Clinical Usefulness of Prostate-specific Membrane Antigen-ligand Positron Emission Tomography/Computed Tomography for the Detection of Prostate Cancer Biochemical Recurrence after Primary Radiation Therapy in Patients with Prostate-specific Antigen Below the Phoenix Threshold: Systematic Review and Meta-analysis.

AIMS: After primary radiotherapy, biochemical recurrence is defined according to the Phoenix criteria as a prostate-specific antigen (PSA) value >2 ng/ml relative to the nadir. Several studies have shown that prostate-specific membrane antigen (PSMA)-ligand positron emission tomography/computed tomography (PET/CT) can help in detecting recurrence in patients with low PSA values. This study aimed to assess the detection rate and patterns of PSMA-ligand PET/CT uptake in patients with suspected biochemical recurrence after primary radiotherapy and with PSA levels below the Phoenix threshold. MATERIALS AND METHODS: The meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Articles providing data on patients with suspected prostate cancer recurrence after primary radiotherapy with a PSA value below the Phoenix threshold and who underwent PSMA-ligand PET/CT were included. Quality assessment was carried out using the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). RESULTS: In total, five studies were included, recruiting 909 patients (202 with PSA ≤2 ng/ml). The PSMA-ligand detection rate in the patients with ≤2 ng/ml ranged from 66 to 83%. The most frequent source of PSMA-ligand PET/CT uptake was local recurrence, followed by lymph node metastasis and bone metastasis. PSMA-ligand PET/CT uptake due to local-only recurrence was more likely in patients with PSA ≤2 ng/ml compared with PSA > 2 ng/ml: risk ratio 0.72 (95% confidence interval 0.58-0.89), P = 0.003. No significant differences were observed in the detection of PSMA-ligand uptake in other areas. Limitations include a lack of biopsy confirmation, cohort reports with small sample sizes and a potentially high risk of bias. CONCLUSION: A significant detection of PSMA-ligand-avid disease was observed in patients with PSA levels below the Phoenix threshold. There was a higher likelihood of detecting local-only uptake when the PSA value was ≤2 ng/ml. The findings suggest that a critical review of the Phoenix criteria may be warranted in the era of PSMA-ligand PET/CT and highlight the need for further prospective trials.

Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies

Background The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown. Materials and methods We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells. Results Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]. Conclusion Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab (AU)

Clinical Practice Guidelines for Diagnosis and Management of Hypersensitivity Reactions to Quinolones.

The consumption of quinolones as first-line treatment has increased in recent years, leading to an increase in the incidence of hypersensitivity reactions (HSRs) to this antibiotic group. Both diagnosis and management of HSRs to quinolones are complex and controversial. These practical guidelines aim to provide recommendations for effective clinical practice. The recommendations were drafted by an expert panel that reviewed the literature regarding HSRs to quinolones and analyzed controversies in this area. Most HSRs to quinolones are immediate and severe. The risk for HSRs is higher in patients who report allergy to ß-lactams, moxifloxacininduced anaphylaxis, and immediate reactions than in patients who report reactions to quinolones inducing other symptoms. The usefulness of skin tests in diagnosing HSRs to quinolones is controversial, with sensitivity and specificity varying between studies. Most in vitro tests are produced in-house, with no validated commercial options. The basophil activation test has proven useful for diagnosing immediate reactions, albeit with diverse results regarding sensitivity. Drug provocation testing is currently the gold standard for confirming or excluding the diagnosis and for finding safe alternatives, although it is contraindicated in patients with severe reactions. Cross-reactivity between quinolones has proven controversial in several studies, with the lowest cross-reactivity reported for levofloxacin. Desensitization may be considered in allergy to quinolones when no other alternatives are available.

Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies.

BACKGROUND: The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown. MATERIALS AND METHODS: We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells. RESULTS: Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]. CONCLUSION: Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab.

Clinical Practice Guidelines for Diagnosis and Management of Hypersensitivity Reactions to Quinolones

The consumption of quinolones as first-line treatment has increased in recent years, leading to an increase in the incidence of hypersensitivity reactions (HSRs) to this antibiotic group. Both diagnosis and management of HSRs to quinolones are complex and controversial. These practical guidelines aim to provide recommendations for effective clinical practice. The recommendations were drafted by an expert panel that reviewed the literature regarding HSRs to quinolones and analyzed controversies in this area. Most HSRs to quinolones are immediate and severe. The risk for HSRs is higher in patients who report allergy to ß-lactams, moxifloxacininduced anaphylaxis, and immediate reactions than in patients who report reactions to quinolones inducing other symptoms. The usefulness of skin tests in diagnosing HSRs to quinolones is controversial, with sensitivity and specificity varying between studies. Most in vitro tests are produced in-house, with no validated commercial options. The basophil activation test has proven useful for diagnosing immediate reactions, albeit with diverse results regarding sensitivity. Drug provocation testing is currently the gold standard for confirming or excluding the diagnosis and for finding safe alternatives, although it is contraindicated in patients with severe reactions. Cross-reactivity between quinolones has proven controversial in several studies, with the lowest cross-reactivity reported for levofloxacin. Desensitization may be considered in allergy to quinolones when no other alternatives are available (AU)

Prognostic and predictive role of the PI3K-AKT-mTOR pathway in neuroendocrine neoplasms

Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K-AKT-mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K-AKT-mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials' design to identify potential predictive or prognostic biomarkers

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Prognostic and predictive role of the PI3K-AKT-mTOR pathway in neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K-AKT-mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K-AKT-mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials' design to identify potential predictive or prognostic biomarkers.

Bruton's tyrosine kinase (BTK) as a promising target in solid tumors.

Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells. Ibrutinib (PCI-32765) is an orally available small molecule that acts as an inhibitor of the BTK and is approved for the treatment of patients with some hematological malignancies. It has been suggested that ibrutinib may also have a potential antitumor activity in solid neoplasms. In this sense, ibrutinib has the ability to revert polarization of TCD4+ to Th1 lymphocytes to increase the cytotoxic ability of T CD8+ and to regulate tumor-induced immune tolerance by acting over tumor infiltrating cells activity and immunosuppressive cytokines release. Furthermore, based on its molecular activity and safety, ibrutinib has been considered as a partner for treatment combination with PI3K/AKT/mTOR inhibitors or with immune-checkpoint inhibitors, inhibiting immunosuppressive signals from the tumor microenvironment, and overcoming the immune resistance to current anti-PD1/PDL1 immunotherapeutic drugs by the CXCR4/CXCL2 pathway regulation. Currently, a broad range of different studies are evaluating the activity of ibrutinib either as single agent or in combination in patients with solid tumors.

Asthma related to Alternaria sensitization: an analysis of skin-test and serum-specific IgE efficiency based on the bronchial provocation test.

BACKGROUND: It is difficult to find a causal relationship between exposure to Alternaria spores and the development of asthma symptoms in sensitized individuals due to the complexity of clinical situations in which positive diagnostic tests are often found. OBJECTIVE: To analyse the diagnostic efficiency of skin testing (ST) and serum-specific IgE to Alternaria, based on the results of a bronchial specific challenge with Alternaria extracts. METHODS: Seventy-four asthmatic patients sensitized to Alternaria underwent a specific bronchial challenge with this mould. Skin-testing weal sizes, serum-specific IgE values (CAP-system) and bronchial challenge results were analysed by receiver operating characteristics curves (ROC curves) and logistic regression. The sensitivity, specificity, positive and negative predictive values were calculated for different cut-off points. RESULTS: Bronchial challenges to Alternaria elicited a positive result in 45 patients (61%). Skin prick testing almost perfectly predicted the outcome of bronchoprovocation tests (area under the ROC curve of 0.957), whereas intradermal skin testing had moderate efficacy. A negative result for skin prick test (SPT) showed a 4% probability of a positive bronchial challenge in the logistic regression analysis. However, weals around 5.5 mm in diameter had 90% probability of a positive challenge. Quantification of serum-specific IgE correctly classified 86% of the cases. In the logistic regression analysis, a CAP value 16 kU(A)/L predicted a positive bronchial challenge result with 99% accuracy, whereas for a CAP value <0.35 kU(A)/L, this probability was 33%. CONCLUSIONS AND CLINICAL RELEVANCE: Most asthmatic patients with positive SPT results to Alternaria would have a positive bronchial challenge. As atmospheric mould levels may vary significantly with the weather conditions, sensitized patients should be instructed on the risk situations, environmental control measures and the importance of correct medication compliance. Immunotherapy with Alternaria could also be taken into account as a valid therapeutic option.

Triatoma infestans in Greater Buenos Aires, Argentina.

The Health Administration Agencies of many municipalities in Greater Buenos Aires (GBA) receive frequent reports on triatomines in houses. The aim of this work was to identify and describe the dispersal foci of Triatoma infestans in an urban neighborhood of GBA, and contribute to the knowledge of the epidemiological situation in the region. In June 1998, potentially infested places were entomologically evaluated. T. infestans was only detected in a hen building for egg production, which housed approximately 6,000 birds. A total of 2,930 insects were collected. Density was about 9 triatomines/m(2). The proportions of fifth instar nymphs and adults were significantly higher than those of the other stages (p<0.001). The number of triatomines collected largely exceeded the highest domestic infestation found in one house from rural endemic areas of Argentina. Though triatomines were negative for Trypanosoma cruzi, they could acquire the parasite by coming in contact with infected people living in GBA. Besides, the numerous and widely distributed places housing hens and chickens, would favor the settlement of the vector. Together, both facts may constitute a risk of parasitic vectorial transmission. It is recommended to intensify systematic activities of vector search and case detection in GBA.

Triatoma infestans in Greater Buenos Aires, Argentina

The Health Administration Agencies of many municipalities in Greater Buenos Aires (GBA) receive frequent reports on triatomines in houses. The aim of this work was to identify and describe the dispersal foci of Triatoma infestans in an urban neighborhood of GBA, and contribute to the knowledge of the epidemiological situation in the region. In June 1998, potentially infested places were entomologically evaluated. T. infestans was only detected in a hen building for egg production, which housed approximately 6,000 birds. A total of 2,930 insects were collected. Density was about 9 triatomines/m². The proportions of fifth instar nymphs and adults were significantly higher than those of the other stages (p<0.001). The number of triatomines collected largely exceeded the highest domestic infestation found in one house from rural endemic areas of Argentina. Though triatomines were negative for Trypanosoma cruzi, they could acquire the parasite by coming in contact with infected people living in GBA. Besides, the numerous and widely distributed places housing hens and chickens, would favor the settlement of the vector. Together, both facts may constitute a risk of parasitic vectorial transmission. It is recommended to intensify systematic activities of vector search and case detection in GBA

Comparative meiotic studies in Triatoma sordida (Stål) and T. guasayana Wygodzinsky & Abalos (Reduviidae, Heteroptera).

Triatoma sordida and T. guasayana are competent Trypanosoma cruzi vectors, with overlapping distribution areas in Argentina. Both species are morphologically similar, and their immature stages are hard to discriminate. Cytogenetic studies in the genus Triatoma reveal scarce karyotypic variations, being 2n = 20 + XY the most frequent diploid number in males. In the present work the meiotic behaviour of different Argentinian populations of T. sordida and T. guasayana has been analyzed; the meiotic karyotype of both species has also been compared. The species differ in total chromosome area and in the relative area of the sex chromosomes. These meiotic karyotypic differences constitute an additional tool for the taxonomic characterization of T. sordida and T. guasayana. The analysis of an interpopulation hybrid of T. sordida (Brazil x Argentina) reveals a regular meiotic behaviour; despite the presence of heteromorphic bivalents. Our observations support the hypothesis that karyotype variations through the gain or loss of heterochromatin can not be considered as a primary mechanism of reproductive isolation in Triatoma.

Comparative meiotic studies in Triatoma sordida (Stal) and T. guasayana Wygodzinsky & Abalos (Reduviidae, Heteroptera)

Triatoma sordida and T. guasayana are competent Trypanosoma cruzi vectors, with overlapping distribution areas in Argentina. Both species are morphologically similar, and their immature stages are hard to discriminate. Cytogenetic studies in the genus Triatoma reveal scarce karyotypic variations, being 2n=20 + XY the most frequent diploid number in males. In the present work the meiotic behaviour of different Argentinian populations of T. sordida and T. guasayana has been analyzed; the meiotic karyotype of both species has also been compared. The species differ in total chromosome area and the relative area of the sex chromosomes. These meiotic karyotypic differences constitute an additional tool for the taxonomic characterization of T. sordida and T. guasayana. The analysis of an interpopulation hybrid of T. sordida (Brazil x Argentina) reveals a regular meiotic behaviour, despite the presence of heteromorphic bivalents. Our observations support the hypothesis that karyotype variatons through the gain or loss of heterochromatin can not be considered as a primary mechanism of reproductive isolation in Triatoma.

Potential colonization of the peridomicile by Triatoma guasayana (Hemiptera:Reduviidae) in Santiago del Estero, Argentina.

Sylvatic triatomines might use the peridomicile as a 1st step in the process of domiciliation. Therefore, we evaluated the capability of sylvatic species to colonize the peridomicile of a rural area in the Province of Santiago del Estero, Argentina. The research was carried out in 6 houses in the village of Trinidad. The person per hour capture method was employed to determine the presence of triatomines in all the buildings (n = 44). Dispersing adults were collected by means of light traps and by villagers when approaching their houses. Triatoma infestans (Klug) was the most abundant species followed by the sylvatic Triatoma guasayana Wygodzinsky & Abalos. The branch pens, which included cacti, Opuntia quimilo, and bromeliads in their structure, were significantly associated with T. guasayana. Most of these insects had fed on domestic blood sources. With the exception of 1 Triatoma sordida (Stål), dispersing adults were T. guasayana; among those approaching houses, 12 were females (2 of which were infected with Trypanosoma cruzi Chagas) and 3 were males. T. guasayana was found to be capable of intensively invading the intradomicile and the peridomicile, showing a high tendency to settle in the ecotopes which included nontransformed raw material from the wild and where T. infestans was less abundant.

[The relationship between Triatoma infestans, poultry, and humans in a rural settlement in Santiago del Estero, Argentina]. / Relação entre Triatoma infestans, aves domésticas e o homem num povoado de Santiago del Estero, Argentina.

An association was determined between Triatona infestans, poultry, and humans in Trinidad, in the Province of Santiago del Estero, Argentina. To collect triatomines, four samples were taken at the area immediately surrounding six houses by the one hour/man capture method (December 1991 - October 1992). Peridomiciliary ecotopes were classified as arthropic (where humans carry out daily activities) or non-anthropic. Tratomine feeding habits were also determined. Of 134 biotopes, 21% had T. infestans, 22% had poultry, and 54% were anthropic. Some 25% of the latter harboured both poultry and T. infestans. Poultry were the only domestic animals associated with T. infestans, a finding that was exclusive to anthropic ecotopes. The proportion of feedings on individual fowl (61/146) was highly significant. Chicken coops are not used in Trinidad, and poultry brood in anthropic structures. Due to the materials used for making their nests and their repeated use, a periodic bug flow can be established from the intra- to the peridomiciliary area and vice versa, through passive transport. The close relationship among T, infestans, poultry, and humans in anthropic biotopes where other T. cruzi reservoirs such as dogs are also present contributes to the maintenance of domestic triatomine colonies and transmission of Chagas' disease to humans.