P. M. van Hagen

Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer

BACKGROUND The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003). CONCLUSIONS Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.).

Anti-TNF-alpha therapy for sight threatening uveitis.

Aim: To describe the effect of additional treatment with anti-TNF-α therapy in a case series of 13 patients with serious sight threatening uveitis. Methods: 13 patients with serious sight threatening uveitis were included, of whom six had Behçet’s disease, five had idiopathic posterior uveitis, one had sarcoidosis, and one birdshot retinochoroiditis. Onset and course of ocular inflammation, inflammatory signs, and visual acuity were assessed. Patients were treated with 200 mg (approximately 3 mg/kg) infliximab infusion. Repeat infusions were given based on clinical response. Results: Infliximab treatment resulted in an effective suppression of ocular inflammation in all patients. In patients with non-Behçet’s disease uveitis visual acuity in six out of eight improved or was stable. In patients with Behçet’s disease visual acuity in five out of six improved or was stable. Conclusion: Anti-TNF-α treatment may be of value in the treatment of uveitis, and in patients with Behçet’s disease, leading to suppression of ocular inflammation, vasculitis, and improvement of vision in the majority. Based on these results a controlled masked study is warranted.

Evaluation of a radiolabelled cyclic DTPA‐RGD analogue for tumour imaging and radionuclide therapy

Tumours depend on sufficient blood supply for their growth. They are able to promote new blood vessel formation (neoangiogenesis) via angiogenic factors. Inhibition of this process results in tumour involution or necrosis. RGD (Arg‐Gly‐Asp) peptides are described to antagonise neoangiogenesis, e.g., by binding to αvβ3 receptors on blood vessels. In order to visualise neoangiogenesis in tumours in vitro and in vivo, we introduced and tested an RGD analogue [c(Arg‐Gly‐Asp‐D‐Tyr‐Lys)], coupled to the chelator diethyleletriamepentaacetic acid (DTPA). This analogue can be radiolabelled with both 111In and 125I. In autoradiography and immunohistochemistry studies, the 125I‐labelled analogue appeared to bind specifically and with high affinity to αvβ3 receptors on neovascular blood vessel sections of different major human cancers, like prostate and breast cancer, which express these receptors. This radioiodinated radiopharmaceutical also bound to and internalised in human carcinoid Bon cells and rat pancreatic CA20948 tumour cells. Internalisation was receptor‐specific and appeared to be time and temperature dependent. In vivo in rats, we investigated administration of different peptide amounts (0.1, 0.5, and 100 μg). The best amount of the radiolabelled analogue to be administered to rats appeared to be 0.1 μg/rat, as uptake decreased with increasing peptide amount. We also found receptor‐specific accumulation of the 111In‐labelled analogue in the transplantable pancreatic tumour CA20948. The introduction of the DTPA group in this peptide resulted in renal clearance of the radiopharmaceutical, in contrast to the non‐DTPA‐conjugated compound that is cleared predominantly via the liver. 111In emits Auger and conversion electrons besides gamma radiation, therefore, this radiopharmaceutical is suitable not only for tumour scintigraphy but also has potential for radionuclide therapy of major human cancers as well. Moreover, after coupling to the chelator DOTA, the analogue could be radiolabelled in a stable way with β‐emitters, e.g., 90Y and 177Lu, enlarging its potential. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 186–198 (2000).

Autologous peripheral retinal pigment epithelium translocation in patients with subfoveal neovascular membranes

Aim: To evaluate the possibility of translocating autologous peripheral retinal pigment epithelial (RPE) cells and enhance their adhesion to improve functional outcome after choroidal neovascular membrane extraction in patients with subfoveal neovascular membranes. Methods: A prospective, non-controlled surgical study in eight consecutive patients operated between February and July 2001 with final data monitoring in July 2002. All patients had mixed subfoveal membranes of 2–4 disc diameters. Functional tests included Snellen vision and central fixation testing. During vitrectomy, after the extraction of the neovascular complex, 8×104–16×104 RPE cells were removed from the periphery and translocated under the macula following the submacular injection of 2 μg of poly-l-lysine to promote adhesion of the cells. Results: With a follow up ranging from 3 months to 16 months, a pigmented area was seen in the extraction bed of the neovascular membrane in only one patient. Fixation was at the edge of the extraction bed in three patients. Vision remained the same in five patients and deteriorated in three (all with retinal detachment). Retinal detachment due to proliferative vitreoretinopathy occurred in three patients. Conclusions: The translocation of autologous peripheral RPE cells after membrane extraction was technically possible in a sterile manner, but was associated with a high proliferative vitreoretinopathy rate and in the present series had no measurable positive effect on functional outcome.

Is imatinib mesylate a promising drug in systemic sclerosis

A patient with therapy-resistant and progressive systemic sclerosis (SSc) with pulmonary involvement who was treated with imatinib mesylate is described herein. Prior to treatment, pulmonary fibroblasts obtained from the patient were cultured and incubated with imatinib mesylate. Preincubation of the fibroblasts for 16 hours with 2.5 microg/ml imatinib mesylate efficiently abrogated platelet-derived growth factor BB-induced fibroblast proliferation. Furthermore, transforming growth factor beta1-induced type I collagen gene transcription was blocked. During treatment, the patients pulmonary involvement stabilized and her skin tightness improved. To our knowledge, this is the first report of a patient with therapy-refractory SSc responding to treatment with imatinib mesylate.

B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency.

Common variable immunodeficiency disorder (CVID) is the most prevalent form of primary idiopathic hypogammaglobulinemia. Identification of genetic defects in CVID is hampered by clinical and immunologic heterogeneity. By flow cytometric immunophenotyping and cell sorting of peripheral B-cell subsets of 37 CVID patients, we studied the B-cell compartment at the B-cell subset level using the κ-deleting recombination excision circle assay to determine the replication history and the Igκ-restriction enzyme hot-spot mutation assay to assess the somatic hypermutation status. Using this approach, 5 B-cell patterns were identified, which delineated groups with unique replication and somatic hypermutation characteristics. Each B-cell pattern reflected an immunologically homogenous patient group for which we proposed a different pathophysiology: (1) a B-cell production defect (n = 8, 18%), (2) an early peripheral B-cell maturation or survival defect (n = 4, 11%), (3) a B-cell activation and proliferation defect (n = 12, 32%), (4) a germinal center defect (n = 7, 19%), and (5) a postgerminal center defect (n = 6, 16%). The results of the present study provide for the first time insight into the underlying pathophysiologic background in 5 immunologically homogenous groups of CVID patients. Moreover, this study forms the basis for larger cohort studies with the defined homogenous patient groups and will facilitate the identification of underlying genetic defects in CVID.

Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival.

Objectives:We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. Background:Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently “sterilize” regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. Methods:Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. Results:One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12–27) and 14 (9–21), with 2 (1–6) and 0 (0–1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P = 0.007), but not in the multimodality arm (hazard ratio 1.00; P = 0.98). Conclusions:The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

Recurrence pattern in patients with a pathologically complete response after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer

Little is known about recurrence patterns in patients with a pathologically complete response (pCR) or an incomplete response after neoadjuvant chemoradiotherapy (CRT) followed by resection for oesophageal cancer. This study was performed to determine the pattern of recurrence in patients with a pCR after neoadjuvant CRT followed by surgery.

Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells

Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases caused by derailment of humoral and cellular immunity. In this study we investigated whether IVIg treatment can modulate regulatory T cells (Tregs) in humans in vivo. Blood was collected from IVIg‐treated patients with immunodeficiency or autoimmune disease who were treated with low‐dose (n = 12) or high‐dose (n = 15) IVIg before, immediately after and at 7 days after treatment. Percentages and activation status of circulating CD4+CD25+forkhead box protein 3 (FoxP3+) Tregs and of conventional CD4+FoxP3− T‐helper cells (Tconv) were measured. The suppressive capacity of Tregs purified from blood collected at the time‐points indicated was determined in an ex‐vivo assay. High‐dose, but not low‐dose, IVIg treatment enhanced the activation status of circulating Tregs, as shown by increased FoxP3 and human leucocyte antigen D‐related (HLA‐DR) expression, while numbers of circulating Tregs remained unchanged. The enhanced activation was sustained for at least 7 days after infusion, and the suppressive capacity of purified Tregs was increased from 41 to 70% at day 7 after IVIg treatment. The activation status of Tconv was not affected by IVIg. We conclude that high‐dose IVIg treatment activates Tregs selectively and enhances their suppressive function in humans in vivo. This effect may be one of the mechanisms by which IVIg restores imbalanced immune homeostasis in patients with autoimmune and systemic inflammatory disorders.

In vivo and in vitro expression of somatostatin receptors in two human thymomas with similar clinical presentation and different histological features

Abstract[111In-DTPA0]octreotide scintigraphy allows the in vivo visualization of several types of SS receptor (SSR)-expressing tumors. Among these, thymomas have been recently detected. Here we report on 2 patients admitted for myasthenia gravis and radiological evidence of thymic mass. Although these patients had similar clinical presentation, in vivo SSR scintigraphy displayed a difference in the degree of the [111In-DTPA0]octreotide uptake. Considering that both thymic masses had comparable volume, [111In-DTPA0]octreotide level was significantly higher in one of the 2 tumors (tumor/background ratio of 5.7 vs 2.6). The SSR subtype expression pattern was studied in vitro on the surgically resected specimens by ligand binding techniques, quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. According to the recent World Health Organization classification, the 2 tumors were classified A and B2 thymomas respectively. In membrane homogenates, we found a higher number of high affinity [125I-Tyr11]-SS-14 binding sites in the B2 thymomas (23.5±2.5 vs 12.0±0.4 fmol/mg membrane protein; p<0.05). RT-PCR analysis showed sst1, sst2A and sst3 mRNA in the 2 thymoma tissues, whereas SS mRNA was detectable only in the A thymoma. Quantitative evaluation of RT-PCR data showed a comparable expression of the relative amount of sst2A mRNA in both tumors, whereas a significant higher expression of sst3 mRNA in the B2 thymoma. Sst2A immunoreactivity was localized mainly on the endothelium of intratumoral vessels, whereas sst3 was present on either tumoral epithelial cells or normal reactive thymocytes. The expression of sst2A receptors in these tumors is in line with the in vivo visualization by [111In-DTPA0]octreotide, which is considered a sst2-preferring ligand. However, since radioligand uptake was significantly higher in the B2 thymoma, which expressed the largest sst3 mRNA levels, it might be possible that this subtype is involved in determining the tumor visualization during SSR scintigraphy. Apart from the affinity of the radioligand for the receptor, also the efficacy of the internalization of the radioligand-receptor complex might play a role in radioactivity accumulation during in vivo SSR scintigraphy. In fact, although octreotide binds with lower affinity to sst3 receptors, this subtype displayed the highest amount of agonist-dependent receptor internalization compared to the other SSR subtypes. Moreover, sst3 was localized on both tumor cells and reactive thymocytes, and these latter cells are characterized by a very active turnover of membrane molecules. Finally, although more cases need to be evaluated, the lack of detection of SS mRNA in the tumor presenting a more aggressive phenotype (B2 thymoma) might have physiopathological or prognostic significance.