.
7 Baar J, Burkes RL, Bell R, Blackstein ME, Fernandes B, Langer F. Primary non-Hodgkin’s lymphoma of bone. A clinicopathologic study. Cancer. Feb 15 1994;73(4):1194-9.
8 Alencar et al Primary bone lymphoma – the university of Miami experience. Leuk lymphoma. Jan 2010;51(1):39-49
9 Jawad et al. Primary Lymphoma of bone in adult patients. Cancer 2010;116(4):871
10 Fidias P, Spiro I, Sobczak ML, Nielsen GP, Ruffolo EF, Mankin H, et al. Long-term results of combined modality therapy in primary bone lymphomas. Int J Radiat Oncol Biol Phys 1999;45:1213-8.
11 Ramadan KM, Shenkier T, Sehn LH, Gascoyne RD, Connors JM. A clinicopathological retrospective study of 131 patients with primary bone lymphoma: A population-based study of successively treated cohorts from the British Columbia Cancer Agency. Ann Oncol 2007;18:129-35.

Osteosarcoma

An osteosarcoma is a malignant tumour containing cells of mesenchymal origin and which is characterised by the formation of malignant osteoid.  Osteosarcomas are the most common primary bone sarcoma, but osteosarcomas also (rarely) occur in bone – in other words the prefix “osteo-” relates to the production of osteoid matrix rather than an origin in bone.

  • Incidence is around 1-2 per million per annum, which is around 131 new cases in England per annum
  • Osteosarcomas have a peak incidence in the second decade of life, and a smaller peak in the elderly
  • They classically occur in the metaphyseal regions of long bones  where most growth occurs (ie distal femur, proximal tibia, proximal humerus)
The WHO histological classification of osteosarcoma recognises the following groups:
1. Central (Medullary) tumours
  • conventional central osteosarcomas (the most common type)
  • telangiectatic osteosarcoma
  • intraosseous well-differentiated (low-grade) osteosarcomas
  • small-cell osteosarcomas
2. Surface (peripheral) tumours
  • parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas
  • periosteal osteosarcoma: low to intermediate-grade osteosarcoma
  • high-grade surface osteosarcoma

References:

Bone Sarcomas: incidence and survival rates in England – NCIN Data Briefing. National Cancer Intelligence Network 2010.

Complications of endoprosthetic reconstruction

The major complications particular to endoprosthetic reconstruction of the limb following tumour resection include:

  • infection
  • aseptic loosening
  • dislocation
  • wear
  • implant fracture
These are in addition to other complications associated with major tumour resection, regardless of the kind of reconstruction, which include:
  • wound complications
  • thromboembolism
  • neurological injury
  • vascular injury
Local recurrence of tumour might be considered a failure of local therapy, rather than a complication.

Classification of primary bone tumours

Primary bone tumours can be classified according to the tissue of differentiation, using the WHO system. Tumours are classified as:

  • cartilage tumours (eg osteochondroma, chondrosarcoma)
  • osteogenic tumours (eg osteoid osteoma, osteosarcoma)
  • fibrogenic tumours (eg desmoplastic fibroma, fibrosarcoma)
  • fibrohistiocytic tumours (eg benign fibrous histiocytoma, malignant fibrous histiocytoma)
  • Ewing sarcoma/Primitive Neuroectodermal tumour (PNET)
  • Haemopoetic tumours (eg plasma cell myeloma)
  • Giant cell tumour of bone
  • Notochordal tumours (eg chordoma)
  • Vascular tumours (eg haemangioma)
  • Smooth muscle tumours (eg leiomyosarcoma)
  • Lipogenic tumours (eg lipoma, liposarcoma)
  • Neural tumours (eg neurilemmoma)
  • Miscellaneous tumours (eg adamantinoma)
  • Miscellaneous lesions (eg aneurysmal bone cyst)
  • Joint lesions (eg synovial chondromatosis)
For more information look here.
A simpler classification can also be helpful:
  • Cartilage forming tumours
  • Bone forming tumours
  • Fibrous tumours
  • Non-matrix producing tumours