Childhood infectious diseases and risk of non-Hodgkin's lymphoma according to the WHO classification: A reanalysis of the Italian multicenter case–control study

Since 1960, incidence of non-Hodgkin's lymphoma (NHL) has been increasing in most industrialized countries, but causes of this trend remain unclear. A role of the decreased exposure to infectious agents during childhood has been proposed. Our study evaluates the association between common childhood infectious diseases and the risk of NHL and its major subtypes by a reanalysis of the Italian multicenter case–control study. After exclusion of next-of-kin interviews, 1,193 cases, diagnosed between 1990 and 1993, and 1,708 population-based controls were included in the analyses. OR estimates were obtained by logistic regression, adjusting for gender, age, residence area, education, smoking habit and exposure to radiations, pesticides and aromatic hydrocarbons. Among B-cell lymphomas (n = 1,102) an inverse association was observed for rubella (OR = 0.80, 95% CI: 0.65–0.99), pertussis (OR = 0.74, 95% CI: 0.62–0.88) and any infection (OR = 0.75, 95% CI: 0.61–0.93). A negative trend by number of infections was observed, which was more evident among mature B-cell lymphoma (OR = 0.66 for three infections or more, 95% CI: 0.48–0.90). Our results indicate a potential protective role of common childhood infections in the etiology of B-cell NHL.     

Primary non-Hodgkin lymphoma of the breast. Is it possible to avoid mastectomy?

Primary lymphoma of the breast is a rare disease that has been estimated to represent from 0.05% to 0.53% of all malignant breast tumors and approximately 2.2% of all extranodal lymphomas. The aim of this study is to review all cases of primary lymphoma of the breast at the Institute of Oncology and Radiology of Serbia from 1984 to 1996 in order to determine the incidence, patterns of clinical presentation, radiological features, histopathology, mode of therapy and outcome of the disease. The criteria for inclusion in this retrospective study corresponded to a revision of the original criteria suggested by Wiseman and Liao. The clinical histories of ten patients with breast lymphomas were reviewed. Clinical follow-up was obtained through a review of the patients hospital chart or by direct contact with the patients. Ten cases of primary lymphoma of the breast have been identified during the 12-yr period, presenting 0.05% of all patients with malignant breast disease. All patients were female, median age at diagnosis 58 years (range 49-69), all presented with breast lumps (3 right, 7 left) of median size 5 cm (range 3.5-8 cm). Mammography and breast echography were unable to bring a suspicion of lymphoma. Histologically, 6 cases were diffuse large cell, 3 of which with features consistent with immunoblastic lymphoma; 2 were diffuse mixed cells and 2 had small lymphocytic morphology. In 4 out of 5 patients, in the clinical stage corresponding to the "operable breast cancer" category, the ex tempore histological analysis could not differentiate lymphoma from cancer, so that all of them had mastectomy with axillary dissection. Those corresponding to the "locally advanced breast cancer" category, escaped mastectomy and a classical biopsy was performed, anticipating eventual neoadjuvant procedures. Thus, four patients underwent radical mastectomy, 1 wide local excision and 5 diagnostic biopsies. Further treatment included chemotherapy for 8 patients. The projected probability of a 10-years survival was 0,60. The rarity of this disease, and uneven treatment modalities make prognosis of breast lymphoma difficult. It seems that cooperation between the surgeon and the pathologist is necessary in order to reach the correct diagnosis during ex tempore analysis. With the limitations of available diagnostic procedures, it appears that most patients with breast lymphoma, in the stage corresponding to the "operable breast cancer" category, will unnecessarily undergo mastectomy and axillary dissection as primary treatment approach.     

Application of the concept synthetic lethality toward anticancer therapy: A promise fulfilled?

Back in 1997, a suggestion to apply the concept of synthetic lethality towards the development of selective, less toxic, cancer drugs and anticancer targets, was brought forward. The availability of large scale synthetic, low-molecular-weight chemical libraries seemed to lend itself to the concept. Human/mouse genome-wide siRNAs and shRNA-expressing libraries allowing high throughput screening for target genes synergistic lethal with defined human cancer aberrations, also raised high hopes of a soon to be established selective therapy. Sixteen years later, the major experimental aspects relating to the implementation of this more focused approach to cancer drug discovery, is briefly and critically reviewed.     

Release of doxorubicin in sweat: first step to induce the palmar-plantar erythrodysesthesia syndrome?

Doxorubicin, one of the most potent single chemotherapeuticagents against solid and angiomatous tumors, is encapsulatedin highly stable Stealth^® liposomes so that its toxicityis significantly reduced [1]. The efficacy and toxicity of doxorubicinis affected by the different liposomal leakage rates; liposomeswith the slowest rate of drug leakage showed the best therapeuticactivity [2     

Docetaxel administration schedule: From fever to tears? A review of randomised studies

The anti-cancer agent docetaxel is approved for the treatment of patients with locally advanced or metastatic breast cancer, non-small cell lung cancer (NSCLC) and for the treatment of androgen-independent prostate cancer. At the recommended dose of 60-100 mg/m2 given every 3 weeks, severe neutropenia is the dose-limiting toxicity and a major concern especially when treating patients at high-risk from myelotoxic complications. A less toxic schedule, involving weekly docetaxel administration was developed for patients with poor performance status, multiple comorbidities, poor haematological reserves or those who were heavily pre-treated, elderly or patients for whom palliation is the focus of treatment. Recent randomised trials allow a comparison of efficacy and toxicity between weekly and 3-weekly treatments. Efficacy appears to be similar for the two schedules regardless of the disease while weekly docetaxel is significantly less myelotoxic. However, this benefit comes at the cost of cumulative increases in hyperlacrimation, skin- and nail-toxicity and negatively affects quality of life. Currently, 3-weekly docetaxel remains the standard schedule for treatment, whereas the weekly schedule offers a possibility of treatment individualisation for those patients where the risk of myelosuppression is considered unacceptable.     

Adding cytokines to monoclonal antibody therapy: does the concurrent administration of interleukin-12 add to the efficacy of rituximab in B-cell non-hodgkin lymphoma?

Interleukin-12 (IL-12) is a cytokine that facilitates cytolytic T-cell responses, enhances the lytic activity of NK cells and induces the secretion of interferon-gamma by both T and NK cells. Binding of rituximab, a chimeric murine/human monoclonal antibody, to CD20 on B-lymphocytes induces apoptosis and the Fc domain of the antibody recruits immune effector functions to mediate cell lysis. Therefore, combining IL-12 with rituximab in patients with B-cell non-Hodgkin lymphoma (NHL) may augment the immune mediated cell lysis induced by rituximab. To determine whether a synergistic effect exists when IL-12 is given in combination with rituximab, clinical trials are being done to evaluate the clinical efficacy of the combination. The two agents, when given in combination, significantly upregulate the patient's immune mechanisms. The combination upregulates gamma interferon and IP-10 expression and increases NK cell lytic activity. The combination appears to have significant clinical activity with a high clinical response rate in early phase clinical trials. However, a randomized controlled trial will be required to determine whether the addition of IL-12 adds to the efficacy of rituximab in B-cell NHL.     

New therapies in HER2-positive breast cancer: A major step towards a cure of the disease?

Overexpression of the human epidermal growth factor receptor 2 (HER2) predicts a poor prognosis in metastatic breast cancer. While the introduction of HER2-targeted therapies, such as the monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib, has significantly improved outcomes in HER2+ breast cancer compared with previously available therapies, use of these targeted therapies is often limited by the development of drug resistance and tolerability issues. These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways. Recently, several agents have demonstrated promising activity in HER2+ metastatic breast cancer, either as monotherapy or in combination therapy, including the tyrosine-kinase inhibitors neratinib (HKI-272) and afatinib (BIBW-2992) and the anti-HER2 monoclonal antibodies pertuzumab and trastuzumab-DM1 (T-DM1). Agents that target other molecular pathways, such as the vascular endothelial growth factor receptor, mammalian target of rapamycin, PI3-kinases, insulin-like growth factor (IGFR), HSP-90, and other kinases also have potential, in combination with anti-HER2 and/or other systemic therapies, to be active in this subtype of breast cancer. Innovative clinical studies are required in well-characterized patient populations to define the true clinical value of these emerging new approaches.     

The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial,Germ Cell,and Mesenchymal Tumors?

This overview of the fifth edition of the WHO classification of thymic epithelial tumors (including thymomas, thymic carcinomas, and thymic neuroendocrine tumors [NETs]), mediastinal germ cell tumors, and mesenchymal neoplasms aims to (1) list established and new tumor entities and subtypes and (2) focus on diagnostic, molecular, and conceptual advances since publication of the fourth edition in 2015. Diagnostic advances are best exemplified by the immunohistochemical characterization of adenocarcinomas and the recognition of genetic translocations in metaplastic thymomas, rare B2 and B3 thymomas, and hyalinizing clear cell carcinomas. Advancements at the molecular and tumor biological levels of utmost oncological relevance are the findings that thymomas and most thymic carcinomas lack currently targetable mutations, have an extraordinarily low tumor mutational burden, but typically have a programmed death-ligand 1^high phenotype. Finally, data underpinning a conceptual advance are illustrated for the future classification of thymic NETs that may fit into the classification scheme of extrathoracic NETs. Endowed with updated clinical information and state-of-the-art positron emission tomography and computed tomography images, the fifth edition of the WHO classification of thymic epithelial tumors, germ cell tumors, and mesenchymal neoplasms with its wealth of new diagnostic and molecular insights will be a valuable source for pathologists, radiologists, surgeons, and oncologists alike. Therapeutic perspectives and research challenges will be addressed as well.     

From chemotherapy to target therapies associated with radiation in the treatment of NSCLC: a durable marriage?

Introduction: The integration between radiotherapy and drugs, from chemotherapy to recently available target therapies, continues to have a relevant role in the treatment of locally advanced and metastatic Non-small cell lung cancer (NSCLC). Aim of the present review is to evaluate the promising and emerging application of the best interaction between new drugs and new modalities of radiotherapy.

Areas covered: We searched Medline, Google Scholar, PubMed, ProQuest Dissertation, and Theses databases for reports published in English. A study was included when it reported on cancer-related radiotherapy and included patients with NSCLC treated with chemo and/or target therapies. Review articles were excluded from the analysis.

Expert commentary: Chemo-radiotherapy still represents the standard of choice in locally advanced NSCLC, while to date the addition of target therapies to chemo-radiotherapy did not demonstrate any robust advantage in this stage of disease. Considering the absence of randomized controlled trials, the role of target therapies in early stage adjuvant NSCLC is not yet recommended in clinical practice. On the contrary, in the setting of oligometastatic and oligoprogressive disease, new molecules demonstrated to be safe and effective, opening to a promising and emerging application of the best interaction between new drugs and new modalities of radiotherapy.     

A review of the intravenous administration of radiolabeled immunoglobulin G to cancer patients. High or low protein dose?

This retrospective analysis of preclinical and clinical radiolabeled immunoglobulin studies focuses on three well-known observations: (1) IV tumor reactive IgG provides higher response rates in patients with hematological malignancies than in patients with solid tumors. (2) Patients with CD20 positive B cell lymphoma require a high IV IgG protein dose for effective tumor targeting. (3) Most patients experience high uptake of IV administered radiolabeled IgG in normal liver. This review supports the following new hypotheses: (1) The blood-tumor barrier in most solid tumors is higher than in most hematological malignancies. (2) The blood-tumor barrier in CD20 positive B cell lymphomas is lowered by the IV administration of high doses [> 100 mg] of anti-CD20 IgG, presumably due to IgG induced intra-tumoral production of vaso-active biological response modifiers. (3) The blood-tumor barrier is low in Hodgkin's disease, presumably due to the continuous and innate production of biological response modifiers in tissues containing Hodgkin's disease. (4) The uptake of tumor reactive IgG in the normal liver is controlled by the Fc portion of the IgG. The radioimmunoconjugate is not catabolized in the liver. This appears to indicate that the F(c) portion of the IgG binds to the MHC class I like, F(c)gammaRn receptors in liver endothelium and hepatocytes and not to F(c)gamma RI, RII or RIII receptors The new hypotheses require verification and can be instrumental in the design of new more effective clinical RIT studies.     

Hypoxia-driven immunosuppression: A new reason to use thermal therapy in the treatment of cancer?

Hypoxia within the tumour microenvironment is correlated with poor treatment outcome after radiation and chemotherapy, and with decreased overall survival in cancer patients. Several molecular mechanisms by which hypoxia supports tumour growth and interferes with effective radiation and chemotherapies are now well established. However, several new lines of investigation are pointing to yet another ominous outcome of hypoxia in the tumour microenvironment: suppression of anti-tumour immune effector cells and enhancement of tumour escape from immune surveillance. This review summarises this important information, and highlights mechanistic data by which hypoxia incapacitates several different types of immune effector cells, enhances the activity of immunosuppressive cells and provides new avenues which help ‘blind’ immune cells to detect the presence of tumour cells. Finally, we discuss data which indicates that mild thermal therapy, through its physiologically regulated ability to alter vascular perfusion and oxygen tensions within the tumour microenvironment, as well as its ability to enhance the function of some of the same immune effector activities that are inhibited by hypoxia, could be used to rapidly and safely release the tight grip of hypoxia in the tumour microenvironment thereby reducing barriers to more effective immune-based therapies.