HER2-positive metastatic breast cancer: a changing scenario.

Adjuvant trastuzumab (AT) dramatically improved HER2-positive breast cancer prognosis. Relapsed disease after AT has different patterns and information is available from observational studies. In this Review Chemotherapy regimens combined to anti-HER2 blockade are discussed, focusing in particular the role of anthracyclines, taxanes and capecitabine. The use of trastuzumab beyond progression and the role of other anti-HER2 agents like lapatinib, pertuzumab and T-DM1 are explored, as also dual blockade and in trastuzumab resistant Patients. Metastatic "de novo" HER2 Luminal (co-expression of HER2 and hormone receptors) Patients are eligible for anastrozole and trastuzumab but if pretreated with trastuzumab they are also eligible for lapatinib and letrozole. In any case endocrine treatment plays a complementary role to chemotherapy which remains pivotal. The last topic explored is treatment options for patients with brain metastases where both trastuzumab given concurrent with radiotherapy or lapatinib and capecitabine appear as potentially active.

The anaesthetic and recovery profile of two concentrations (0.25% and 0.50%), of intrathecal isobaric levobupivacaine for combined spinal-epidural (CSE) anaesthesia in patients undergoing modified Stark method caesarean delivery: a double blinded randomized trial.

BACKGROUND: In spinal anaesthesia for a Caesarean delivery, it is important to limit anaesthesia only at the surgical area, and to resolve fast motor block. We compared the intraoperative effectiveness, hemodynamic effects, anaesthetic recovery times and patients satisfaction after isobaric levobupivacaine (L) 0.25% versus L0.50% spinal anaesthesia during elective Caesarean deliveries performed with the Stark technique. PATIENTS AND METHODS: In this double-blinded prospective study, seventy women undergoing elective caesarean delivery were randomized to receive either intrathecal 7.5 mg Levobupivacaine 0.25% plus sufentanil 2.5 µg (Group L0.25), or intrathecal 7.5 mg L 0.50% plus sufentanil 2.5 µg (GroupControl). The onset time, duration of anaesthesia, analgesia and sensory and motor block and hemodynamic parameters were measured from the beginning of spinal anaesthesia until four hours after spinal anaesthesia (T240). RESULTS: Onset time, duration of anaesthesia and haemodynamic variations were similar in the two groups. No patients required general anesthesia to complete surgery. Motor block vanished faster in Group L0.25 as compared with GroupControl (p < .01). The cephalad spread of the 0.50% solution was higher than that of the 0.25% solution: no patient in Group L0.25 experienced paresthesia of the upper limbs vs 14% in GroupControl (p < .05). In GroupControl anaesthesia reached the dermatome T1 in 15% of cases. Maternal and surgeon satisfaction was good in every patient. CONCLUSIONS: Levobupivacaine 7.5 milligrams at 0.25% may be used as a suitable alternative to L 0.50% for spinal anaesthesia for caesarean deliveris with the Stark technique with good maternal satisfaction. In Group L0.25 a lower appearance of nausea and hypotension were observed and motor and sensitive block developed and diminished faster while no clinically significant differences in hemodynamic behavior was observed between groups.

Implementation of epidural analgesia for labor: is the standard of effective analgesia reachable in all women? An audit of two years.

BACKGROUND: Social and cultural factors combined with little information may prevent the diffusion of epidural analgesia for pain relief during childbirth. The present study was launched contemporarily to the implementation of analgesia for labor in our Department in order to perform a 2 years audit on its use. The goal is to evaluate the epidural acceptance and penetration into hospital practice by women and care givers and safety and efficacy during childbirth. PATIENTS AND METHODS: This audit cycle measured epidural analgesia performance against 4 standards: (1) Implementation of epidural analgesia for labor to all patients; (2) Acceptance and good satisfaction level reported by patients and caregivers. (3) Effectiveness of labor analgesia; (4) No maternal or fetal side effects. RESULTS: During the audit period epidural analgesia increased from 15.5% of all labors in the first trimester of the study to 51% in the last trimester (p < 0.005). Satisfaction levels reported by patients and care givers were good. A hierarchical clustering analysis identified two clusters based on VAS (Visual Analogue Scale) time course: in 226 patients (cluster 1) VAS decreased from 8.5±1.4 before to 4.1±1.3 after epidural analgesia; in 1002 patients (cluster 2) VAS decreased from 8.12±1.7 before (NS vs cluster 1), to 0.76±0.79 after (p < 0.001 vs before and vs cluster 2 after). No other differences between clusters were observed. CONCLUSIONS: Present audit shows that the process of implementation of labor analgesia was quick, successful and safe, notwithstanding the identification of one cluster of women with suboptimal response to epidural analgesia that need to be further studies, overall pregnant womens'adhesion to labor analgesia was satisfactory.

Micro opioid receptor A118G polymorphism and post-operative pain: opioids' effects on heterozygous patients.

The single-nucleotide-polymorphism (SNP) 118A>G in the micro-1 opioid receptor gene (OPRM1) is associated with a decrease in the analgesic effects of opioids. The aim of this study is to assess whether 118A >G polymorphism could influence the analgesic response to opioid-based postoperative pain (POP) therapy. The study consisted of two parts: section alpha, observational, included 199 subjects undergoing scheduled surgical procedures with pain management standardized on surgery invasiveness and on expected level of postoperative pain; section beta, randomized, included 41 women undergoing scheduled caesarean delivery with continuous intra-operative epidural anesthesia and post-operative analgesia (CEA). In both sections, POP was measured over 48 h (T6h-T24h-T48h) by the visual analogue scale (VAS). In section beta we also tested the responsiveness of hypothalamic-pituitary-adrenal axis (HPA) expressed by cortisol levels. In section alpha, with cluster analysis, subjects were analyzed according to their genotype: a group (no. 1) of 34 patients reporting VAS score >3 at every time lapse was identified and included only A118G carriers, while wild-type (A118A - absence of 118A>G polymorphism) patients were unevenly distributed between those with cluster no. 2 (VAS score <3 at every study steps) and those with cluster no. 3 (VAS score progressively reducing from T6h). In section beta, A118G carriers receiving epidural sufentanil had the lowest VAS scores at T24h; also in these patients, cortisol levels remained more stable, with a mild decrease at T6h. This study shows that the OPRM1 118A>G polymorphism affects postoperative pain response in heterozygous patients: they have a different postoperative pain response than patients with wild-type genes, which may affect the efficacy of the analgesic therapy.

Moving ahead in diabetics' cancer screening; food for thought from the Hellenic experience.

Although data from literature suggest that diabetic women are frequently under screened for gynaecological cancers little is known about screening implementation for other cancers for both genders. This study investigates comprehensive cancer screening practices of diabetics as compared with non-diabetics; analyses screening patterns both by gender and level of evidence and reveals target subgroups that should be paid more attention for screening implementation. 675 diabetics vs. 5772 non-diabetic Greek individuals entered the PACMeR 02 cancer screening study. Diabetic women reported significantly lower performance for the sex-specific evidence-based cancer screening tests and digital rectal examination (DRE) as compared with non-diabetics (P < 0.05). Diabetic women older than 60 years old, of elementary education, housewives and farmers showed the lowest performance rates (P < 0.01). Prostate cancer screening was higher among diabetic men with ultrasound and DRE reaching statistical significance (P < 0.05). Subgroups analysis did not reveal a hidden relationship. Both genders of diabetics reported never performing skin examination at higher rates (P < 0.001), although screening intent is extremely low in both diabetics and non-diabetics (<1%). Evidence-based screening coverage was inconsistent in both genders independently by the diabetic status. Primary care efforts should be provided to implement presymptomatic cancer control.

Physiological effects of a lung-recruiting strategy applied during one-lung ventilation.

BACKGROUND: One-lung ventilation (OLV) affects respiratory mechanics and ventilation/perfusion matching, reducing functional residual capacity of the ventilated lung. While the application of a lung-recruiting manoeuvre (RM) on the ventilated lung has been shown to improve oxygenation, data regarding the impact of RM on respiratory mechanics are not available. METHODS: Thirteen patients undergoing lung resection in lateral decubitus were studied. During OLV, a lung-recruiting strategy consisting in a RM lasting 1 min followed by the application of positive end-expiratory pressure 5 cmH(2)O was applied to the ventilated lung. Haemodynamics, gas exchange and respiratory mechanics parameters were recorded on two-lung ventilation (TLV(baseline)), OLV before and 20 min after the RM (OLV(pre-RM), OLV(post-RM), respectively) and TLV(end). Haemodynamics parameters were also recorded during the RM. RESULTS: The PaO(2)/FiO(2) ratio was 358+/-126 on TLV(baseline); it decreased to 235+/-113 on OLV(pre-RM) (P<0.01) increased to 351+/-120 on OLV(post-RM) (P<0.01 vs. OLV(pre-RM)), and remain stable thereafter. During the RM, CI decreased from 3.04+/-0.7 l/m(2) OLV(pre-RM) to 2.4+/-0.6 l/m(2) (P<0.05), and returned to baseline on OLV(post-RM) (3.1+/-0.7 l/m(2), NS vs. OLV(pre-RM)). The RM resulted in alveolar recruitment and caused a significant decrease in static elastance of the dependent lung (16.6+/-8.9 cmH(2)O/ml OLV(post-RM) vs. 22.3+/-8.1 cmH(2)O/ml OLV(pre-RM)) (P<0.01). CONCLUSIONS: During OLV in lateral decubitus for thoracic surgery, application to the dependent lung a recruiting strategy significantly recruits the dependent lung, improving arterial oxygenation and respiratory mechanics until the end of surgery. However, the transient haemodynamic derangement occurring during the RM should be taken into account.

Effect of Propofol, Sevoflurane and Desflurane on systemic redox balance.

We studied the effects of Propofol, Desflurane, and Sevoflurane on the systemic redox balance in patients undergoing laparohysterectomy. We measured blood concentration of glutathione (GSH), plasma antioxidant capacity (Trolox Equivalent Antioxidant Capacity-TEAC), and lipid peroxidation products (malondialdehyde (aMDA) and 4-hydroxynonenal (aHNE) protein adducts). Sixty patients were randomly placed into three groups of twenty people each. In Group P anesthesia was induced with Propofol 2 mg/kg and maintained with 12-10-8 mg/kg/min; in Groups S and D anesthesia was induced with 3 mg/kg Sodium Thiopental and maintained with 2 percent Sevoflurane and 6 percent Desflurane, respectively. Blood samples were collected prior to induction (T0 bas), 60min and 24h postoperatively (T1 60 and T2 24 h). In Group P, GSH increased on T1 60 and returned to baseline on T24h, while TEAC remained unmodified; in Groups S, GSH and TEAC decreased on T1 60 in Group D, on T1 60 there was a slight decrease of GSH and TEAC. The levels of aMDA slightly decreased throughout the study periods in Group P, increased in Group D, and remained stable in Group S. Propofol showed antioxidant properties, while Sevoflurane and Desflurane seemed to shift the redox balance towards oxidation, yet without inducing overt oxidative damage.

Airways humidification during mechanical ventilation. Effects on tracheobronchial ciliated cells morphology.

AIM: Airways humidification during mechanical ventilation (MV) can be performed by means of heat and moisture exchangers (HME). Good performance of selected hygroscopic HME was shown in terms of tracheal temperature and humidity control and low tube obstruction rates. However, few data are available on their effects on tracheobronchial ciliated cells. The purpose of this study was to evaluate the effects of 2 different HME on ciliated cell during MV. METHODS: Twenty consecutive patients undergoing elective surgery lasting <4 h were randomly assigned to be treated with Rusch (Group 1) or Mediflux (Group 2) hygroscopic HME. The morphology of tracheobronchial ciliated cells was evaluated from cytologic smears of endotracheal aspirate. Smears were prepared by using the thin-prep processor, stained using the Papanicolau method and examined in triplicate: recognizable respiratory cells were graded on a six-point scale, according to the normal appearance of cilia, cytoplasm and nucleus. RESULTS: In Group 1, 178.3+37 cells were retrieved from aspirates and , 155.6+58 in Group 2 (NS). The score was 739+241 in Group 1 and 617+329 in Group 2 (NS). Cilia and end plate were undamaged in 80+17% and 81+20% cells respectively in Group 1 and in 56+23% and 62+22% cells respectively in Group 2 (P<0.01 and <0.05). CONCLUSIONS: During MV epithelial tracheobronchial cells can be affected by the humidification device used. Our findings suggest that the 2 HME tested in the present study have a different impact on ciliated cells structure.

Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study.

BACKGROUND: The cisplatin and gemcitabine (GC) regimen is usually administered as a 4- or 3-week schedule; however, the best schedule to use is still unclear. We therefore started a randomized phase II trial to compare toxicity and dose intensity (DI) between these two GC schedules. PATIENTS AND METHODS: Ninety-six patients with non-small-cell lung cancer (NSCLC) and an additional 11 patients with an advanced epithelial neoplasm [bladder (n = 5), head and neck (n = 3), cervix (n = 1), esophageal (n = 1) or unknown primary carcinoma (n = 1)] were randomized to receive cisplatin 70 mg/m(2) intravenously on day 2 plus either gemcitabine 1000 mg/m(2) on days 1, 8 and 15 of a 28-day cycle or gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21-day cycle. Planned DI (PDI) for the 4-week schedule was 750 mg/m(2)/week for gemcitabine and 17.5 mg/m(2)/week for cisplatin; for the 3-week regimen PDI was 666 mg/m(2)/week and 23 mg/m(2)/week for gemcitabine and cisplatin, respectively. RESULTS: From July 1998 to March 2000, 107 patients were randomized. Grade 3/4 neutropenia was observed in 27.8% of patients in the 3-week versus 22.5% in the 4-week arm (P = 0.69), while grade 3/4 thrombocytopenia was higher in the 4-week arm (29.5% versus 5.5% of patients; P = 0.14). A total of 398 cycles of therapy were delivered. Overall, 51% of cycles were modified in dose, timing or both in the 4-week arm, and 19% in the 3-week arm. The 21-day schedule of GC leads to a similar received DI of gemcitabine and higher cisplatin DI. Both regimens had activity in NSCLC, with a response rate of 39% (38% for the 4-week arm, and 42% for the 3-week arm). CONCLUSIONS: The 3-week schedule has similar DI to the 4-week schedule. However the 3-week regimen has a better compliance profile and a comparable response rate in NSCLC, supporting the use of such a schedule.

[Hemodynamic and respiratory changes during hip and knee arthroplasty. An echocardiographic study]. / Modificazioni emodinamiche e respiratorie in corso di protesi di anca e di ginocchio. Studio ecocardiografico.

BACKGROUND: The "bone cement implantation syndrome" is a rare but severe complication observed especially during the insertion of cemented prostheses in hip and knee replacement surgery. Several mechanisms are involved: effects of methylmethacrilate, embolism of fat, air and bone marrow, and release of tissue thromboplastin during acetabular and femoral reaming. Aim of this study was to detect embolic events, right heart impairment, hemodynamic and respiratory changes during hip and knee replacement surgery. DESIGN: Prospective study, between February-May 2001. ENVIRONMENT: Orthopedic Operative room. PATIENTS: Twenty-one patients who underwent total hip or knee arthroplasty under general anesthesia. Patients were divided in methylmethacrylate cemented prostheses groups (CEM, n=10) and totally uncemented prostheses (NON CEM, n=11). DATA COLLECTION: Standard anesthesia monitoring and omniplane TEE were performed. TEE probe was positioned in order to obtain "inflow-outflow" views of right heart. Measurements were obtained after anesthesia induction (T1), during femoral realing (T2) at prostheses insertion (T3), and at the end of surgery (T4). RESULTS: Hemodynamic and respiratory parameters measured in different phases of surgical procedures were not different within groups and between groups. Fourtheen patients had TEE evidence of emboli, and the phenomenon was more evident in CEM group (Z= -347; p<0.001). During prostheses insertion, a slight, not significant increase in right ventricular dimensions was observed in both groups, without any right ventricular wall kinetic abnormality. No difference was observed between groups. No adverse cardiac or cerebrovascular events in intra- and postoperatory period were observed. CONCLUSIONS: In normal patients total hip or knee arthroplasty is associated with embolic phenomena, without any significant change in systemic and right heart hemodynamics. Insertion of cemented prostheses does not modify hemodynamic profile. It remains to be elucidated if the occurrence of emboli has a critical role in patients with cardiorespiratory disease.

Independent lung ventilation in patients with unilateral pulmonary contusion. Monitoring with compliance and EtCO(2).

OBJECTIVE: a) to describe a non-barotraumatic ventilatory setting for independent lung ventilation (ILV); b) to determine the utility of single lung end-tidal CO(2) (EtCO(2)) monitoring to evaluate the ventilation to perfusion (V/Q) matching in each lung during ILV and for ILV weaning. DESIGN: prospective study. SETTING: general intensive care unit in a university teaching hospital. PATIENTS: twelve patients with unilateral thoracic trauma needing ILV. INTERVENTIONS AND RESULTS: ILV was started with each lung ventilated with the same tidal volume (Vt): plateau airway pressure (Pplat) was 34.2+/-3.2 cmH2O in diseased lungs (DL) and 18.1+/-1.9 cmH2O in normal lungs (NL) ( P<0.01). Static compliance (Cst) was 9.9+/-1.1 ml/cmH(2)O in DL and 19.3+/-1.7 ml/cmH(2)O in NL ( P<0.01). EtCO2 was 22.5+/-2.2 mmHg in DL and 36.6+/-1.9 mmHg in NL ( P<0.01). PaO(2)/FiO(2) was at 151+/-20. PEEP was applied on the DL and each lung was ventilated with a Vt that developed Pplat < or =26 cmH2O. With this setting, Vt given to the NL was unchanged, whereas it was reduced in the DL (238+/-30 ml vs 350+/-31 ml; P<0.01). Cst and EtCO2 were still significantly lower in the DL ( P<0.01, respectively), while the PaO(2)/FiO(2) ratio remained unchanged. Vt was then progressively increased in the DL as Pplat decreased, but remained unchanged in the NL. ILV was discontinued when Vt, Cst and EtCO(2) were the same in each lung. PaO(2)/FiO(2) ratio had then increased to 295+/-18. CONCLUSIONS: a) during ILV, adequate oxygenation and a reduction in V/Q mismatch can be obtained by setting Vt and PEEP to keep Pplat below a safe threshold for barotrauma; b) measurement of single lung EtCO2 can be useful to evaluate progressive V/Q matching.

[Respiratory emergencies in the extra-hospital environment]. / Le emergenze respiratorie in ambiente extraospedaliero.

Prehospital care is a fundamental element for the patient's outcome, in the field of medical and surgical emergencies. There are different strategies about it, defined "scoop and run" and "stay and play". The choice among the different strategies, in our opinion, must be well-suited to the underlying pathophysiology of the illness. The best approach to the care of Acute Respiratory Failure is chosen on the ground of the possible and rapid reversibility of the pathology. Nowadays, classical semeiology is integrated by portable devices that allow the real time monitoring of pulse oximetry, electrocardiography, arterial pressure and heart rate, capnometry, blood gas analysis, serum electrolites, etc. Maintenance of airway patency can be achieved by many devices, according to the patient's neurological conditions. In common opinion the early respiratory support reduces patient's stay in hospital and his outcome.

Effects of positive end-expiratory pressure and different tidal volumes on alveolar recruitment and hyperinflation.

BACKGROUND: The morphologic effect of positive end-expiratory pressure (PEEP) and of two tidal volumes were studied by computed tomography to determine whether setting the tidal volume (Vt) at the upper inflection point (UIP) of the pressure-volume (P-V) curve of the respiratory system or 10 ml/kg have different effects on hyperinflation and alveolar recruitment. METHODS: Alveolar recruitment and hyperinflation were quantified by computed tomography in nine patients with the acute respiratory distress syndrome (ARDS). First, end expiration was compared without PEEP and with PEEP set at the lower inflection point of the P-V curve; second, at end inspiration above PEEP, a reduced Vt set at the UIP (rVt) and a standard 10 ml/kg Vt (Vt) ending above the UIP were compared. Three lung zones were defined from computed tomographic densities: hyperdense, normal, and hyperinflated zones. RESULTS: Positive end-expiratory pressure induced a significant decrease in hyperdensities (from 46.8 +/- 18% to 38 +/- 15.1% of zero end-expiratory pressure (ZEEP) area; P < 0.02) with a concomitant increase in normal zones (from 47.3 +/- 20.9% to 56.5 +/- 13.2% of the ZEEP area; P < 0.05), and a significant increase in hyperinflation (from 8.1 +/- 5.9% to 17.8 +/- 12.7% of ZEEP area; P < 0.01). At end inspiration, a significant increase in hyperinflated areas was observed with Vt compared with rVt (33.4 +/- 17.8 vs. 26.8 +/- 17.3% of ZEEP area; P < 0.05), whereas no significant difference was observed for both normal and hyperdense zones. CONCLUSIONS: Positive end-expiratory pressure promotes alveolar recruitment; increasing Vt above the UIP seems to predominantly increase hyperinflation.

Long-term toxicity in adjuvant treatment with tamoxifen.

Long-term treatment with tamoxifen has produced few side effects, which are generally mild. Of the serious ones, all of them except eye toxicity seem to be related to the molecule's intrinsic mildly estrogen-like action, such as, for example, endometrial carcinoma. This property is also responsible for some favorable clinical effects including a lower risk of osteoporosis and cardiovascular disease. Whether tamoxifen causes neoplastic growth in patients who develop resistance to this drug is still controversial. Further prospective clinical studies are therefore needed to investigate such problems and also to evaluate less frequent side effects. Moreover, decisions on the overall duration of hormone therapy should be based on possible side effects as well as on therapeutic response.

Multiplane transesophageal echocardiography to detect effectiveness of selective pulmonary recombinant tissue-type plasminogen activator thrombolysis in pulmonary embolism and patent foramen ovale.

A functionally patent foramen ovale can create a relevant right-to-left shunt during massive pulmonary embolism. This associated feature, although maintaining adequate cardiac output, may explain both the paradoxic embolism and the uneffectiveness of peripherally administered drugs. This case demonstrates the potential of transesophageal echocardiography in monitoring the hemodynamic findings of such patients and, consequently, the effectiveness of thrombolytic treatment.