Systemic treatment in advanced phyllodes tumor of the breast: a multi-institutional European retrospective case-series analyses.

BACKGROUND: We aimed at investigating outcome of systemic treatments in advanced breast PT. METHODS: All cases of advanced breast PT treated with systemic treatments from 1999 to 2019, in one of the referral sarcoma centers involved in the study, were retrospectively reviewed. RESULTS: 56 female patients were identified. Median age was 52 (range of 25-76) years. Patients received a median number of 2 systemic treatments (range of 1-4). Best responses according to RECIST were 1 (3.7%) CR, 11 (40.7%) PR, 6 (22.2%) SD, 9 (33.3%) PD with anthracyclines plus ifosfamide (AI); 2 (16.7%) PR, 4 (33.3%) SD, 6 (50.0%) PD with anthracycline alone; 3 (18.8%) PR, 4 (25.0%) SD, 9 (56.3%) PD with high-dose ifosfamide given as a continuous infusion (HD-IFX); 3 (20.0%) SD, 12 (80.0%) PD with a gemcitabine-based regimen (with 2 patients not evaluable); 1 (8.3%) PR, 2 (16.7%) SD, 9 (75.0%) PD with trabectedin (with 1 patient not evaluable); 1 (16.7%) PR, 1 (16.7%) SD, 4 (66.7%) PD with tyrosine-kinase inhibitors (TKI). The median PFS were 5.7 (IQR 2.5-9.1) months with AI; 3.2 (IQR 2.2-5.0) months with anthracycline alone; 3.4 (IQR 1.4-6.7) months with HD-IFX; 2.1 (IQR 1.4-5.2) months with gemcitabine-based chemotherapy; 1.8 (IQR 0.7-6.6) months with trabectedin; 3.4 (IQR 3.1-3.8) months with TKI. With a median follow-up of 35.3 (IQR 17.6-66.9) months, OS from the start of first-line systemic treatment was 15.2 (IQR 7.6-39.6) months. CONCLUSION: In this series of advanced PT (to our knowledge, the largest reported so far), AI was associated with a high rate of responses, however, with a median PFS of 5.7 months. Other systemic treatments were poorly active.

Targeting immunoliposomes to EGFR-positive glioblastoma.

BACKGROUND: We assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed glioblastoma harboring an EGFR amplification. We aimed to assess the tolerability and effectiveness of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in glioblastoma multiforme patients. PATIENTS AND METHODS: Patients with EGFR-amplified, relapsed glioblastoma were included in this phase I pharmacokinetic trial. Patients received up to four cycles of anti-EGFR ILs-dox. Twenty-four hours later, plasma and cerebrospinal fluid (CSF) samples were obtained. In addition, we also treated three patients with anti-EGFR ILs-dox before resection of their relapsed glioblastoma. Doxorubicin concentrations were measured in plasma, CSF, and tumor tissue. Safety and efficacy parameters were also obtained. RESULTS: There were no or negligible levels of doxorubicin found in the CSF demonstrating that anti-EGFR ILs-dox are not able to cross the blood-brain barrier (BBB). However, significant levels were detected in glioblastoma tissue 24 h after the application, indicating that the disruption of BBB integrity present in high-grade gliomas might enable liposome delivery into tumor tissue. No new safety issues were observed. The median progression-free survival was 1.5 months and the median overall survival was 8 months. One patient undergoing surgery had a very long remission suggesting that neoadjuvant administration may have a positive effect on outcome. CONCLUSIONS: We clearly demonstrate that anti-EGFR-immunoliposomes can be targeted to EGFR-amplified glioblastoma and cargo-in this case doxorubicin-can be delivered, although these immunoliposomes do not cross the intact BBB. (The GBM-LIPO trial was registered as NCT03603379).

First-line surgery in prolactinomas: lessons from a long-term follow-up study in a tertiary referral center.

CONTEXT: Although consensus guidelines recommend dopamine agonists (DAs) as the first-line approach in prolactinomas, some patients may opt instead for upfront surgery, with the goal of minimizing the need for continuation of DAs over the long term. While this approach can be recommended in selected patients with a microprolactinoma, the indication for upfront surgery in macroprolactinomas remains controversial, with limited long-term data in large cohorts. We aimed at elucidating whether first-line surgery is equally safe and effective for patients with micro- or macroprolactinomas not extending beyond the median carotid line (i.e., Knosp grade ≤ 1). METHODOLOGY: Retrospective study of patients with prolactinomas Knosp grade ≤ 1 treated with upfront surgery. The primary endpoint was patients' dependence on DAs at last follow-up. The secondary endpoint was postoperative complications. Independent risk factors for long-term dependence on DAs were analyzed. RESULTS: A microadenoma was noted in 45 patients (52%) and a macroadenoma in 41 (48%), with 17 (20%) harboring a Knosp grade 1 prolactinoma. Median follow-up was 80 months. First-line surgery resulted in long-term remission in 31 patients (72%) with a microprolactinoma and in 18 patients (45%) with a macroprolactinoma (p = 0.02). DA therapy was ultimately required in 11 patients (24%) with microadenomas vs. 20 (49%) with macroadenomas (p = 0.03). As for the latter, DA was required in 13 patients (76%) with Knosp grade 1 macroadenomas vs. 7 patients (29%) with Knosp grade 0 macroadenomas (p = 0.004). There was no mortality, and morbidity was minimal. Knosp grade 1 prolactinomas (OR 7.3, 95% CI 1.4-37.7, p = 0.02) but not adenoma size (i.e., macroprolactinomas) were an independent predictor of long-term dependence on DAs. CONCLUSIONS: First-line surgery in patients with microprolactinomas or macroprolactinomas Knosp grade 0 resulted in a good chance of non-dependency on DA therapy. However, in patients with prolactinomas Knosp grade 1, first-line surgery cannot be recommended, as adjuvant DA therapy after surgery is required in the majority of them over the long term.

Unilateral vocal fold paralysis post-thyroidectomy: does early intervention allow for better voice recovery?

OBJECTIVE: Thyroidectomy is the primary cause of unilateral vocal fold paralysis (UVFP). A delay in rehabilitation may cause dysfunctional phenomena and worsen dysphonia. The main aim is to investigate the impact of early Speech Therapy (ST) on voice recovery in UVFP post-thyroidectomy and propose an appropriate treatment schedule. PATIENTS AND METHODS: 93 patients with UVFP were analysed. 72 presented transient paralysis and 21 permanent ones. Individuals with permanent paralysis were retrospectively divided in two groups. Group A was composed of 11 patients (8 F, 3 M; mean age: 50.5 ± 8.6) who received ST within 8 weeks; Group B comprised 10 patients (7 F, 3 M; mean age: 57 ± 11.5) treated after more than 8 weeks. Videolaryngostroboscopy (VLS) was assessed and both objective and subjective voice parameters were collected. The non-parametric Wilcoxon test was applied to the sample. RESULTS: The resolution of supraglottic compensations was observed in 91% of cases in Group A, whereas in only 40% of cases in Group B. A functional glottal closure occurred in 73% of patients in group A, while it was completely absent in group B. Group A showed a statistically significant difference between the values of Jitter, NHR, TMF and VHI collected pre-ST compared to that collected after 1 year. Conversely, a statistically significant difference was found only for VHI values in group B. CONCLUSIONS: Early ST brings benefits to patients with permanent UVFP, both on voice recovery and on quality of life. A ST protocol should be applied both before and after thyroidectomy. The ST treatment should start early after surgery.

Extending Human Papillomavirus (HPV) vaccination beyond female adolescents and after treatment for high grade CIN: the Italian HPV Study Group (IHSG) review and position paper.

OBJECTIVE: Human PapillomaVirus (HPV) vaccination has been introduced in recent years in clinical practice as the most effective primary prevention strategy for cervical cancer and HPV-induced lesions, either pre-malignant or benign. Since its introduction, HPV vaccination has been progressively demonstrated as extremely effective in preventing extra-genital and male diseases also; furthermore, non only adolescents but adult subjects have been investigated and reported as positively responding to vaccine immunostimulation. More recently, effectiveness of post-treatment vaccine administration has been preliminarily investigated with very promising results in terms of decreased recurrences. On this basis, we report an Italian-focused picture of the state of the art and take a position in favour of the extension of HPV vaccination to male adolescents, to older age groups and to already treated subjects.

Iatrogenesis and neurological manifestations in the elderly.

Older people are often exposed to polypharmacy in a multimorbidity context. Inappropriate polypharmacy is often harmful, increasing the risk of inappropriate prescriptions and therefore adverse drug events (ADEs). Five to 20% of all hospital admissions are related to ADE in older people, among which 40 to 70% could be prevented. However, identifying ADEs and drug-related admissions in the elderly is challenging because ADEs often present as common geriatric problems such as falls, delirium, which might be due to the aging process, underlying diseases, and/or medications. In the pharmacovigilance database of the World Health Organization, drug-related neurological manifestations are the third reported cause of ADEs in the elderly, and neurological drugs are the third leading class of medications involved in ADEs. We must therefore be particularly vigilant, both in our prescriptions but also in our diagnoses to avoid prescribing inappropriate treatments and detect ADEs. Even though multiple pharmacologic changes occur in the elderly (absorption, distribution, drug metabolism and excretion), most of medications are still often prescribed at the same daily dosage as in young adults. When prescribing any drug for old patients, we should remember that daily intake should be adapted to these specificities, keeping in mind the old well-known aphorism "start low, go slow". In this review, we describe the main drug-related neurological manifestations (drug-induced movement disorders, falls, seizures, delirium, hypoglycemia, stroke, hyponatremia, peripheral neuropathy and myopathy, and serotonin syndrome) and the main drugs associated with neurological manifestations (dopamine receptor blocking agents, antithrombotics, anticholinergics, beta-lactams, antidepressants, benzodiazepines, mood stabilizers).

Toxic response of the bacterium Vibrio fischeri to sodium lauryl ether sulphate residues in excavated soils.

Sodium lauryl ether sulphate (SLES) is the main chemical component in several lubricant products used for soil conditioning in the mechanized excavation industry using Earth Pressure Balance-Tunnel Boring Machines. During the tunnelling process, huge amounts of excavated soil are produced and the SLES presence can affect the subsequent re-use of this material as a by-product. Currently, there is still no regulatory indication of reliable and sensitive bioassays for monitoring soil quality during the excavation process. The main objective of this work was to verify if the Vibrio fischeri screening test was suitable as a consistent and precautionary tool for this specific purpose. Firstly, the ecotoxicity (EC20 and EC50) of the SLES standard solution and three commercial products (SLES content from 10 to 50%) were evaluated to select the most environmental friendly product. Subsequently, soil samples from about 2 years of tunnelling in a real construction site, conditioned with the selected product, were evaluated for their environmental compatibility with the prescriptions of an Italian site-specific protocol. The latter established 2 mg/L as a threshold value for SLES concentration in soil water extracts and a no toxic response (≤20%) for the Vibrio fischeri test. The comparison of the bacterium bioluminescence inhibition values (%) with analytical determinations showed an ecotoxicity when SLES was >2 mg/L. The toxicity was directly related to SLES concentration, indicating that the V. fischeri test and the SLES analyses are suitable tools for assessing excavated soil as a by-product, ensuring its safe reuse in accordance with a green production process (circular economy).

Activity of axitinib in progressive advanced solitary fibrous tumour: Results from an exploratory, investigator-driven phase 2 clinical study.

BACKGROUND: To explore the activity of axitinib in advanced solitary fibrous tumour (SFT). PATIENTS AND METHODS: In this investigator-driven phase II study on axitinib in advanced and progressive SFT, patients received axitinib, 5 mg bis in day (BID), until progression or limiting toxicity. Pathologic diagnosis was centrally reviewed, distinguishing malignant SFT (M-SFT) and high-grade/dedifferentiated SFT (HG/D-SFT) subtypes. The primary end-point was the overall response rate (ORR) by Choi criteria (Choi). Secondary end-points were response by Response Evaluation Criteria in Solid Tumours (RECIST), progression-free survival (PFS) and overall survival (OS). RESULTS: From April 2015 and October 2017, 17 eligible patients entered the study (metastatic: 17; SFT subtype: 13 M-SFT, 4 HG/D-SFT; prior treatment: 9 antiangiogenics, 5 cytotoxics). All patients were evaluable for response. The best Choi response was seven partial response (PR) (ORR, 41.2%), six stable disease (SD) and four progressions. Choi-ORR was 54% (7/13) when only M-SFTs were considered. Four of seven responsive patients were pretreated with pazopanib. No responses were detected in HG/D-SFT. Best RECIST response was one PR (5.9%), 14 SD and two progressions. Toxicity was as expected. Median Choi-PFS was 5.1 (interquartile range [IQR]: 2.5-14.8) months. Median Choi-PFS was 14.8 (IQR: 5.1-18.0) and 2.8 (IQR: 2.0-5.9) months for patients responsive and non-responsive by Choi, respectively (p = 0.0416). At a 14.4-month median follow-up, median OS was 25.3 months. CONCLUSION: This study showed that axitinib is active in progressive advanced SFT. One-half of patients carrying the malignant variant of the disease responded, with a >12-month median progression arrest. Responses were better detected with Choi and seen even in patients resistant to other antiangiogenics. Tolerability was good.

Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer.

BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.

Rotator cuff degeneration of the healthy shoulder in patients with unilateral arm amputation is not worsened by overuse.

PURPOSE: In order to evaluate whether overuse has a significant role in rotator cuff tear (RCT) aetiology, we evaluated both shoulders of patients with old unilateral arm amputation expecting a higher rate of RC degeneration in the healthy side. METHODS: Nineteen males and six females (mean age: 57.3 ± 10.1) with an old (>20 years) unilateral arm amputation were submitted to an MRI of both shoulders. Tendon status and muscle tropism were evaluated according to Sugaya and Fuchs classifications, respectively; the acromion humeral distance was measured. Statistical analysis was performed to verify the prevalence of Sugaya and Fuchs categories in each sides. RESULTS: A significant prevalence of Sugaya type II in the amputated side (p = 0.02) and of type I in the healthy side (p < 0.001) was found. Rotator cuff was healthy in 28 and 52% of amputated and non-amputated side, respectively. The mean acromio-humeral distances of the amputated and healthy side were 0.8 cm (SD: 0.1) and 0.9 cm (SD: 0.1), respectively, (p = 0.02). A significant prevalence of Fuchs type II category in the healthy side (p < 0.001) was found. Fuchs III/IV were observed in 40 and 12% of amputated and healthy side, respectively. CONCLUSIONS: The present study resizes the role of overuse on the aetiology of RCT. Cuff tear prevalence in not amputated shoulders, inevitably submitted to functional overload, was not higher than that of coetaneous subjects with two functional upper limbs. Shoulder non-use is a risk factor for rotator cuff tear. As the prevalence of rotator cuff degeneration/tear is higher in the amputee side, non-use is a more relevant risk factor than overuse. In the daily clinical practice, patients with rotator cuff tear should be encouraged to shoulder movement because rotator cuff tendon status could be worsened by disuse. LEVEL OF EVIDENCE: III.

Human papillomavirus 9-valent vaccine for cancer prevention: a systematic review of the available evidence.

In 2014, the Food and Drug Administration approved a new human papillomavirus 9-valent vaccine (9vHPV), targeting nine HPV types: HPV types 6, 11, 16, and 18, which are also targeted by the quadrivalent HPV vaccine (qHPV), plus five additional high cancer risk HPV types (HPV types 31, 33, 45, 52, and 58). The aim of the current study was to systematically retrieve, qualitatively and quantitatively pool, as well as critically appraise all available evidence on 9vHPV from randomized controlled trials (RCTs). We conducted a systematic review of the literature on 9vHPV efficacy, immunogenicity and safety, as well as a systematic search of registered, completed, and ongoing RCTs. We retrieved and screened 227 records for eligibility. A total of 10 publications reported on RCTs' results on 9vHPV and were included in the review. Sixteen RCTs on 9vHPV have been registered on RCT registries. There is evidence that 9vHPV generated a response to HPV types 6, 11, 16 and 18 that was non-inferior to qHPV. Vaccine efficacy against five additional HPV type-related diseases was directly assessed on females aged 16-26 years (risk reduction against high-grade cervical, vulvar or vaginal disease = 96·7%, 95% CI 80·9%-99·8%). Bridging efficacy was demonstrated for males and females aged 9-15 years and males aged 16-26 years (the lower bound of the 95% CIs of both the geometric mean titer ratio and difference in seroconversion rates meeting the criteria for non-inferiority for all HPV types). Overall, 9vHPV has been proved to be safe and well tolerated. Other RCTs addressed: 9vHPV co-administration with other vaccines, 9vHPV administration in subjects that previously received qHPV and 9vHPV efficacy in regimens containing fewer than three doses. The inclusion of additional HPV types in 9vHPV offers great potential to expand protection against HPV infection. However, the impact of 9vHPV on reducing the global burden of HPV-related disease will greatly depend on vaccine uptake, coverage, availability, and affordability.

Pazopanib in advanced germ cell tumors after chemotherapy failure: results of the open-label, single-arm, phase 2 Pazotest trial.

Background: Therapeutic options for patients with chemoresistant germ cell tumors (GCTs) are limited. Pazopanib is a selective tyrosine kinase inhibitor with distinct antiangiogenic activity. We aimed to evaluate pazopanib activity in patients with refractory GCT. Patients and methods: In the open-label, single-arm, phase 2 Pazotest study (NCT01743482), patient eligibility included failure of ≥2 platinum-based regimens, and allowed prior high-dose chemotherapy administration. Patients were given pazopanib 800 mg/day until disease progression (PD) or onset of unacceptable toxicity. Measurements of serum tumor markers (STM), computed tomography and FDG-PET were carried out at baseline, after 4 weeks of pazopanib treatment, and every 8 weeks thereafter. PD was defined as increasing levels of STM, increasing size of non-teratomatous masses, or appearance of new lesions. The study primary endpoint was progression-free survival (PFS, H0: 3-month PFS ≤ 10%, H1: ≥25%, α = 5%, ß = 20%). Results: Forty-three patients were enrolled from May 2013 to July 2016. The number of prior chemotherapy regimens was: 2 (11.6%), 3 (51.2%), >3 (37.2%). Grade 3 adverse events were observed in six patients (13.9%). Overall, 70.3% of patients had reduced levels of STM after 4 weeks. There were 2 partial responses (4.7%), 19 cases of stable disease, and 16 cases of PD (6 not evaluable by RECIST). The median follow-up duration was 29.6 months. The 3-month PFS probability was 12.8% [95% confidence interval (CI): 5.7%-28.9%]. The 24-month OS probability was 14.2% (95% CI: 6.0%-33.7%). In patients with a >50% decline in STM, the 24-month OS probability was 24.1% (95% CI: 8.3%-69.6%). The small sample size was the major limitation. Conclusions: Despite pazopanib showed potent but short-lived activity in refractory GCT, long-term survival was obtained in a proportion of treated patients. According to the kinetics of pazopanib activity, this drug may be investigated in less pre-treated patients as an optimal bridging therapy preceding and/or combined with salvage chemotherapy.

Cost-effectiveness analysis of the temporary percutaneous ileostomy for faecal diversion after colorectal resection in elderly.

BACKGROUND: Conventional loop ileostomy (CLI) is a suitable procedure for transitory faecal diversion after colorectal anastomosis, but it causes relevant morbidities (dehydration, discomfort, peristomal infections) and requires a second operation to be closed. We already described an alternative technique of temporary percutaneous ileostomy (TPI), which can be removed without surgery. AIMS: We analyse the outcomes and the costs of the TPI in protecting low colorectal anastomosis in elderly, compared to the CLI. METHODS: Data of patients underwent elective anterior rectal resection for rectal cancer with extra-peritoneal colorectal anastomosis protected by ileostomy from January 2011 to December 2015 were reviewed. Sixty-one out of 132 patients were older than 70; 35 underwent faecal diversion by TPI and 26 by CLI. RESULTS: The two groups resulted homogenous about age, sex, operative time, short-term post-operative complications. None of the patients reported anastomotic leakage. The hospital stay and the cost for the first surgical procedure did not show statistically significant differences between TPI and CLI. When comparing the overall hospital stay and costs the differences are statistically significant: the TPI showed a shorter hospital stay (12.4 vs 19.3 days, -35.7%) and a lower cost of hospitalization (7954.0 vs 14,372.1€, -44.7%), compared to CLI. DISCUSSION: The limited duration of the faecal diversion and the uselessness of a second surgical procedure to remove the TPI are the most important advantages of TPI, especially in elderly. CONCLUSION: The TPI not only improved the post-operative outcome of the patients, but also allowed a remarkable saving for the National Health System.

Sleep quality and disturbances in patients with different-sized rotator cuff tear.

INTRODUCTION: The literature is unanimous in saying that shoulder pain, due to rotator cuff tear (RCT), may be mostly at night; to our knowledge, this statement is not supported by scientific evidence. Our aim was to investigate sleep quality and disturbances in patient with RCT and in a control group. MATERIALS AND METHODS: A case-control design study was used. We enrolled 324 consecutive patients (Group A) (156M-168F, mean age ± SD: 64.94 ± 6.97; range 47-74) who underwent arthroscopic rotator cuff repair. Tear size was determined intraoperatively. The control group (Group B) included 184 subjects (80M-104F, mean age ± SD = 63.34 ± 6.26; range 44-75) with no RCT. All participants were submitted to two standardized self-reported questionnaires evaluating sleep quality and disturbances: the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS). Data were submitted to statistics. RESULTS: We found no significant differences between the two groups according to both PSQI (Group A: 5.22 ± 2.59; Group B: 5.21 ± 2.39) and ESS (Group A: 2.59 ± 2.54; Group B: 5.76 ± 2.63), p > 0.05. Patients with small tears had average PSQI and ESS higher than patients with large and massive lesions (p < 0.005). Pearson's test showed that tear severity was negatively correlated with both sleep latency (r 2 = -0.35, ß = 0.069, p < 0.005) and sleep disturbances (r 2 = -0.65, ß = 0.053, p < 0.001). CONCLUSIONS: RCT is only one of the responsible causes for sleep disturbance in middle-aged and elderly subjects. Patients with small tears have a poorer sleep quality with respect to those with a more severe tear; particularly, they not only take more time to fall asleep, but also have a more disturbed sleep compared to patients with large and massive tears. LEVEL OF EVIDENCE: III.

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact.

BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and ß, RET, KIT). PATIENTS AND METHODS: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRß in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRß, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRß immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). CONCLUSIONS: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRß-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.

The Long-Term Benefit of Liver Transplantation for Hepatic Metastases From Neuroendocrine Tumors.

Selection criteria and benefit of liver transplantation for hepatic metastases from neuroendocrine tumors (NETs) remain uncertain. Eighty-eight consecutive patients with metastatic NETs eligible for liver transplantation according to Milan-NET criteria were offered transplant (n = 42) versus nontransplant options (n = 46) depending on list dynamics, patient disposition, and age. Tumor burden between groups did not differ. Transplant patients were younger (40.5 vs. 55.5 years; p < 0.001). Long-term outcomes were compared after matching between groups made on multiple Cox models adjusted for propensity score built on logistic models. Survival benefit was the difference in mean survival between transplant versus nontransplant options. No patients were lost or died without recurrence. Median follow-up was 122 months. The transplant group showed a significant advantage over nontransplant strategies at 5 and 10 years in survival (97.2% and 88.8% vs. 50.9% and 22.4%, respectively; p < 0.001) and time-to-progression (13.1% and 13.1% vs. 83.5% and 89%; p < 0.001). After adjustment for propensity score, survival advantage of the transplant group was significant (hazard ratio = 7.4; 95% confidence interval (CI): 2.4-23.0; p = 0.001). Adjusted transplant-related survival benefit was 6.82 months (95% CI: 1.10-12.54; p = 0.019) and 38.43 months (95% CI: 21.41-55.45; p < 0.001) at 5 and 10 years, respectively. Liver transplantation for metastatic NETs under restrictive criteria provides excellent long-term outcome. Transplant-related survival benefit increases over time and maximizes after 10 years.

Targeting immune response with therapeutic vaccines in premalignant lesions and cervical cancer: hope or reality from clinical studies.

Human papillomavirus (HPV) is widely known as a cause of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN). HPVs related to cancer express two main oncogenes, i.e. E6 and E7, considered as tumorigenic genes; their integration into the host genome results in the abnormal regulation of cell cycle control. Due to their peculiarities, these oncogenes represent an excellent target for cancer immunotherapy. In this work the authors highlight the potential use of therapeutic vaccines as safe and effective pharmacological tools in cervical disease, focusing on vaccines that have reached the clinical trial phase. Many therapeutic HPV vaccines have been tested in clinical trials with promising results. Adoptive T-cell therapy showed clinical activity in a phase II trial involving advanced CC patients. A phase II randomized trial showed clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN. Several trials involving peptide-protein-based vaccines and live-vector based vaccines demonstrated that these approaches are effective in CIN as well as in advanced CC patients. HPV therapeutic vaccines must be regarded as a therapeutic option in cervical disease. The synergic combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, immunomodulators or immune checkpoint inhibitors opens a new and interesting scenario in this disease.

Propensity score analysis of outcomes following laparoscopic or open liver resection for hepatocellular carcinoma.

BACKGROUND: Liver resection is a potentially curative approach for hepatocellular carcinoma (HCC). Laparoscopic liver resections may reduce complication rates, especially in patients with cirrhosis. The aim of this study was to compare the results of laparoscopic liver resection with those of open liver resection for HCC. METHODS: Patients with cirrhosis who underwent minor liver resections for HCC from 2006 to 2013 were identified retrospectively from a prospective database according to the technique adopted (laparoscopic or open). Short- and long-term outcomes were compared between the two groups before and after 1 : 1 propensity score matching. RESULTS: A total of 269 patients were considered: 226 who underwent open liver resection and 43 who had a laparoscopic procedure. The two groups differed at baseline in terms of median age, sex, performance status, tumour location and type of resection. After propensity score matching, two comparable groups of 43 patients each were obtained. Intraoperative bleeding, margin clearance and operative mortality were similar in the two groups, whereas complication rates were lower (49 versus 19 per cent in open versus laparoscopic groups respectively; P = 0·004) and median hospital stay was shorter (8 versus 5 days; P < 0·001) in the laparoscopic group. On multivariable logistic regression analysis, the only independent factor that reduced the risk of postoperative complications was the use of laparoscopy (odds ratio 0·12, 95 per cent c.i. 0·03 to 0·55; P = 0·006). Median overall survival was 57·8 months in the open group and 48·8 months in the laparoscopic group (P = 0·802). Median disease-free survival was 31·7 and 25·5 months respectively (P = 0·990). CONCLUSION: In comparison with the open approach, laparoscopic minor liver resections for HCC improved short-term outcomes, with similar survival results.