Davide Adriano Santeufemia

Current medical treatment of estrogen receptor-positive breast cancer.

Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (1) ovarian function suppression (OFS), usually obtained using gonadotropin-releasing hormone agonists (GnRHa); (2) selective estrogen receptor modulators or down-regulators (SERMs or SERDs); and (3) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type I are permanent steroidal inhibitors of aromatase, while type II are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.

Tufted hair folliculitis in a woman treated with lapatinib for breast cancer.

puncture skin test (0%; P < 0.001). The proportion of positive APST was in line with that found in larger groups of patients with CU. One reason why the puncture skin test was negative in all our patients might be that in this technique the concentration of autoantibodies or other histamine-releasing factors is too low to increase the permeability of the capillary wall significantly. Furthermore, Kimura et al. used a serum containing high levels of autoantibodies to perform the puncture skin test, whereas we used plasma, which may not contain autoantibodies but rather other histaminereleasing factors. Irrespective of the possible explanation, our results suggest that (at least in adult patients with CU) the APST remains the best means to detect an autoreactive status in vivo and that the puncture skin test cannot be considered a valid substitute for the intradermal test.

Advances in the Treatment of Triple-negative Early Breast Cancer.

Triple-negative breast cancer represents approximately 10-20% of all breast cancers and is associated with worse prognosis than other subtypes, with a higher risk of recurrence and death than other breast cancer types. This cancer is considered a heterogeneous disease comprising a spectrum of cancers with distinct activated biological pathways, various levels of chemosensitivity and different propensity for metastasis. Currently, chemotherapy represents the mainstay of medical treatment of these patients, because of the absence of well-defined molecular target agent, and we cannot use investigational classifications to determine appropriate systemic therapy outside of clinical trials. The specific adjuvant chemotherapy that may be most effective is still being determined but there is general consensus that regimens containing anthracyclines and taxanes are the standard approach for patient after surgery. Unfortunately, although some patients respond to treatment, other women have a high degree of intrinsic resistance to the same therapy. Moreover, in some studies, the pathological complete response was significantly higher in women treated with platinum-based regimen with respect to those treated with other chemotherapy regimen. The systematic evaluation of the predictive value of genomic alterations is critically important for a better comprehension of this entity and to develop new effective therapeutic strategies. In the future, a personalized therapeutic approach based on biology-oriented characteristics and molecular profiling may be effective for the patients.

Second-line chemotherapy in recurrent clear cell ovarian cancer: Results from the Multicenter Italian Trials in Ovarian cancer (MITO-9)

Background and Aims: Ovarian clear cell carcinoma (CCC) has a poorer prognosis than other subtypes of ovarian cancer. In this study, we evaluated the responsiveness to second-line chemotherapy in recurrent ovarian CCC. Methods: The MITO-9 project investigated a cohort of patients observed between 1991 and 2007 in 20 centers. We identified 72 out of 240 patients with recurrent disease (28% stage I-II and 72% stage III-IV at diagnosis). Results: In 56% of patients, the clear cell histology was pure. Twenty-five patients were platinum-resistant, 18 were platinum-sensitive with a platinum-free interval (PFI) of 6-12 months, and 29 had a PFI >12 months. Upon recurrence, 47% of patients were treated with platinum chemotherapy according to the PFI. The overall response rate (RR) to platinum was 80%, with 55, 100, and 80% RR in patients with PFI of 6-12, >12, and >24 months. The RR to nonplatinum agents in resistant patients was 33%. Among the nonplatinum agents used in primary and secondary resistant cases, gemcitabine, administered in 12 cases, had a higher activity (RR = 66%) compared to topotecan or liposomal doxorubicin (n = 31; RR = 33 and 10%, respectively). Conclusions: This study showed that the treatment of recurrent ovarian CCC should be based on the PFI as in the other subtypes. Data in platinum-resistant patients suggest gemcitabine as the drug with the highest activity. We recommend that gemcitabine be studied prospectively in a phase 2 trial.

Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype

The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target in metastatic GC (mGC). Trastuzumab, in combination with various chemotherapeutic agents, is a standard treatment for these tumors leading to outcome improvement. Unfortunately, the survival benefit is limited to a fraction of patients. The aim of this study was to improve knowledge of the HER2 and the E-cadherin alterations in the context of GC to characterize subtypes of patients that could better benefit from targeted therapy. An association between the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T) and a subset of HER2-positive mGC with better prognosis was observed. Results indicated the potential evaluation of CDH1 haplotypes in mGC to stratify patients that will benefit from trastuzumab-based treatments. Moreover, data may have implications to understanding the HER2 and the E-cadherin interactions in vivo and in response to treatments.

Adjuvant Treatment of Early Breast Cancer in the Elderly

Breast cancer is common in the elderly, as more than 50% of these tumors are diagnosed in patients aged 65 years or older. Elderly women may also delay reporting or underreport to their physician suspicious symptoms and lesions, so that breast cancer is more likely to be diagnosed at a more advanced stage, with putatively inferior outcomes. Adjuvant hormonal therapy has clear benefits for all women with hormone receptor-positive early breast cancer, despite the fact that it is still under-prescribed in elderly women, but the benefits of tamoxifen are more evident than that observed in younger patients. Aromatase inhibitors significantly prolong disease-free survival, reducing the risk of metastases and contralateral cancer compared with tamoxifen, and these benefits are greater in women aged ≥65 years. However, in case of a history of pathological fractures, arthritis or chronic musculoskeletal pain syndromes, tamoxifen still represents the preferred adjuvant option. In patients with a high risk of recurrence with hormonal therapy alone, the cardiac toxicity of nonanthracycline regimens should be taken into account. Trastuzumab-based therapy should be offered to most patients with HER2-overexpressing tumors. Older patients have an increased risk of disease recurrence and cancer-related mortality, because they are usually undertreated due to their age and longevity. Thus, a multidisciplinary geriatric approach is required, but the optimal management of these patients is still not well defined.

P16 immunostaining and HPV testing in histological specimens from the uterine cervix.

H rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and chronic obstructive pulmonary disease exacerbations. Currently there is no vaccine for RV which is most likely due to the existence of ~150 serotypes/strains and little or no cross-protective immunity generated from natural infections. Highly conserved regions of the RV polyprotein, when used as an immunogen, are hypothesized to generate broadly cross-reactive protective immunity to RV. A bioinformatic approach to define highly conserved areas of the RV proteome was performed. Recombinant protein was produced and tested for usefulness as candidate immunogen for a broadly cross-reactive vaccine using a mouse RV infection model. Regions of the VP0 (VP4+VP2) capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after challenge with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies, specific T cells and caused more rapid virus clearance. In conclusion, conserved domains of the RV capsid are immunogenic in mice, inducing cross-reactive immune responses that neutralize RV in vitro and are protective in vivo. This approach has identified a candidate for the continued development of a broadly reactive subunit RV vaccine.Background and Aim: High-risk type of human papilloma viruses (HPVs) can be considered as the etiologic agents of cervical cancer. At present, two prophylactic vaccines have been designed to prevent HPV infections. Both vaccines (Cervarix and Gardasil) are included VLP structure derived from L1 protein of HPV16 and 18. Both of these vaccines are highly immunogenic and elicit high titers of neutralizing antibody responses. Type-specific antibody responses of L1 VLPs are one limitation of these vaccines. So, current vaccine strategy provides protection against HPV types associated with cervical cancer and it won’t be able to induce immunity against other important HPV types. Alternatively, L2 minor capsid protein is a suitable candidate for next-generation of HPV vaccine. L2 has important functions in both papilloma virus assembly and the infectious process. Sequence analysis indicates L2 proteins as highly conserved with no changes in amino acid sequences during development. Indeed, L2 vaccine targeting can provide much more comprehensive protection against infection by various HPV types. However, L2 VLP typically elicits much lower neutralizing antibody titers than L1 VLP. The aim of this study is to evaluate the L1-L2 protein expression in mammalian cell lines.Objective: The presence of molds in a hospital environment became a subject of concern both for the healthcare professionals and for the users. Indeed, in spite of the absence of indicators allowing to measure their roles in the arisen of the fungal infections, it is established that bio contamination at the hospital is a major risk for the weakened patients, also for the certain places where are practiced the care or invasive acts. Their gravity is a real problem of Public health an in first row of morbidity, mortality. The causes are often multiple: air, water, renovation work without taking precautions standards, the cases of fungal contamination and the cases of fungal contamination we declared follow in serology realized.D decades of effort, an efficacious prophylactic HIV vaccine remains unavailable. To date, a number of pre-clinical and clinical studies have been conducted testing the efficacy of candidate HIV/SIV vaccines delivered by different viral vectors (e.g. Ad5, CMV and others. Despite inducing comparable levels of T cell responses, immunization with these candidate vaccines led to distinct outcomes of vaccine efficacy from stringent viral control to increased risk of HIV acquisition. The immunologic basis for such profound difference in vaccine effects on HIV acquisition is not known. CD4 T cells play a central role in orchestrating host immune responses by interacting with B cells, CD8 T cells and other innate immune effectors. However, CD4 T cells represent major target by HIV for infection and depletion in vivo. In our group, we have established a novel system assessing HIV infection of different antigen-specific CD4 T cells to HIV in vitro and found that human antigenspecific CD4 T cells manifest remarkable difference in susceptibility to HIV with CMV-specific CD4 T cells being particularly resistant compared to bacterial (tetanus toxoid) and fungal (Candida) antigens. More recently, we identified that human Ad5specific CD4 T cells are substantially more susceptible to HIV and are preferentially lost in HIV-infected individuals compared to CMV-specific CD4 T cells. Our findings suggest the importance of more thorough assessing the quality of vaccine-generated, vector and insert-specific CD4 T cells, and have important implications for testing new HIV/SIV vaccine antigens, vectors and adjuvants.Background: Since their discovery it has become clear that peroxisome proliferator-activated receptors (PPARs) are ligandactivated transcription factors involved in the genetic regulation of the lipid metabolism and energy homoeostasis. Subsequently, accumulating evidence suggests a role of PPARs in genomic pathways including the regulation of cell growth, apoptosis and differentiation. Recent studies point to the pathophysiological role of the peroxisome proliferators-activated receptor gamma (PPARgamma) in the inflammatory immune response. PPARs represent a major research target for the understanding and treatment of many skin diseases, such as benign epidermal tumors, psoriasis and atopic dermatitis.BACKGROUND The cellular tumor suppressor protein pl61NK4a (p16) has been identified as a biomarker for transforming human papilloma virus (HPV) infections. P16 is a cyclin-dependent kinase inhibitor that regulates the cell cycle and cell proliferation by inhibiting cell cycle G1 progression. PURPOSE OF THE STUDY To confirm the role of p16 as biomarker for transforming HPV infections and possible clinical applications in histological samples from the uterine cervix. MATERIALS AND METHODS The subject of this study included 56 biopsies of the cervical canal collected from January 2012 to September 2012 in the Institute of Pathology of the University of Sassari. The search for HPV immunohistochemistry was performed with the monoclonal antibody DAKO 1:25, while for the detection of p16 was used CINtecTM p16 (INK4a) histology kit. RESULTS In 56 biopsies performed in women aged between 23 and 69 years, the authors highlighted, by histological analysis, 24 cases of low-grade squamous intraepithelial lesion (LSIL) - cervical intraepithelial neoplasia (CIN1) and 31 cases of high-grade squamous intraepithelial lesion (HSIL) - CIN2/3); 15 CIN2, 14 CIN3, and two cervical squamous cell carcinoma in situ (SCIS). One case was an infiltrating squamous cell carcinoma (ISC). In 24 CIN1, there was a 16.67% positivity for p16 and an equal percentage occurred for HPV. In 15 cases of CIN2 the percentage of positivity for p16 was considerably increased (73.33%), unlike the search for HPV which had a positivity rate of 20%. Finally, in 14 cases of CIN3, and in three carcinomas, the positivity for p16 was equal to 100%, however the search for HPV positivity was between 0% and 7.14%. CONCLUSIONS These results demonstrated that p16 was a highly sensitive marker of cervical dysplasia. The authors have shown that p16 overexpression increased with the severity of cytological abnormalities and that had a greater ability to identify the viral infection compared to the classical immunohistochemical staining for HPV.W have used a number of techniques to identify tumour antigens recognized by the immune system of acute myeloid leukaemia (AML) patients including RT-PCR, SEREX, protein and cDNA arrays. We identified synovial sarcoma X breakpoint 2-interacting protein (SSX2IP) as a biomarker for survival. We analyzed 312 presentation AML samples and segregated AML patients based on aboveand below-median levels of expression of SSX2IP. Analysis of Kaplan-Meier curves showed a significant association between elevated SSX2IP expression and improved survival times in AML patients who lacked detectable cytogenetic abnormalities (log-rank test, n=180; P=0.007). We have also identified the cancer-testis antigen PASD1 through the immunoscreening of a testes cDNA library with pooled AML patient sera. We identified a number of algorithmselected naturally occurring 9 amino acid peptides which could bind HLA-A*0201 however these peptides failed to show detectable MHC binding in T2 assays. We modified one of the two anchor residues and showed these analogue peptides had enhanced binding, with decreased off-rates, in T2 assays. T cells from patients and normal donors responded to analogue peptide-loaded antigen presenting cells by secreting IFNγ. For clinical application, a DNA fusion gene vaccine encoding Pa14 was designed and tested in “humanized” mice. Splenocytes from vaccinated mice showed in vitro cytoxicity against tumor cells, either exogenously loaded with the corresponding wild type peptide (Pw8) or expressing endogenously processed PASD1 protein. We show for the first time that a DNA vaccine encoding an altered PASD1 epitope can induce CTL able to target the natural peptide expressed by human tumor cells.

Chemo/tomotherapy stereotactic body radiation therapy (chemo/SBRT) for the salvage treatment of esophageal carcinoma following trimodality therapy: A case report

BACKGROUND Esophageal cancer (EC) patients presenting a local recurrence following trimodality therapy (chemoradiaton and surgery) have limited palliative treatment options when the three major modalities of therapy have been exhausted. In addition, some patients experience a local recurrence or develop a metachronous cancer in a previously irradiated site, without evidence of systemic disease. For these patients there is a potential for cure, although the risk of further distant recurrences remains high. CASE REPORT We report of a successful concomitant chemo/SBRT treatment in a case of locally advanced metachronous squamous cervical EC, which was diagnosed in a patient previously treated with trimodality therapy for a squamous tonsillar carcinoma. RESULT Chemo/SBRT seems to be a reasonable salvage option for patients without distant metastases who have exhausted standard therapies. CONCLUSIONS Our experience also suggests that a concomitant chemo/SBRT treatment appears to be either feasible or effective and chemo/SBRT can be considered also in selected patients affected by EC with squamous histology and with neoplastic infiltration of the trachea.

Tamoxifen Induced Severe Hypertriglyceridemia in a Male Patient with Breast Carcinoma

To the Editor: Despite the tamoxifen is the most widely used drug in the management of the endocrine responsive male breast cancer it is difficult to obtain detailed information regarding its side-effects in men. This is probably due to the low incidence of male breast cancer, which can explain the scarcity of randomized prospective trials in those patients, added to the fact that treatment recommendations are usually inferred from female breast cancer or came from case reports or retrospectives studies. Anyway, female and male breast cancers have distinct clinical and pathologic features, especially with regards to the role of male hormones and estrogens, and so, it is interesting to note that tamoxifen related sideeffects may have a different impact in either genders. Despite in early reports the drug showed a low toxicity, as many as 25% of males discontinue the therapy because of its related toxicity. The drug interferes with the proliferation of breast cancer cells by its anti-estrogenic activity, but it has also shown to have an agonistic activity on bone, liver and endometrium. While uterine carcinogenicity, which obviously does not exist in men, is major concern among women, other problems such as hot flushes have a lower prevalence and intensity in males. Sexual dysfunctions, weight gain, mood alterations such as depression, insomnia, thromboebolic disease, are the most relevant side-effect affecting men. In October 2004, a 49-year-old Caucasian man came under our observation (B.M.I. 25.3 Kg ⁄ m), who had noted the presence of a fixed and indolent nodule of about 2 · 2 cm of size in the lower external quadrant of the right breast. General examination confirmed the presence of the breast mass and showed no other specific complaints. Laboratory findings including lipid profile were normal. Biopsy of the breast mass showed the presence of a breast carcinoma. Staging with chest X-rays, abdominal ultrasonography, and bone scintigraphy detected no metastases, so the patient underwent a radical right mastectomy with lymphadenectomy. Histological examination showed an intermediate differentiated ductal infiltrating carcinoma with pathological stage T2 N1 M0. Estrogen and progesterone receptors were both positive (60% each), Mib 1 was 9% and C-erb B2 was negative. Following surgery, on December 15th 2004, the patient was treated with six cycles of CMF adjuvant chemotherapy and subsequently underwent radiotherapy for a total amount of 50 Gy delivered to the right chest wall. After the chemotherapy completion, on June 6th 2005, hormonal therapy with tamoxifen (20 mg ⁄ day) was started. In the following time the patient underwent periodical clinical and instrumental checks, which were always negative for disease recurrence, and he did not complain any symptoms. Despite routine laboratory findings and tumour markers (Ca15–3, CEA) resulted normal, an extremely high plasma triglycerides value (7200 mg ⁄ dL) was detected on November 2005. Other lipid parameters were normal. Considering the effect of tamoxifen therapy as the possible triggering factor, as reported in female patients, we decided to discontinue the drug administration and to admit the patient to our Internal Medicine unit for further cheeks. At the admission, physical examination showed only a slight liver enlargement confirmed by a further abdomen ultrasonography which showed a fatty liver. No cutaneous and retinal signs of primary hypertrigliceridemia were detected. He had no family history of hyperlipidemia, diabetes, alcohol abuse, or other drugs able to intake the lipid profile. To exclude a genetic influence, a Address correspondence and reprint requests to: Davide Adriano Santeufemia, MD, Medical Oncology, University of Sassari, Viale San Pietro 8, Sassari 07100, Italy, or e-mail: davidesanteufemia@yahoo.it.

A new mutation of the CDH1 gene in a patient with an aggressive signet-ring cell carcinoma of the stomach

ABSTRACT Germline mutations in CDH1, the gene coding for the E-cadherin adhesion protein, are known to cause hereditary diffuse gastric cancer. We identified a new truncating germline mutation (p.Asp538Thrfs*19) in exon 11 of the CDH1 gene in a 41-year-old male with a diffuse gastric cancer. Although he had no parental history of gastric cancer, the co-segregation study in the family detected the same mutation in his healthy 31-year-old brother. The mutation affects one of the extracellular repeat (CAD repeats) domains which is essential for the homophilic binding specificity that directs “E-cadherin” to bind with itself each others. In this case, immunohistochemical analysis showed no expression of E-cadherin in the tumor sample and was a useful prescreening tool to genetic testing. This finding was associated with a poor response to trastuzumab-based treatment.