Howard Florey, Alexander Fleming and the fairy tale of penicillin

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.The public myth of the discovery of penicillin is an archetypal "quest story" of the type common to every human culture. But the real story of the discovery, testing and refinement of penicillin is a complex tale of accident, serendipity, oversight, conflict, the pressure of war, idiosyncratic personalities and even - the invention of history.Peter D Goldsworthy and Alexander C McFarlan

Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery

Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents

Diagnostic algorithm, prognostic factors and surgical treatment of metastatic cancer diseases of the long bones and spine

Oncological management of skeletal metastases has changed dramatically in the last few decades. A significant number of patients survive for many years with their metastases.Surgeons are more active and the technical repertoire is broader, from plates to intramedullary devices to (tumour) endoprostheses.The philosophy of treatment should be different in the case of a trauma-related fracture and a pathological fracture. A proper algorithm for establishing a diagnosis and evaluation of prognostic factors helps in planning the surgical intervention.The aim of palliative surgery is usually to eliminate pain and to allow the patient to regain his/her mobility as well as to improve the quality of life through minimally invasive techniques using life-long durable devices.In a selected group of patients with an oncologically controlled primary tumour site and a solitary bone metastasis with positive prognostic factors, which meet the criteria for radical excision (approximately 10% to 15% of the cases), a promising three to five years of survival may be achieved, especially in cases of metastases from breast and kidney cancer.Spinal metastases require meticulous evaluation because decisions on treatment mostly depend on the tumour type, segmental stability, the patient's symptoms and general state of health.Advanced radiotherapy combined with minimally invasive surgical techniques (minimally invasive stabilisation and separation surgery) provides durable local control with a low complication rate in a number of patients. Cite this article: EFORT Open Rev 2017;2:372-381

Distal femur resection with endoprosthetic reconstruction: A long-term followup study

The distal femur is a common site for primary and metastatic bone tumors and therefore, it is a frequent site in which limb-sparing surgery is done. Between 1980 and 1998, the authors treated 110 consecutive patients who had distal femur resection and endoprosthetic reconstruction. There were 61 males and 49 females who ranged in age from 10 to 80 years. Diagnoses included 99 malignant tumors of bone, nine benign-aggressive lesions, and two nonneoplastic conditions that had caused massive bone loss and articular surface destruction. Reconstruction was done with 73 modular prostheses, 27 custom-made prostheses, and 10 expandable prostheses. Twenty-six gastrocnemius flaps were used for soft tissue reconstruction. All patients were followed up for a minimum of 2 years. Function was estimated to be good or excellent in 94 patients (85.4%), moderate in nine patients (8.2%), and poor in seven patients (6.4%). Complications included six deep wound infections (5.4%), six aseptic loosenings (5.4%), six prosthetic polyethylene component failures (5.4%), and local recurrence in five of 93 patients (5.4%) who had a primary bone sarcoma. The limb salvage rate was 96%. Distal femur endoprosthetic reconstruction is a safe and reliable technique of functional limb sparing that provides good function and local tumor control in most patients

Enchondromas of the Hand: Treatment With Curettage and Cemented Internal Fixation

Removal by means of curettage is the mainstay of surgical treatment of enchondromas of the hand. Reconstruction traditionally entails filling the tumor cavity with a bone graft, or it may be decided not to perform a reconstruction. In either case a period of protected activity is needed until the tumor cavity has healed. The current study describes the use of cemented internal fixation for the purpose of reconstruction of these cavities. This technique provides immediate mechanical stability and allows early mobilization. Between 1986 and 1999, we treated 13 patients who were diagnosed as having enchondroma of the hand. Surgery included tumor removal with hand curettes and high-speed burr drilling. The remaining tumor cavity was reconstructed by using bone cement and intramedullary hardware. All patients were followed-up for more than 2 years. There were no postoperative infections or fractures, and all patients returned to their presurgical functional capability within 4 weeks. At the most recent follow-up evaluation, none of the patients had local tumor recurrence. Although 7 patients had a decrease in flexion of the metacarpophalangeal or interphalangeal joints, none reported a functional limitation. Reconstruction of the tumor cavity with cemented hardware provides immediate mechanical stability, allows early mobilization, and is associated with good functional outcome. (J Hand Surg 2002;27A:870 -875

Synergistic antitumor activity of histamine plus melphalan in isolated limb perfusion: preclinical studies.

BACKGROUND: We have previously shown how tumor response of isolated limb perfusion (ILP) with melphalan was improved when tumor necrosis factor alpha (TNF-alpha) was added. Taking into account that other vasoactive drugs could also improve tumor response to ILP, we evaluated histamine (Hi) as an alternative to TNF-alpha. METHODS: We used a rat ILP model to assess the combined effects of Hi and melphalan (n = 6) on tumor regression, melphalan uptake (n = 6), and tissue histology (n = 2) compared with Hi or melphalan alone. We also evaluated the growth of BN-175 tumor cells as well as apoptosis, necrosis, cell morphology, and paracellular permeability of human umbilical vein endothelial cells (HUVECs) after Hi treatment alone and in combination with melphalan. RESULTS: The antitumor effect of the combination of Hi and melphalan in vivo was synergistic, and Hi-dependent reduction in tumor volume was blocked by H1 and H2 receptor inhibitors. Tumor regression was observed in 66% of the animals treated with Hi and melphalan, compared with 17% after treatment with Hi or melphalan alone. Tumor melphalan uptake increased and vascular integrity in the surrounding tissue was reduced after ILP treatment with Hi and melphalan compared with melphalan alone. In vitro results paralleled in vivo results. BN-175 tumor cells were more sensitive to the cytotoxicity of combined treatment than HUVECs, and Hi treatment increased the permeability of HUVECs. CONCLUSIONS: Hi in combination with melphalan in ILP improved response to that of melphalan alone through direct and indirect mechanisms. These results warrant further evaluation in the clinical ILP setting and, importantly, in organ perfusion