Mark Smithers

Population-Based 20-Year Survival Among People Diagnosed With Thin Melanomas in Queensland, Australia

PURPOSE The 20-year survival rates are unknown for the majority of melanoma patients-those with thin melanomas. We determined 20-year survival rates of patients diagnosed with thin melanomas (≤ 1.00 mm) in the general population and also determined the main prognostic factors. PATIENTS AND METHODS Available clinical and histologic data from the Queensland Cancer Registry were obtained for all patients diagnosed with a single thin invasive melanoma from 1982 to 2006 and matched against national death registration data. Melanoma-specific survival estimates to December 31, 2007, were assessed, and subgroup differences in prognosis were determined by fitting multivariate Cox proportional hazard models. RESULTS Among 26,736 people in the state of Queensland diagnosed with thin melanomas, the 20-year survival was 96%. The most influential determinants of prognosis were tumor thickness ≥ 0.75 mm (adjusted hazard ratio [HR], 4.33; 95% CI, 2.8 to 6.8 compared with tumors < 0.25 mm) and patient age at diagnosis older than 65 years (HR, 2.8; 95% CI, 1.8 to 4.5) compared with age younger than 25 years. Acral lentiginous and nodular tumors, male sex, tumor site on the scalp or neck, or tumor invasion of the entire papillary dermis each independently increased the risk of dying from thin invasive melanoma. CONCLUSION The outlook for patients with thin invasive melanoma is positive, although continued clinical vigilance is warranted for patients with nodular melanoma and those with the thickest tumors.

Psychological responses to malignant melanoma: An investigation of traumatic stress rections to life-threatening illness

A cross-sectional study of 95 individuals with malignant melanoma was conducted to investigate posttraumatic stress responses to a diagnosis of melanoma and to validate the use of the Impact of Event Scale (IES) as a measure of the response to the trauma of life-threatening disease. The diagnosis and progression of malignant disease are likely to present a range of acute and chronic trauma to the individual and the individuals family. The findings suggest that the IES is a reliable and valid measure of this distress, with scores varying according to disease progression and prognostic status of nonmetastatic disease patients. This indicates the importance of clinical attention to the specific symptoms that may best reflect the traumatic impact of life-threatening illness and its progression, and the applicability of posttraumatic stress syndromes in understanding the psychological distress of this clinical population.

Clinical response after intradermal immature dendritic cell vaccination in metastatic melanoma is associated with immune response to particulate antigen

Abstract. Metastatic melanoma is poorly responsive to treatment, and immunotherapeutic approaches are potentially beneficial. Predictors of clinical response are needed to identify suitable patients. We sought factors associated with melanoma-specific clinical response following intradermal vaccination with autologous melanoma peptide and particulate hepatitis B antigen (HBsAg)-exposed immature monocyte-derived dendritic cells (MDDC). Nineteen patients with metastatic melanoma received a maximum of 8, 2-weekly vaccinations of DC, exposed to HBsAg in addition to autologous melanoma peptides. A further 3 patients received an otherwise identical vaccine that did not include HBsAg. Patients were assessed 1–2 monthly for safety, disease volume, and cellular responses to HBsAg and melanoma peptide. There was no significant toxicity. Of 19 patients receiving HBsAg-exposed DC, 9 primed or boosted a cellular response to HBsAg, and 10 showed no HBsAg response. HBsAg-specific responses were associated with in vitro T cell responses to melanoma peptides and to phytohemagglutinin (PHA). Zero out of 10 non-HBsAg-responding and 4/9 HBsAg-responding patients achieved objective melanoma-specific clinical responses or disease stabilization – 1 complete and 2 partial responses and 1 case of stable disease (P=0.018). Development of melanoma-specific cellular immunity and T cell responsiveness to mitogen were greater in the group of patients responding to HBsAg. Therefore stimulation of an immune response to nominal particulate antigen was necessary when presented by melanoma peptide-exposed immature DC, to achieve clinical responses in metastatic melanoma. Since general immune competence may be a determinant of treatment response, it should be assessed in future trials on DC immunotherapy.

Immature human monocyte-derived dendritic cells migrate rapidly to draining lymph nodes after intradermal injection for melanoma immunotherapy.

Injected antigen-loaded immature monocyte-derived dendritic cells (DCs) may be incapable of migrating from skin to draining lymph nodes for antigen presentation. The in vivo migratory capacity of intradermally administered immature monocyte-derived DCs was therefore investigated during a phase I/II clinical trial for metastatic melanoma. DCs cultured from adherent monocytes in the presence of autologous serum, granulocyte-macrophage colony stimulating factor and interleukin-4 were pulsed with antigen and labelled with technetium-99m hexamethylpropylene-amineoxime (99mTc-HMPAO) ex vivo, then injected intradermally. A 99mTc-HMPAO control containing an equivalent amount of radioactivity was injected into the opposite thigh. The pelvis was then imaged with a gamma camera. The DCs were characterized as immature by functional and phenotypic analysis. Labelled DCs travelled to the draining inguinal lymph nodes within 10 min, and the draining lymph nodes were clearly outlined up to 4 h after injection. Free NmTc outlined draining lymph nodes after 10 min but was cleared from the nodes within 1 h. Thus, immature human monocyte-derived DCs migrate rapidly to and remain in draining lymph nodes after intradermal injection for immunotherapy.

Urban-rural differences in survival from cutaneous melanoma in Queensland

Objective:To assess how much of the urban‐rural disparity in melanoma survival in Queensland is due to later diagnosis.

Salvage definitive chemo-radiotherapy for locally recurrent oesophageal carcinoma after primary surgery: Retrospective review

To determine the overall survival and gastrointestinal toxicity for patients treated with salvage definitive chemo‐radiotherapy after primary surgery for locoregional relapse of oesophageal carcinoma. A retrospective review of 525 patients who had a resection for oesophageal or oesophagogastric carcinoma at Princess Alexandra Hospital identified 14 patients treated with salvage definitive radiotherapy or chemo‐radiotherapy, following localized recurrence of their disease. We analysed the patient and treatment characteristics to determine the median overall survival as the primary end point. Gastrointestinal toxicity was examined to determine if increased toxicity occurred when the stomach was irradiated within the intrathoracic radiotherapy field. The median overall survival for patients treated with curative intent using salvage definitive chemo‐radiotherapy was 16 months and the 2‐year overall survival is 21%. One patient is in clinical remission more than 5 years after therapy. Age <60 years old and nodal recurrence were favourable prognostic factors. Treatment compliance was 93% with only one patient unable to complete the intended schedule. Fourteen per cent of patients experienced grade 3 or 4 gastrointestinal toxicity. Salvage definitive chemo‐radiotherapy should be considered for good performance status patients with oesophageal carcinoma who have a locoregional relapse after primary surgery. The schedule is tolerable with low toxicity and an acceptable median survival.

An innovative approach for locally advanced stage III cutaneous melanoma: radiotherapy, followed by nodal dissection

Patients with advanced nodal melanoma are typically managed with a regional nodal dissection; however, they have a high rate of distant relapse after surgery. This study assesses the role of preoperative radiotherapy to assist with the regional control in this subset of patients. Patients who had histologically confirmed stage III malignant melanoma and were treated with preoperative radiotherapy between 2004 and 2011 were eligible. All patients were staged with computer tomography and most with [18F]-fluorodeoxyglucose (FDG) PET. Patients received preoperative radiotherapy, followed by a planned regional dissection at 12–14 weeks from completion with assessment of clinical, radiological and pathological responses. The primary outcome measure was the 1-year actuarial in-field control. There were 12 patients, with nine having disease of the axilla. All patients received radiotherapy up to a median dose of 48 Gy in 20 fractions, with seven patients achieving a partial clinical response. Ten patients proceeded to surgery, with four patients developing minor wound complications. The FDG-PET response did not appear to correlate with the pathological response. The 1-year in-field control rate was 92% (95% confidence interval 54–99) and the 1-year relapse-free survival was 54% (95% confidence interval 21–78). For selected patients with high-volume regional disease, we have successfully used preoperative radiotherapy, followed by a nodal dissection. Whether this type of protocol is of value in a more general group of patients with high-volume regional disease is currently under investigation.

Metastatic lesions in the joint associated with acute inflammatory arthritis after dendritic cell immunotherapy for metastatic melanoma.

A 47 year old man undergoing immunotherapy for metastatic melanoma with autologous dendritic cells pulsed with autologous tumour peptide and hepatitis B surface antigen developed acute left ankle arthritis. Gout and acute infection were excluded, and an autoimmune aetiology or occult metastasis were considered. The arthritis initially subsided with indomethacin, but the symptoms recurred 2 months later, and magnetic resonance imaging demonstrated metastatic melanoma of the left talus. Immunohistochemical staining of a cerebral metastatic deposit biopsied 1 week after the onset of arthritis demonstrated T-cell and macrophage infiltration of the tumour. In addition, the patient developed melanoma-specific delayed type hypersensitivity and cytotoxic T-cell responses after vaccination. Thus, the monoarthritis represented an ‘appropriate’ inflammatory response directed against metastatic melanoma.

Coping with esophageal cancer approaches worldwide

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on approaches to the epidemiology, diagnosis, and treatment of esophageal cancer in Europe, South Africa, Kenya, Australia, and China; the molecular classification of esophageal cancers (including cancers at the gastroesophageal junction); the Japanese classification; the scope of the Human Variome Project; and the topographic–anatomic subclassification of adenocarcinomas of the gastroesophageal junction.

Two cases of NSAID-induced gastropathy and enteropathy of the ileum

Case 1: A 32-year-old male presented with weight loss, vomiting and persistent anaemia. Examination revealed a gastric splash and signs of malnutrition. He had a distal gastrectomy 2 years prior, with a Bilroth II reconstruction, performed elsewhere for resistant duodenal stenosis. There was a short history of intense non-steroidal anti-inflammatory drug (NSAID) intake 1 month prior to presentation. After instituting gastric drainage and intravenous nutrition, an endoscopy revealed a dilated gastric remnant with inflammation and a tight stricture at the gastro-jejunostomy. Two weeks after admission, with continuous intravenous nutrition, a tight stricture persisted. At laparotomy, there was a significant, residual, dilated gastric remnant with no other intra-abdominal abnormalities noted. A gastrectomy (Fig. 1), leaving the proximal third of the stomach, was performed with a Roux-en-Y reconstruction. Histology of the jejunal anastomosis revealed fibromuscular proliferation with chronic inflammatory infiltrates, possibly related to NSAID abuse. One month later, the patient presented with visible small intestinal peristalsis, with a computed tomography scan showing a distal small bowel obstruction. At laparotomy, there was a transition point in the ileum with several strictures adjacent, which were not evident on the initial laparotomy. The segments of bowel with the dense strictures were resected and a stricturoplasty performed on a palpable mucosal band (Fig. 2). Histology reported submucosal thickening and scarring with muscularis propria hyperplasia, consistent with postinflammatory stricture secondary to NSAID abuse. Case 2: A 36-year-old female presented with weight loss, nausea, vomiting and anorexia. Examination revealed a gastric splash, signs of malnutrition, peripheral oedema and associated hypoalbuminaemia. Four years earlier, she had an omental patch to repair a perforated duodenal ulcer at another institution. Two years later, she had a distal gastrectomy with a Bilroth I anastomosis for prepyloric ulceration and iron-deficient anaemia, despite proton pump inhibitor treatment. Following intravenous feeding and nasogastric decompression, endoscopy revealed a tight inflammatory stricture at the gastro-duodenal anastomosis with passage past the stricture impossible. Urine drug testing on admission was positive for NSAIDs. On further questioning, she admitted using children’s liquid ibuprofen regularly. Following 3 weeks of nutritional support, a laparotomy revealed a 2to 3-cm inflamed segment of duodenum at the anastomosis. A partial gastrectomy was performed leaving the proximal third of the stomach with a Roux-en-Y reconstruction. Inspection of the small intestine revealed numerous circumferential bands of fibrosed tissue with increased vascularity in short, 1-cm lengths in the distal ileum with evidence of subacute obstruction. This segment of ileum was resected (Fig. 3). Histology revealed fibrosis of the submucosa and vertical collagen fibres, consistent with NSAID-induced diaphragm disease of the ileum. These cases report NSAID abuse in young patients with gastroduodenal and ileal stenosis, so-called NSAID-induced gastropathy and ileal diaphragm disease. In both cases, the first resection was performed without the knowledge of NSAID abuse. The initial gastrectomy was less than the historically recommended ‘two-thirds’ gastrectomy for peptic ulcer disease. Whether that was an issue with the recurrent inflammatory stenosis at the anastomosis and the continued abuse of NSAIDs is unclear. In the first case, the presence of small bowel involvement was not clear at the gastric resection. Prior to gastrectomy, he had no solid food, which possibly limited visible small bowel involvement. The patient denied continued NSAID ingestion following the gastrectomy. In the second case, the small bowel strictures were evident and palpable at laparotomy.