Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

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.

The triad of bilateral retinoblastoma, dysplastic naevus syndrome and multiple cutaneous malignant melanomas: a case report and review of the literature.

We report a case of a patient with the triad of retinoblastoma, dysplastic naevus syndrome (DNS) and multiple cutaneous melanomas. The combination of retinoblastoma and DNS is a significant risk factor for the development of cutaneous melanoma. This risk extends to family members. We recommend that survivors of (inherited) retinoblastoma and their relatives are closely screened for the presence of dysplastic naevi.

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.

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.

Laparoscopy in the management of diaphragmatic rupture due to blunt trauma.

BACKGROUND: Traumatic diaphragmatic rupture remains a diagnostic challenge often unrecognized until laparotomy in over 40% of patients and the diagnosis is delayed in a further 15%. This report describes four patients diagnosed at laparoscopy with a ruptured diaphragm. METHODS: One patient had a left diaphragmatic rupture amenable to laparoscopic repair in the emergency setting. Three patients underwent laparoscopy 2, 7 and 10 days after injury which revealed two right-sided and one extensive left-sided rupture, respectively; each required open repair. RESULTS: While laparoscopy is an excellent diagnostic tool, particularly in the delayed setting, repair is not possible for right-sided ruptures because of the liver bulk. CONCLUSIONS: Thoracoscopy in the instance of delayed presentation may offer the best chance for minimal-access diagnosis and treatment when there is suspicion of a right-sided diaphragmatic rupture.

Psychological responses to malignant melanoma. An investigation of traumatic stress reactions 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 individual's 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.

Videothoracoscopic primary repair of early distal oesophageal perforation.

Distal oesophageal perforation following dilation of oesophageal strictures or achalasia is usually recognized soon after the event. Treatment of two patients with perforation resulting from vigorous achalasia, diagnosed within hours of the procedure, was approached by videothoracoscopic exposure and successful primary repair was achieved in both instances. Details relating to patient preparation and operative technique are presented. Both patients recovered, with normal diet being tolerated by the seventh day after surgery, were discharged on day eight and 10 and returned to normal activities within 3 weeks of surgery. The technique presented is apparently well suited to distal oesophageal perforations diagnosed early, when primary closure can be achieved safely, and significantly improves patient recovery after this often iatrogenic injury.

Quinazoline antifolates inhibiting thymidylate synthase: variation of the amino acid.

Five new analogues (1c-g) of the antifolate N10-propargyl-5,8-dideazafolic acid (1a) are described in which the benzoyl-L-glutamate moiety was replaced by benzoic acid (desglutamyl-N10-propargyl-5,8-dideazafolic acid), benzoyl-L-aspartate, 4-phenylbutyrate, benzoylglycine, and benzoyl-L-alanine. The esters of the appropriate 4-aminophenyl (benzoyl) starting materials were sequentially alkylated upon nitrogen, first with a propargyl halide and then with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide. Saponification of the antifolate esters so produced gave the desired analogues. The new derivatives (1c-g) and also the known diethyl ester of 1a (1b) were tested for their inhibition of purified L1210 thymidylate synthase (TS) and for their inhibition of the growth of L1210 cells in culture. The TS inhibition of the analogues 1b-g was estimated by calculating the inverse relative potency, defined as the ratio IC50(compound)/IC50(1a). The results obtained were as follows: greater than 62, 84, 9, 333, 21, and 5, respectively. All were thus less inhibitory than 1a. None of the compounds improved upon 1a in inhibiting the growth of L1210 cells in culture.

Quinazoline antifolates inhibiting thymidylate synthase: variation of the N10 substituent.

The synthesis of 12 new 5,8-dideazafolates with isopropyl, cyclopropylmethyl, 2-fluoroethyl, carbamoylmethyl, phenacyl, 3-fluorobenzyl, 5-uracilylmethyl, carboxymethyl, 2-carboxyethyl, 3-cyanopropyl, 3-hydroxypropyl, and cyanomethyl substituents at N10 is described. In general, the synthetic route involved monoalkylation of diethyl N-(4-amino-benzoyl)-L-glutamate, coupling of the resulting secondary amine with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide in N,N-dimethylacetamide with calcium carbonate as the base, and deprotection using mild alkali. The cyanomethyl derivatives was found to be unexpectedly base labile and was therefore prepared by mild acid deprotection of a di-tert-butyl ester. The compounds were tested as inhibitors of purified L1210 thymidylate synthase (TS). Four members of the series were more potent that the N10-hydrogen compound, but none was superior to the previously described N10-propargyl-5,8-dideazafolic acid. Selected compounds were examined as inhibitors of purified L1210 dihydrofolate reductase (DHFR). As desired, N10 substitution in general reduced DHFR inhibitory activity; these results are discussed. As a measure of cytotoxicity, the compounds were examined for their inhibition of the growth of L1210 cells in culture. None of the new substituents conferred enhanced potency relative to N10-propargyl-5,8-dideazafolic acid (ID50 = 5 microM), which, as the best TS inhibitor and a relatively poor DHFR inhibitor, continues to lead this series.