Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer.

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS: Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS: Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively). CONCLUSIONS: The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.

Increased pathological complete response rate after a long-term neoadjuvant letrozole treatment in postmenopausal oestrogen and/or progesterone receptor-positive breast cancer.

BACKGROUND: The objective of this study was to determine the optimal scheduling of 2.5 mg daily letrozole in neoadjuvant breast cancer patients to obtain pathological complete response (pathCR) and assess Ki-67 expression as an early predictor of response. PATIENTS AND METHODS: This single institution study comprised 120 oestrogen receptor (ER)-positive postmenopausal women with primary breast cancer (clinical stage ≥ T2, N0-1), from three sequential cohorts (cohort A of 40, cohort B of 40 and cohort C of 40 patients, respectively) based on different duration of the neoadjuvant letrozole. Biological markers such as ER, progesterone receptor, HER2 and Ki-67 expression were tested at diagnosis and at definitive surgery. RESULTS: A total of 89 patients (75.4%) achieved an objective response with 44 (37.3%) clinical CRs and 45 (38.1%) partial responses. The clinical CRs were significantly observed in cohort C (23 out of 40 patients, 57.5%) and B (16 out of 38 patients, 42.1%) compared with cohort A (5 out of 40 patients, 12.5%) (P-value for trend <0.001). Letrozole induced a similar significant reduction in Ki-67 index after treatment in all cohorts. The pathCR rate was significantly more frequent in cohort C (7 out of 40 patients, 17.5%) than in cohort A (1 out of 40 patients, 2.5%) and B (2 out of 40 patients, 5.0%) (P-value for trend <0.04). CONCLUSION: One-year neoadjuvant letrozole therapy leads to a higher pathCR rate and may be the optimal length of drug exposure.

Perioperative myocardial infarction in noncardiac surgery: the diagnostic and prognostic role of cardiac troponins.

Despite the number of technologies used, the diagnosis of perioperative myocardial infarction is still a challenge. Studies conducted in surgical series have demonstrated that cardiac troponins (cTns) have both a superior diagnostic sensitivity and specificity, compared with other traditional techniques, and an independent power to predict short- and long-term prognosis. Nevertheless, some points need to be clarified. They include the usefulness of cTns in patients with end-stage renal failure; the standardization of the cTns cut-off for the diagnosis of myocardial injury; the timing of postoperative blood samplings; the cost-effectiveness of a screening in asymptomatic patients; and the possible therapeutic strategies.

Oxidative stress and age-related cataract.

The authors review the available evidence supporting the possible role of oxidative stress in cataract formation from an epidemiological and a clinical point of view. They discuss in more detail what is presently known about the molecular mechanisms of response of the mammalian lens to an oxidative insult and report unpublished data on gene modulation upon oxidative stress in a bovine lens model. Main research endeavors that seem to be a most promising source of new insights into the problem of age-related cataract formation are briefly discussed.

Coordinate modulation of maize sulfate permease and ATP sulfurylase mRNAs in response to variations in sulfur nutritional status: stereospecific down-regulation by L-cysteine.

To gain insight into the regulatory mechanisms and the signals responsible for the adaptation of higher plants to conditions of varying sulfate availability, we have isolated from a sulfate-deprived root library maize cDNAs encoding sulfate permease (ZmST1) and ATP sulfurylase (ZmAS1), the two earliest components of the sulfur assimilation pathway. The levels of ZmST1 and ZmAS1 transcripts concomitantly increased in both roots and shoots of seedlings grown under sulfate-deprived conditions, and rapidly decreased when the external sulfate supply was restored. This coordinate response, which was not observed under conditions of limiting nitrate or phosphate, correlated with the depletion of glutathione, rather than sulfate stores. However, drastically reducing glutathione levels through treatment with buthionine sulfoximine, a specific inhibitor of gamma-glutamyl cysteine synthetase, did not provide an adequate stimulus for the up-regulation of either sulfate permease or ATP sulfurylase messengers. Indeed, L-cysteine, but not D-cysteine, effectively down-regulated both transcripts when supplied to sulfur-deficient seedlings under conditions of blocked glutathione synthesis. Altogether, these data provide evidence for the coordinate regulation of sulfur assimilation mRNAs in higher plants and for the glutathione-independent involvement of cysteine as a stereospecific pretranslational modulator of the expression of sulfur status-responsive genes.

A maize gene encoding an NADPH binding enzyme highly homologous to isoflavone reductases is activated in response to sulfur starvation.

we isolated a novel gene that is selectively induced both in roots and shoots in response to sulfur starvation. This gene encodes a cytosolic, monomeric protein of 33 kD that selectively binds NADPH. The predicted polypeptide is highly homologous ( > 70%) to leguminous isoflavone reductases (IFRs), but the maize protein (IRL for isoflavone reductase-like) belongs to a novel family of proteins present in a variety of plants. Anti-IRL antibodies specifically recognize IFR polypeptides, yet the maize protein is unable to use various isoflavonoids as substrates. IRL expression is correlated closely to glutathione availability: it is persistently induced in seedlings whose glutathione content is about fourfold lower than controls, and it is down-regulated rapidly when control levels of glutathione are restored. This glutathione-dependent regulation indicates that maize IRL may play a crucial role in the establishment of a thiol-independent response to oxidative stress under glutathione shortage conditions.

Continuous veno-venous hemofiltration in critically ill patients with multiple organ failure.

18 critically ill patients, with multiple organ failure (MOF) (from shock either septic, n = 15, or cardiogenic, n = 3), oliguria and increase in BUN and creatinine were treated with pump driven, high flux continuous veno-venous hemofiltration (CVVH). Replacement fluids were administered in predilution mode. All patients were under respiratory support and vasoactive drugs, and received early nutritional support (N input: 0.2-0.3 g/kg/day). Mean duration of treatment was 9.2 days and mean ultrafiltrate production was 21.4 l/day; treatment resulted in a significant reduction of both urea nitrogen and creatinine blood levels (-20 and -40% of initial values respectively) in spite of a very severe catabolism. The total amount of urea nitrogen removed through CVVH ranged from 15 to 73 g/day (mean 33.5), the median value of urea nitrogen clearance was 12.8 ml/min with a median ultrafiltration coefficient of 0.8. The mean duration of hemofilters was 69 hours (38-108); the efficacy of filters remained stable throughout the entire lifespan and changes were made in case of sudden decrease of ultrafiltration (< ml/min). No major complication was observed in over than 4000 hours of treatment. Pump driven, high flux CVVH proved effective in the control of water electrolyte balance and metabolic homeostasis in a group of critically ill, hemodynamically unstable, catabolic patients with MOF and acute renal failure. In no case we had to add intermittent hemodialysis or to use hemodiafiltration. The constant extracorporeal blood flow and the stable efficacy of hemofilters allowed an easy control of the overall effectiveness of this technique.

[Intensive care of AIDS patients. Clinical experience]. / L'assistenza intensiva al paziente con AIDS. Esperienza clinica.

Six patients with AIDS and severe respiratory failure from diffuse interstitial pneumonia, have been treated in one year in ICU. The authors describe diagnostic and therapeutic characteristics and management problems, underlining the good results in the short and medium term.

[Propofol-ketamine vs propofol-fentanyl in short gynecologic surgery]. / Propofol-ketamina vs propofol-fentanyl nella piccola chirurgia ginecologica.

The study was performed to investigate efficacy and tolerability of the association propofol-ketamine as alternative to propofol-fentanyl. Forty female, classified ASA I-II, aged 18-50 years and scheduled for short gynecologic procedures under general anesthesia were included in a comparative, randomized, single blind study. Patients were divided in two groups; in group K anesthesia was induced with propofol 1.5 mg/kg and ketamine 1 mg/kg i.v. In group F anesthesia was induced with propofol 2.5 mg/kg and fentanyl 1.5 micrograms/kg. Arterial blood pressure (BP), heart rate (HR), respiratory rate (RR) and arterial O2 saturation (SATO2) were measured. Though preliminary, our data suggest that the association propofol-ketamine reach an adequate level of anesthesia with few and negligible effects on cardiorespiratory system, thus allowing a better operability and safety. The incidence of post operative psychotic disturbances seems to be low and moderate. We can't draw any definitive conclusion, but we think that other studies should be performed to clarify the possible role of ketamine in propofol anesthesia.

[Acute polyneuropathy in the critical patient. Description of a clinical case]. / Polineuropatia acuta nel paziente critico. Descrizione di un caso clinico.

Polyneuropathy syndromes were described during prolonged sepsis and multiple organ failure. This kind of polyneuropathy should be discriminated from Guillain-Barré syndrome. The authors report their experience concerning a clinical case.