Controversies in the treatment of early-stage oral squamous cell carcinoma.

The treatment of early-stage oral squamous cell carcinoma (OSCC) is still a controversial issue. Thanks to the 8th edition of TNM by AJCC there is a better distinction between the stages of OSCC. However, Stages I and II still share the same treatment protocol, even if the prognosis is radically different. A retrospective study has been conducted including 70 previously untreated patients with Stage I or II OSCC, treated with tumorectomy and selective neck dissection. The study focuses on the link between pT1/2 and various other factors, particularly histological grading, vascular and perineural invasion, local and cervical recurrence, surgical margins and overall survival. These data reveal significant differences between pT1 and pT2 in histological grade, perineural invasion, cervical recurrence, surgical margins, and overall survival, emphasizing the necessity of different treatment protocols for T1 and T2 OSCC. Distinct strategies should be proposed to treat Stage I and II OSCC, with Stage II patients possibly benefitting from more aggressive treatments: following these data, a wait-and-see strategy should only be considered in Stage I, while certain treatments at the cervical level - such as prophylactic neck dissection and sentinel node biopsy - should always be considered for Stage II tumors.

Impact of histological tumor grade on the behavior and prognosis of squamous cell carcinoma of the oral cavity.

INTRODUCTION: Unlike other types of cancers, the prognostic value of histological tumor grade is not well determined for oral squamous cell carcinoma (OSCC). This study therefore aimed to evaluate the impact of tumor differentiation on prognosis and overall survival of patients affected by squamous cell carcinoma of the oral cavity. MATERIALS AND METHOD: A retrospective analysis was conducted using the records of patients diagnosed with squamous cell carcinoma of the oral cavity between 2010 and 2015. The study included 162 patients treated with a tumorectomy and selective neck dissection. The influence of histological tumor grade on several prognostic factors such as T-Stage, N-stage, recurrence rate, perineural invasion, vascular invasion, surgical margins, and overall survival was analyzed. RESULTS: Histological grade strongly correlated with N-stage, recurrence rate, perineural invasion, vascular invasion, surgical margins, and overall survival. Overall survival was 71.6% in patients with well-differentiated tumors and 43.2% in those with moderately and poorly differentiated tumors. CONCLUSIONS: Histological grade represents an important prognostic factor for OSCC. Therefore, various treatment strategies based on this histological parameter could improve the overall survival rate of patients affected by oral squamous cell carcinoma.

Multicenter study of the epidemiology of Clostridioides difficile infection and recurrence in southern Brazil.

Clostridioides (Clostridium) difficile is the main etiology underlying antibiotic-associated diarrhea (AAD). Still, few Brazilian data are available on this infection. The aims of this multicenter study were to identify the prevalence, clinical characteristics, and outcomes of C. difficile infection (CDI) in patients with antibiotic associated diarrhea at eight hospitals in Curitiba, southern Brazil, during the years 2017-2019. Stool samples were tested using enzyme immunoassay for glutamate dehydrogenase antigen (GDH) and A/B toxins. Positive GDH samples were further evaluated by real-time polymerase chain reaction (PCR) for the presence of genes encoding toxin B (tcdB), binary toxin (cdt), and marker of hypervirulent C. difficile strain (tcdC deletion). The prevalence of CDI in 351 patients with AAD included in the study was 17.7% (n = 62). Among the CDI cases, tcdB was positive in all 62 stool samples, while cdt was positive in 10 samples, and tcdC deletion was positive in only two. Carriage of carbapenem-resistant Gram-negative bacilli, previous hospitalization, and use of broad-spectrum cephalosporin and carbapenem were associated with CDI. Among patients with CDI, 64.5% presented with severe diarrhea, and 8% (5/62) progressed with colitis and required intensive care. The 30-day mortality was 24% (15/62), and the CDI-associated mortality was 4.8% (3/62). Overall, 83.8% (52/62) of the patients achieved primary cure, and 20.8% of the evaluated patients (10/48) presented CDI recurrence. The treatment administered was not significantly associated with the 60-day recurrence or mortality. In conclusion, we reported in this study data of prevalence and recurrence rates of CDI in patients with AAD and evaluated the number of severe cases and infection-related mortality, which were up to now unknown in Southern Brazilian hospitals.

Foraging activity and seasonal food preference of Linepithema micans (Hymenoptera: Formicidae), a species associated with the spread of Eurhizococcus brasiliensis (Hemiptera: Margarodidae).

Linepithema micans (Forel) (Hymenoptera: Formicidae) is the main ant species responsible for the spread of Eurhizococcus brasiliensis (Wille) (Hemiptera: Margarodidae), a soil scale that damages vine plants in southern Brazil. The daily foraging activity of L. micans and its seasonal preference for protein- and carbohydrate-based foods were evaluated. The study was carried out in a greenhouse using seedlings of the Paulsen 1103 rootstock (Vitis berlandieri x Vitis rupestris) planted individually in pots and infested with colonies of L. micans. To determine the daily foraging activity and seasonal preference, a cricket (Gryllus sp.) and a 70% solution of inverted sugar and water were offered once a month for 12 mo. The ants foraging on each food source were counted hourly for 24 h. L. micans foraged from dusk until the end of the next morning, with higher intensity in the spring and summer. Workers of L. micans showed changes in food preference during the year, with a predominance of protein-based food during winter and spring and carbohydrate-based food during autumn. The implications of this behavior for control of the species with the use of toxic baits are discussed.

Brownian particles in an external field: Asymptotic distribution functions and mean square displacement.

A simple procedure is proposed by which the long-time form of the distribution of large (or heavy) ions in a fluid, in a time-varying electric field, is obtained as asymptotic solution of the Fokker-Planck (or Klein-Kramers) equation. In this way, it is shown that, when the initial ion distribution is the product of a delta function in position space times a shifted Maxwellian in velocity space, the asymptotic ion distribution, at sufficiently large times, coincides with the asymptotic form of the corresponding fundamental solution of the Fokker-Planck equation. Moreover, it is shown that a simplified (even if incorrect) form of the ion distribution can successfully be used to obtain correct values of a large class of average quantities. In this connection, the proper, asymptotic formula for the ion mean square displacement in time-varying electric fields is widely discussed and compared to the corresponding result following from the appropriate diffusion equation.

Heavy (or large) ions in a fluid in an electric field: The diffusion equation exactly following from the Fokker-Planck equation.

The problem of the derivation of the diffusion equation exactly following from the Fokker-Planck (or Klein-Kramers) equation for heavy (or large) particles in a fluid in an external force field is solved in the case in which the particles are ions subject to a uniform (but in general time-varying) electric field. It is found that such a diffusion equation maintains memory of the initial ion velocity distribution, unless sufficiently large values of time are considered. In such temporal asymptotic limit, the diffusion equation exactly becomes (i) the Smoluchowski equation when the electric field is constant in time, and (ii) a new equation generalizing the Smoluchowski equation, when the electric field is arbitrarily time varying. Finally, it is shown that the obtained exact (or asymptotic) results make questionable the procedures and the results of approximate theories developed in the past to get a "corrected" Smoluchowski equation when the external force can also be, in general, position dependent.

Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours?

PURPOSE: The aim of this trial was to evaluate the safety and efficacy of oxaliplatin and capecitabine (XELOX) in neuroendocrine tumours' (NETs) treatment. METHODS: Forty patients (pts) with advanced NETs were treated. Of these, 13 had untreated poorly differentiated NETs, 27 had well-differentiated NETs in progression after somatostatin analogues. Patients received oxaliplatin e.v. 130 mg/mq i.v. and capecitabine 2,000 mg/mq/die. The primary sites of the disease were: lung (10 pts), pancreas (15 pts), small bowel (8 pts), unknown (1 pt), others (6 pts). RESULTS: In 13 pts with poorly differentiated NETs objective responses (OR) were: 3 PR (23%), 1 SD (7%), 9 PD (70%). Biochemical responses were 11%. In 27 patients with well-differentiated NETs the OR were: 8 PR (30%), 13 SD (48%) and 6 PD (22%). Biochemical and symptomatic responses were 20 and 50%, respectively. CONCLUSIONS: The XELOX regimen is effective and tolerated in well-differentiated NETs after progression following somatostatin analogues.

Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: a Phase III Study.

BACKGROUND: The noninferiority of a 6-week dosing schedule of lanreotide Autogel (Lan ATG) at a dose of 120 mg compared with a 3-week dosing schedule of lanreotide microparticles (Lan MP) at a dose of 60 mg was investigated in patients with neuroendocrine tumors (NET). METHODS: Patients who had sporadic, well differentiated NET with a low grade of malignancy were recruited for this open-label, Phase III, multicenter trial. Patients were randomized to receive either 3 deep subcutaneous injections of Lan ATG (120 mg, every 6 weeks) or 6 intramuscular injections of Lan MP (60 mg, every 3 weeks). Tumor markers, tumor size, and symptoms were assessed between baseline and Week 18. Success was classified as a response that ranged from disappearance to an increase <25% in tumor marker, tumor size, or symptom frequency. RESULTS: Sixty patients were randomized, and 46 patients completed the study. Both for tumor markers and for tumor size, Lan ATG was not inferior to Lan MP (55% and 59% of patients responded on tumor markers, respectively; 68% and 66% of patients responded on tumor size, respectively). There were too few symptomatic patients to compare carcinoid symptoms. Both treatments were tolerated well, and no safety concerns were identified. CONCLUSIONS: Lan ATG at a dose of 120 mg every 6 weeks was as effective for controlling NET as Lan MP at a dose of 60 mg every 3 weeks.

Neuroendocrine tumors of the larynx: a clinical report and literature review.

Neuroendocrine tumors of the larynx represent a rare group of neoplasms characterized by pathological and biological heterogeneity. The histological diagnosis is the most important step in the appropriate management of these tumors and the prognosis varies according to histological types. Here we report on a case of a laryngeal neuroendocrine tumor occurring in a 67-year-old man who underwent several locoregional and systemic treatments. Because of the very low incidence of neuroendocrine tumors in the larynx, a review of the literature has also been performed.

Kit protein (CD117) and proliferation index (Ki-67) evaluation in well and poorly differentiated neuroendocrine tumors.

AIMS AND BACKGROUND: Kit protein expression seems to be associated with a poor outcome in cancer patients and may be an important target for new anticancer drugs. We examined by immunohistochemistry the presence of Kit protein in neuroendocrine tumors (NETs) to explore its relationship with histological grade and proliferation index. PATIENTS AND METHODS: Thirty-five tumor specimens from patients with 24 well differentiated and 11 poorly differentiated NETs were examined for the presence of Kit protein and the proliferation index marker Ki-67. RESULTS: Eleven specimens were positive for Kit protein expression, 8 of which had poorly-differentiated histology and only 3 had well-differentiated histology. Most of the tumors showing immunopositivity for Kit protein were also characterized by a high proliferation index. CONCLUSIONS: Immunohistochemical positivity for Kit protein is mainly related to poorly differentiated NETs. In our study, the percentage of tumors with immunopositivity for Kit protein was lower than that observed by other authors. This difference could be attributable to the different immunohistochemistry procedures used and to the biological heterogeneity of NETs. The number of Kit protein-positive NETs may justify targeted therapy with a tyrosine kinase receptor-associated inhibitor only in a selected subset of patients, whenever no other therapy is available and an autocrine loop sustained by the Kit receptor and its specific ligand has been demonstrated.

Treatment of cancer-related anemia with epoetin alfa: a review.

Erythropoietin (EPO) is a hematopoietic growth hormone that regulates survival, proliferation, and differentiation of erythroid progenitor cells. A reduction in tissue oxygenation stimulates EPO production, through a complex feedback mechanism. Patients with cancer-related anemia have an inadequate EPO response that is further impaired by cancer treatments such as chemotherapy. Cancer-related anemia substantially impairs patient functioning and may contribute to poor treatment outcomes. A significant number of studies demonstrates that treatment of anemia in cancer patients using recombinant human EPO (rHuEPO, epoetin alfa) significantly increases haemoglobin (Hb) levels, reduces transfusion requirements, and improves quality of life, particularly by relieving fatigue. Recent data also show that epoetin alfa therapy may improve cognitive function in patients receiving chemotherapy. In addition, the correction of anemia may prolong survival by enhancing tumor oxygenation, thus increasing tumor sensitivity to chemotherapy or radiation. The indicated dose of epoetin alfa is 150-300 IU/kg three times per week, but it is commonly dosed at 40,000-60,000 IU once weekly based on trial data and extensive clinical use. Determining the timing of initiation of epoetin alfa is a clinical judgement; however, data suggest that patient functioning declines and the risk of transfusion increases when the Hb level falls under 12 g/dL.

Treatment options in hormone-refractory metastatic prostate carcinoma.

Prostate cancer represents one of the most important health problems in industrialized countries. It is the second leading cause of cancer-related death in the United States. Therapeutic options are different according to the stage of the disease at the diagnosis. Patients with localized disease may be treated with surgery or radiation, whereas the treatment for patients with a metastatic disease is purely palliative. Hormonal treatment represents the standard therapy for stage IV prostate cancer, but patients ultimately become unresponsive to androgen ablation and are classified as hormone-refractory prostate cancer patients. The molecular mechanisms involved in progression in hormone resistance are characterized by mutations, down and up-regulation in the androgen receptor gene, mutations in p53 and over-expression of Bcl2 and other alterations in genes and in gene expression. The important thing is that we understand these mechanisms to define potential therapeutic agents for the treatment of hormone-refractory prostate cancer patients. Conventional options for patients with hormone-refractory prostate cancer include secondary hormone therapy, radiotherapy and cytotoxic chemotherapy. The commonest antineoplastic agents are mitoxantrone, estramustine and taxanes. Despite an improvement in the palliative benefit, none of these agents has demonstrated a beneficial impact on the overall survival of patients. Therefore, there is no standard therapy for these patients, thus we need new approaches which should be studied in clinical trials. The evaluation and incorporation of new agents into current treatment regimens could have a role in the treatment of hormone-refractory prostate cancer, but their efficacy has not yet been demonstrated.

Update on the treatment of neuroendocrine tumors.

Neuroendocrine tumors represent a group of neoplasias characterized by significant histopathological and biological heterogeneity. The basic study of the biological features of neuroendocrine tumors should allow the oncologist to identify those tumor subsets more sensitive to a particular medical treatment. For example, in metastatic or advanced disease, locoregional treatments, as well as radionuclide therapies, should be suggested only in selected cases. Although it has no significant effect on tumor growth, biotherapy with somatostatin analogs and/or interferon-alpha is recommended for either well-differentiated or functioning tumors. On the other hand, chemotherapy is effective in the treatment of those tumors characterized by a poor differentiation grade and a high proliferation rate. Novel therapies, new pharmacological formulations and more selective somatostatin analogs are now under clinical investigation for the treatment of neuroendocrine tumors.

Particle swarms in gases: the velocity-average evolution equations from Newton's law.

The evolution equation for a generic average quantity relevant to a swarm of particles homogeneously dispersed in a uniform gas, is obtained directly from the Newton's law, without having recourse to the (intermediary) Boltzmann equation. The procedure makes use of appropriate averages of the term resulting from the impulsive force (due to collisions) in the Newton's law. When the background gas is assumed to be in thermal equilibrium, the obtained evolution equation is shown to agree with the corresponding one following from the Boltzmann equation. But the new procedure also allows to treat physical situations in which the Boltzmann equation is not valid, as it happens when some correlation exists (or is assumed) between the velocities of swarm and gas particles.

Bone turnover markers and insulin-like growth factor components in metastatic breast cancer: results from a randomised trial of exemestane vs megestrol acetate.

The aim of this randomised study was to compare the effects of progestins and aromatase inactivators on bone remodelling markers and the components of insulin-like growth factor in patients with metastatic breast cancer. Within the framework of a large (769 patients), randomised double-blind clinical trial comparing exemestane (EXE) with megestrol acetate (MA), serum 17 beta-estradiol (E2), estrone (E1), estrone sulphate (E1S), bone alkaline phosphatase (BAP), carboxy-terminal cross-linking telopeptide of type I collagen (ICTP) and the components of insulin-like growth factor (IGF) family (IGF-1, IGF-2 and IGFBP-3) were determined in 53 patients (24 randomised to EXE and 29 ramdomised to MA). After eight weeks of treatment, both ICTP and BAP increased (p < 0.01) in the EXE group, but only ICTP in the MA group (p < 0.03). The 8-week suppression of E2 and E1S was more pronounced in the EXE group (to, respectively, 11.2% and 9.9% of baseline values) than in the MA group (33.1% and 29.7%). IGF-1 increased (p < 0.01) in both groups, but more so in the patients treated with MA. Estrogen levels negatively correlated with ICTP in both groups, but were not related to BAP in either. IGF-1 negatively correlated with estrogens in both groups. The results of this study indicate that anti-aromatase therapy is associated with increased osteoclast activity, and suggest the existence of possible differential effects of different hormonal therapies on bone remodelling markers regardless of the estrogen suppression induced by EXE.

Current treatments of neuroendocrine tumors role of biotherapy and chemotherapy.

Neuroendocrine tumors are rare neoplasms originating from cells belonging to a diffuse or confined neuroendocrine system and characterized by a significant histopatologic and biologic heterogeneity. Timely diagnosis is delayed because they are often clinically silent for their low differentiation grade and the absence of any symptom due to abnormal hormone release. For these reasons, many neuroendocrine tumor patients are not treated medically for metastatic or inoperable disease. Medical treatments include biotherapy, with interferon-alpha and somatostatin analogues, and chemotherapy. Somastostatin analogues are widely used in patients with symptoms and with carcinoids of low differentiation grade. Interferon-alpha is used alone or in combination with somatostatin analogues. Chemotherapy is active in patients with poorly differentiated neuroendocrine tumors. The therapeutic regimen commonly used is the combination of cisplatinum and etoposide. In conclusion, no standard treatment for NET has yet been identified, and the response criteria suggested by ITMO remain a reference point. The clinical aspect of the disease and biologic features suggest the identification of neuroendocrine tumors patients suitable for the appropriate therapies. On these bases, it is recommended that diagnosis and treatment of neuroendocrine tumors be carried out at specialized oncological centers involved in clinical trials.

Could exemestane affect insulin-like growth factors, interleukin 6 and bone metabolism in postmenopausal advanced breast cancer patients after failure on aminoglutethimide, anastrozole or letrozole?

Postmenopausal hormone-sensitive breast cancer is currently treated with either antioestrogens or aromatase inhibitors (AIs), due to the clinical efficacy and safety of these drugs. Today's challenge is the sequential use of AIs with different structure and no cross-resistance to improve the therapeutic outcome. The present study describes the biological action of the steroidal structure (SS)-AI exemestane (EXE), in patients progressing on aminoglutethimide (AG) or other non-steroidal structure (NSS)-AIs (letrozole or anastrozole). Thirteen patients were evaluated for serum insulin-like growth factor (IGF) components [total IGF-1, IGF-2 and IGF binding protein (IGFBP)-3], interleukin (IL)-6 system [IL-6 and soluble IL-6 receptor (sIL-6-R)] and bone metabolism markers [bone gla protein/osteocalcin (BGP), bone-specific isoform of alkaline phosphatase (BAP) and carboxy-telopeptide of type I procollagen (ICTP)]. IGF system components show a trend to increase both in patients progressing on AG and in patients progressing on other NSS-AIs. Such an increase depends on the wash-out length from the previous treatment and is strictly linked to the circulating oestrogen levels. Serum IL-6 and sIL-6-R are mainly related to the patients' clinical outcome. Bone formation (BGP and BAP) and bone resorption (ICTP) markers seem to be at equilibrium with oestrogen levels when starting EXE and do not appear to be uncoupled over treatment. The observed variations seem to be mainly linked to the circulating oestrogen levels rather than directly to the way of action of the AI employed.

Renal cancer treatment: a review of the literature.

Renal carcinoma represents about 3% of all adult tumors, with an estimate of 31,900 new cases diagnosed in 2003 in the United States. In the early phase of its natural history, renal cancer is potentially curable by surgery, but if the disease presents any signs of metastasis, the chances of survival are remote, even though anecdotal cases characterized by long survival have been reported. In fact, the treatment of metastatic renal cancer remains unsatisfactory. Systemic treatment with single agents and with polychemotherapy, with or without cytokine-based immunotherapy, has not been successful, obtaining very low response rates without a significant benefit in overall survival. This review highlights the most interesting issues regarding conventional therapeutic strategies, in localized and in advanced disease. New approaches such as monoclonal antibodies, vaccines, gene therapy, angiogenesis inhibitors and allogeneic cell transplantation and their possible clinical applications are also discussed.

Diagnostic and therapeutic aspects of iatrogenic hypoparathyroidism.

Postsurgical hypoparathyroidism is the most common cause of chronic hypocalcemia. This condition may occur after removal of all parathyroid glands or after interruption of the blood supply to the parathyroid glands during thyroidectomy and radical neck dissection. The severity of the clinical presentation of hypocalcemia may vary from an asymptomatic laboratory finding to a severe life-threatening condition. Persistent hypoparathyroidism requires treatment that must be maintained throughout the patient's lifetime, and for this reason care is required to avoid complications. In this review the most relevant aspects of calcium homeostasis and its alteration in hypoparathyroidism are briefly discussed. In addition, the main approaches to treatment of the hypocalcemic state are presented.