CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2.

BACKGROUND: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. METHODS: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50). RESULTS: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. CONCLUSION: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.

Efficacy of sodium hyaluronate in the management of chemical and radiation cystitis.

Onset of cystitis in patients receiving immuno-chemotherapeutic agents by intravesical instillation for non-muscle invasive transitional cell carcinoma of the bladder or after radiotherapy for prostatic cancer is frequent and problematic, since it responds poorly and slowly to the usual symptomatic treatments. This iatrogenic complication often means that cancer therapy has to be interrupted on account of the bladder pathology symptoms and of course this has further clinical implications. The symptoms resemble those of the urgency/frequency and painful bladder syndromes, so we tested the treatment used for these disorders to see whether it helped in this difficult clinical situation. This prospective study therefore enrolled 69 male consecutive patients, between 54 to 81 years of age, with iatrogenic acute cystitis; in 15 the symptoms had appeared after radiotherapy for prostatic cancer, in 24 after intravesical BCG, in 30 after instillation of Mitomycin C (with Synergo thermotherapy for 12 of them). All patients were given intravesical instillations of sodium hyaluronate, 40 mg/50 mL, weekly for from 8 to 24 weeks, depending on how the symptoms released. In the first four weeks dexamethasone 32 mg was mixed in as a "cocktail", on account of its prompt and effective topical antiinflammatory action and good mucosal penetration. Longer use of cortisone is contraindicated because of the high risk of sensitization and it provided no evidence of any ability to overcome the severe urinary disturbances with lasting effect. In order to allow patients with marked overactive bladder to keep these drugs within the bladder, we instilled lidocaine 2% 30 mL, 30 minutes before. Patients recorded their bladder capacity (BC) by filling a micturition diary. Pain was assessed using a Visual Analog Scale (VAS) from 0 to 10 for the chemical cystitis cases at the beginning and end of treatment. After only four weeks BC increased in all patients, and urgency and pain disappeared. Treatment was continued, however, for another four weeks, even in patients with total remission of their symptoms as we had seen earlier that if it was stopped too soon the symptoms could return. In the chemical cystitis group the VAS score dropped from an initial mean of 8.6 to 0.9 at the end of treatment (P<0.0001). Mean BC rose from 58.4 to 283.7 mL in the chemical cystitis cases (P<0.0001), and from 85 to 243.3 mL (P<0.0001) in the radiotherapy patients. Overall 67 patients (97%) reported complete relief of dysuria and pain. Two treatment failures were due to a reduced compliance to treatment by the patients themselves. No adverse reactions were observed related to the catheters or drugs used. Patients with non-invasive bladder tumors were able to restart their cancer therapy. For cystitis induced by intravescical immuno-chemotherapy or pelvic radiotherapy this approach appears to achieve an effective and rapid cure with no adverse reactions, allowing the conclusion of treatments for non-invasive transitional cell-bladder cancer. Patients with chemical cystitis responded a little better than those who had received radiotherapy. Subsequent urinary cytology and cystoscopy ruled out bladder cancer progression in these cases after temporary postponement of the oncological treatment. Intravescical sodium hyaluronate seems a valid and quick therapeutic solution for iatrogenic cystitis from chemo or radiotherapy. After review literature, this strategy does not appear to have been used before for this particular problem.

[Prevention of the recurrence of urinary lithiasis: mineral waters with high or low calcium content?]. / Profilassi della recidiva della litiasi urinaria: acque minerali ad alto o basso contenuto di calcio?

The influence of a calcium-rich mineral water on urine crystallisation in patients with recurring kidney stones was investigated. A calcium and magnesium rich water like the one tested increases the calcium and magnesium content of the urine but decreases oxaluria even after a dietary oxalate load.