Immunotherapy in HER2-positive breast cancer: state of the art and future perspectives.

Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.

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.

Fertility drugs and breast cancer risk.

PURPOSE OF INVESTIGATION: Female infertility is a widespread problem in Western countries. During past years, an association between ovarian stimulation in unfertile women and breast cancer risk has been hypothesized. OBJECTIVE: Purpose of the present investigation was to comment the most updated studies about an eventual relationship between fertility drugs and breast cancer risk. MATERIALS AND METHODS: The authors performed a review of the current literature regarding the possible association between the use of fertility drugs and the enhanced risk of breast cancer. They searched digital databases including Pubmed, EMBASE, and the Cochrane Library. The literature search was performed using various combinations of keywords. They carefully analyzed only the full versions of all relevant studies. RESULTS: Using various combination of keywords, the authors examined 930 papers. They considered only papers written in English. With these criteria they selected the studies that had been discussed in detail on the text. CONCLUSION: None of the works commented provides an indisputable evidence about a link between ovarian stimulation and breast cancer risk. On the contrary, most of them actually suggest a lack of interaction between them or even a protective role of ovarian stimulation.

New perspectives: role of Sunitinib in breast cancer.

Sunitinib malate (SU11248) is a multitarget oral tyrosine kinase receptor (RTKs) inhibitor which was approved by FDA in renal cells carcinoma (RCC) and imatinib-resistant or imatinib-intollerant gastro-intestinal stromal tumour (GIST). Sunitinib is able to inhibit RTKs such as receptors for platelet-derived growth factor (PDGF-Rα and ß) and for vascular endothelial growth factor (VEGFRs). It is able to inhibit KIT receptor, colony stimulating factor type 1 receptor (CSF-1R), glial cell line neutrophic factor receptor (RET), fms-like tyrosine kinase receptor-3 (FLT-3 or CD135), signal transducer and activator of transcription 3 (STAT3) and AKT (protein kinase B) in tumour cells. Many Sunitinib targets play important roles in growth and survival of human breast cancer (BC). The "rationale" of Sunitinib in BC (with or without others antiagiogenetic therapy) is its ability to block simultaneously intracellular portion of RTKs inhibiting many downstream signals. We overviewed the most relevant studies concerning Sunitinib in metastatic BC.

[Specificity of action of anticancer agents]. / Specificità d'azione dei farmaci antineoplastici.

Since the first cancer chemotherapy use, efforts have been made in identifying drugs with an antitumor specific action, but cancer is a very complex situation to be cured with a single agent, and to increase drugs selective cytotoxicity new agent combinations, or innovative cellular cycle related schedule, or the use of pro-drugs have been developed. Notwithstanding some relevant improvements in results, chemotherapy remains often a palliative approach. The improved knowledge of the biology of cancer, and of molecular mechanisms and specific targets, has recently modified the approach to various tumors. In particular, the identification of a single and specific genetic alteration in some tumors such as myeloid chronic leukaemia or gastrointestinal stromal tumors (GIST) led to the development of imatinib, a "target" drug with a multikinase inhibitor activity towards the specific genetic alteration; this unique opportunity is not applicable to other tumors, because usually tumors have multiple genetic alterations with very complex molecular pathways. The development of drugs with a multitarget action is probably the best approach to the majority of human cancers, but other possibility are the combination of multiple agents, each with known selective activity towards a specific molecular target, or the choice of a chemotherapic drug in combination with one or more molecularly targeted drugs. The knowledge of the multiple and extremely complex molecular pathways of the neoplastic cells will hopefully drive oncologic science towards a more "exact" science, with the use of "personalized" treatment in each cancer patient.

Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in locally advanced stage IB2-IIB cervical cancer patients after neoadjuvant chemotherapy.

OBJECTIVE: To evaluate the feasibility and morbidity of total laparoscopic class C2 radical hysterectomy (TLRH) with pelvic lymphadenectomy in patients with locally advanced cervical cancer stage IB2 to IIB after neoadjuvant chemotherapy (NACT). METHODS: A prospective study was conducted from October 2004 to September 2009. Cervical cancer patients, stage IB2-IIB with complete clinical response after 3 courses of NACT with paclitaxel 175 mg/m(2), ifosfamide 5 g/m(2) and cisplatin 75 mg/m(2) (TIP) underwent TLRH. RESULTS: Forty patients were included, with a median age of 46 years (range, 25-65), BMI of 24 kg/m(2) (range, 15-49). FIGO staging was IB2 in 23, IIA > 4 cm in 6 and IIB in 11 patients. Four patients required conversion to laparotomy. Pathological evaluation showed 9 complete response (pCR), 9 partial response (pPR1) with microscopic tumour, and 15 partial response (pPR2) with macroscopic tumour. Three patients had no response. The median operative time was 305 min (range, 215-430); the median estimated blood loss was 250 ml (range, 100-400), with four postoperative blood transfusion; the median number of removed pelvic lymph nodes was 25 (range, 11-64). The median length of hospital stay was 6 days (range, 3-12). The median follow-up time was 37 months (range, 10-69), with three patients having a recurrence. One patient died of disease (DOD) after 12 months. CONCLUSIONS: TLRH can be safely performed in patients with stage IB2-IIB carcinoma of cervix after NACT, with advantages of minimal blood loss and morbidity.

New perspectives: role of sunitinib in breast cancer.

Sunitinib malate (SU11248) is a multitarget oral tyrosine kinase receptor (RTKs) inhibitor which was approved by FDA in renal cells carcinoma (RCC) and imatinib-resistant or imatinib-intollerant gastrointestinal stromal tumour (GIST). Sunitinib is able to inhibit RTKs such as receptors for platelet-derived growth factor (PDGF-R alpha and beta) and for vascular endothelial growth factor (VEGFRs). It is able to inhibit KIT receptor, colony stimulating factor type 1 receptor (CSF- 1R), glial cell line neutrophic factor receptor (RET), fms-like tyrosine kinase receptor-3 (FLT-3 or CD135), signal transducer and activator of transcription 3 (STAT3) and AKT (protein kinase B) in tumour cells. Many sunitinib targets play important roles in growth and survival of human breast cancer (BC). The "rationale" of sunitinib in BC (with or without others antiagiogenetic therapy) is its ability to block simultaneously intracellular portion of RTKs inhibiting many downstream signals. We overviewed the most relevant studies concerning sunitinib in metastatic BC.

Immunogenicity of allo-vesicle carrying ERBB2 tumor antigen for dendritic cell-based anti-tumor immunotherapy.

Dendritic cells (DCs) are able to orchestrate innate and acquired immunity and can activate and sustain a long-lasting anti-tumor immune response in vivo when used as anti-tumor cell therapy. The selection of the antigen and the choice of its formulation are key points in designing anti-cancer DC-based vaccines. Cell released vesicles/exosomes have been shown to transfer antigens, HLAI/peptide complexes and co-stimulatory molecules to recipient cells. In this study we describe the generation of an allogenic microvesicle cell factory in which the expression of a specific tumor antigen was combined to the expression of co-stimulatory and allogeneic molecules. The DG75 lymphoblastoid cell line was selected as microvesicle producer and transfected with ErbB2, as tumor antigen prototype. The shed microvesicles transferred antigenic components to recipient DCs, increasing their immunogenicity. DC pulsing resulted in cross-presentation of ErbB2 both in HLAI and HLAII compartments, and ErbB2-specific CD8+ T cells from cancer patients were activated by DCs pulsed with vesicle-bound ErbB2. The microvesicle cell factory proposed may represent a source of cell free immunogen to be used for DC-based cancer therapy.

Migrant women and cervical cancer: background of a prevention study.

The study was scheduled in order to organize a program of prevention against cervical cancer in female migrants in Rome, and therefore to facilitate access to appropriate preventive oncological facilities for discriminated women. Moreover, the study will also investigate the risk factors and social conditions (HPV-subtypes, sexual behavior, smoking habits) of such women since their migration to Italy. This is scientific and cultural background of a longitudinal, observational study on the cervical cancer risk in Roman migrant population. By means of a mother language questionnaire (with the presence of a cultural mediator) it will be possible to achieve data on social conditions and the new life-style. An HPV-testing (HC2) combined with Pap-test (with further genotype distribution) will be performed in all women enrolled in the study. Further diagnostic/therapeutic decisions will depend on the results of both tests. Scientific results are expected in the next two years, but an increasing of cancer prevention awareness among female migrant populations is expected from the beginning of the program. The present study was aimed at culturally appropriate intervention strategies to limit the disparities that migrants usually suffer in most of the developed Western nations in respect to the native counterparts.

Hemoglobin variation and blood transfusion rates in patients affected by locally advanced cervical cancer undergoing neo-adjuvant chemotherapy followed by radical surgery: the role of erythropoietic growth factors.

BACKGROUND: The objectives of the present study were to evaluate hemoglobin levels and consequent clinical behaviors related to anemia developed in patients affected by locally advanced cervical cancer treated with neo-adjuvant chemotherapy in the last decade and to evaluate the impact that the introduction of erythropoietic growth factors had in the clinical practice. PATIENTS AND METHODS: Blood chemistries, prospectively recorded from 98 cervical cancer patients, treated with neo-adjuvant chemotherapy and, if necessary, erythropoietic growth factors, were compared with matched historical controls before the introduction of growth factors in clinical practice. RESULTS: Hemoglobin level in the study group did not differ significantly during chemotherapy. At the third cycle of chemotherapy and at the end of chemotherapy, hemoglobin level was significantly higher in the study group compared with the control group. Transfusion rates in the study group were significantly lower. The analysis within the study group revealed that hemoglobin level in patients who suffer at diagnosis from anemia tends to increase whereas hemoglobin level in nonanemic patients tends to decrease. CONCLUSIONS: Erythropoietic growth factors increase hemoglobin level and reduce blood transfusions in cervical cancer patients undergoing neo-adjuvant chemotherapy followed by radical surgery. An appropriate autologous blood donation program can noticeably reduce homologous blood transfusions.

Trastuzumab in metastatic breast cancer.

Metastatic breast cancer is an incurable disease in a very high percentage of patients. Despite new progress in endocrine and other systemic therapies, this evidence remains challenging for patients and clinicians. HER2 protein is a member of the epidermal growth factor family of transmembrane receptors. HER2 is overexpressed in approximately 20% to 30% of breast cancers. Overexpression of HER2 has been shown to be associated with increased tumor proliferation and relative resistance to some types of chemotherapy and hormonal therapies. Trastuzumab, a humanized monoclonal antibody directed against HER2 protein, has been shown to be an efficacious and well tolerated treatment for HER2-overexpressing metastatic breast cancer, both as a single agent and when it is used in combination with chemotherapy.

Retroperitoneal schwannoma presenting as an ovarian tumor.

A mass in the left annexal zone was discovered in a 56-year-old woman at the Department of General Surgery and was diagnosed as ovarian cancer. After the operation the mass appeared histologically to be retroperitoneal leyiomiosarcoma and because of residual disease, confirmed by computed tomography (CT) and nuclear magnetic resonance (NMR), complementary radiotherapy was carried out. Restaging supported the persistence of the tumor and so a second laparotomy was performed with complete tumor resection; the pathologic diagnosis was retroperitoneal benign schwannoma. The importance of careful preoperative imaging, such as echography, CT, NMR, arteriography and urography should be stressed for a correct clinical and surgical approach. Moreover, considering that in some selected clinical cases these tumors could be confused with others deriving from contiguous organs and structures, a different surgical approach may be needed together with dedicated and expert surgeons.

Anticancer treatment and fertility effects. Literature review.

Chemotherapic regimens include mutagenic agents. The risk for reproductive abnormalities is increased in patients treated with such antiblastic drugs, mostly before or during their fertile period. The effect of chemotherapy on male and female gonadal function is related to the type of used agent and their cumulative doses. Other antineoplastic approaches, such as radiation therapy or hormonal therapy, can also negatively influence fertility. In the evaluation of quality of life of people affected by malignancies, infertility is considered an important issue. For this reason a large number of options have been tested as fertility preserving strategies--many are promising but still at an experimental stage.

Breast cancer and distress resulting from Magnetic Resonance Imaging (MRI): the impact of a psychological intervention of emotional and informative support.

The present study assesses the adaptation of a group of female patients with either manifest or suspected breast cancer who have undergone Magnetic Resonance Imaging (MRI) after receiving psychological support. Several studies in literature have reported the effectiveness of such support in reducing anti-oxidant and depression aspects related to MRI. Two random groups of patients, from the Service of Diagnostics Imaging of the Oncological Unit of the Regina Elena Institute of Rome, were enrolled. The experimental group (EG) received routine information together with extra psychological. The control group (CG) received only routine information. All the patients underwent a psychological evaluation, before (TO) and after (T1) the exam. The following evaluation instruments were used: the Crown Crisp Experimental Index (C.C. E.I.), the State-Trait Anxiety Inventory (S.T.A.I. Y1-Y2) and the Self Rating Depression Scale (S.D.S.) for TO and the State-Trait Anxiety Inventory (S.T.A.I. Y1 and the Self Rating Depression Scale (S.D.S.) for T1. Results prior to the MRI exam (TO), show that the women receiving extra information and emotional support (EG) suffer considerably less anxiety and depression compared to the control group. Results after the MRI exam (T1), indicate that the way the exam is carried out is also relevant in reducing anxiety. The level of anxiety, however, was significantly lower in the experimental group compared to the control. Depression levels, on the other hand, remained unaltered. Our results indicate that a psychological intervention aimed at providing more information and giving more emotional support helps patients adapt with a reduction of anxiety and depression.

[Vulvovaginal candidiasis: a therapeutic approach]. / Vulvovaginiti da candida. Approccio terapeutico.

The vulvovaginal candidiasis represents, after the bacterial vaginosis, the most frequent cause of vaginal affection. It is esteemed that around the 75% of the women of reproductive age suffered from an episode of vulvovaginitis from candida and 40-45% have had more episodes, of which 10-20% in complicated form. The kind of candida more frequently isolated in the vagina of symptomatic women is the Candida albicans: in the 10-20% of the cases the agent is present in absence of symptomatology, and we can almost consider it a saprophytic. On the other hand, always with greater frequency fetterses can be isolated of not albicans Candida, particularly the tropicalis and the glabrata kind, usually resistant to the common therapies. The classification of the vulvovaginal candidiasis proposed by Sobel, and by now universally approved, foresees 2 clinical forms of vulvovaginal candidiasis, the vulvovaginitis from not complicated candida (VVC) and the vulvovaginitis from complicated candida (VVCC): different for pathogenesis, elapsed clinical, symptomatology and frequency. They have to be considered in the substance 2 different nosological entities, and they request a diagnostic approach and a well different therapeutic appointment. In this study we will shortly reassume the principal characteristics of it, detaining us on the most recent acquisitions in theme of therapy. The base medicines of ac. boric, to parity of effectiveness, seem to introduce the most contained cost and the best compliance, and they offer him to a complementary use or, in some cases, alternative to the more you consolidate therapies with azoli.

Histiocyte-rich B-cell lymphoma.

This is the second report of histiocyte-rich B-cell lymphoma and the first case analyzed by flow cytometry and cytogenetic study. The immunophenotype determined by flow cytometry was that of a B-cell antigen-positive, surface immunoglobulin-negative B-cell lymphoma with 79% CD11c positive histiocytes. The lymphoid cells were composed of 76% neoplastic B-cells and 24% reactive T-cells. Immunohistochemical staining showed large numbers of histiocytes positive for CD68 and lysozyme in the lymph node and the bone marrow. Neoplastic lymphoid cells were positive for CD20, CD45, CD74 and CDw75. The monoclonality of the tumor cells was established by the evidence of rearrangements of the heavy chain and kappa light chain genes and a complex clonal cytogenetic abnormalities including t(8;14)(q11;q32). The tumor cells were large, pleomorphic lymphoid cells and showed no features resembling those of the L/H cells of Hodgkin's disease as previously reported. The rapidly progressive clinical course in the present case is consistent with the clinical features shown in the original study. The histiocytic component in this tumor is presumably recruited by a lymphokine with the nature of a growth factor from the tumor cells that may also be responsible for the rapid proliferation of the tumor cells and the aggressive clinical course. This entity merits special recognition because it leads to a predictable poor prognosis and because of its potential of being misdiagnosed as true histiocytic lymphoma.

Malignant lymphoma with genitourinary symptoms.

Two cases are reported of patients with widespread intra-abdominal malignant lymphoma who althoug they initially presented with urologic complaints had no evidence of direct genitourinary involvement. Transrectal biopsy established the diagnosis in both cases. This unusual presentation of lymphoma is discussed together with a review of urologic involvement. The necessity for accurate diagnosis is stressed since effective treatment with radiation and chemotherapy is available.