Protection Induced by Plasmodium falciparum MSP142 Is Strain-Specific, Antigen and Adjuvant Dependent, and Correlates with Antibody Responses

Vaccination with Plasmodium falciparum MSP142/complete Freund's adjuvant (FA) followed by MSP142/incomplete FA is the only known regimen that protects Aotus nancymaae monkeys against infection by erythrocytic stage malaria parasites. The role of adjuvant is not defined; however complete FA cannot be used in humans. In rodent models, immunity is strain-specific. We vaccinated Aotus monkeys with the FVO or 3D7 alleles of MSP142 expressed in Escherichia coli or with the FVO allele expressed in baculovirus (bv) combined with complete and incomplete FA, Montanide ISA-720 (ISA-720) or AS02A. Challenge with FVO strain P. falciparum showed that suppression of cumulative day 11 parasitemia was strain-specific and could be induced by E. coli expressed MSP142 in combination with FA or ISA-720 but not with AS02A. The coli42-FVO antigen induced a stronger protective effect than the bv42-FVO antigen, and FA induced a stronger protective effect than ISA-720. ELISA antibody (Ab) responses at day of challenge (DOC) were strain-specific and correlated inversely with c-day 11 parasitemia (r = −0.843). ELISA Ab levels at DOC meeting a titer of at least 115,000 ELISA Ab units identified the vaccinees not requiring treatment (noTx) with a true positive rate of 83.3% and false positive rate of 14.3 %. Correlation between functional growth inhibitory Ab levels (GIA) and cumulative day 11 parasitemia was weaker (r = −0.511), and was not as predictive for a response of noTx. The lowest false positive rate for GIA was 30% when requiring a true positive rate of 83.3%. These inhibition results along with those showing that antigen/FA combinations induced a stronger protective immunity than antigen/ISA-720 or antigen/AS02 combinations are consistent with protection as ascribed to MSP1-specific cytophilic antibodies. Development of an effective MSP142 vaccine against erythrocytic stage P. falciparum infection will depend not only on antigen quality, but also upon the selection of an optimal adjuvant component

Breast cancer in women < or = 35 years: review of 1002 cases from a single institution.

BACKGROUND: Early-onset breast cancer may differ with respect to etiology, clinical features and outcome compared with breast cancer in older women. To gain further insight, we retrospectively reviewed the clinical features and outcome of women 2 cm in 61%) and nodal status in 888 (lymph node positive in 52%). Modified radical mastectomy was performed in 568 (57%) and breast-conservation surgery (BCS) in 422 (42%). Five hundred sixteen (51%) patients received adjuvant radiotherapy and five hundred thirty-four (53%) adjuvant systemic therapy. Two hundred ninety-three (29%) patients had a family history of breast cancer (FH). Contralateral breast cancer (CBC) occurred more frequently in women with FH (P range 0.042-0.008). Local recurrence (LR) was 37% and 73% at 10 years in those treated by BCS with and without radiotherapy, respectively. At 10 years, disease-free survival (DFS) was 30% and overall patient survival 48%. CONCLUSIONS: In this cohort, breast cancer was usually self-diagnosed and tumors were > 2 cm at presentation in approximately two-thirds of cases, suggesting the possibilities of a delay in diagnosis, more aggressive tumors or both. Our results are compatible with the known association of breast cancer FH with increased CBC. Our data also corroborates the suggestion that positive genetic testing in this age group should lead to consideration of more aggressive ipsilateral and contralateral breast management. In those receiving adjuvant irradiation after BCS, the LR rate was high, but did not impact on overall survival

Breast cancer in women &lt; or = 35 years: review of 1002 cases from a single institution.

BACKGROUND: Early-onset breast cancer may differ with respect to etiology, clinical features and outcome compared with breast cancer in older women. To gain further insight, we retrospectively reviewed the clinical features and outcome of women &lt; or = 35 years with primary breast cancer seen at our institution over a 30-year period. PATIENTS AND METHODS: Charts were reviewed for women with operable breast cancer diagnosed &lt; or = 35 years of age seen at the Princess Margaret Hospital (PMH), Toronto from 1965-1994. RESULTS: One thousand eighty-six women with non-metastatic invasive breast cancer, aged 18.3-35.6 years (median 32.1 years) were referred to PMH. Symptoms at presentation included: self-detected breast lump (83%), other breast symptom (10%), physician diagnosis (4%) and unknown (3%). Tumor size was known in 936 (&gt;2 cm in 61%) and nodal status in 888 (lymph node positive in 52%). Modified radical mastectomy was performed in 568 (57%) and breast-conservation surgery (BCS) in 422 (42%). Five hundred sixteen (51%) patients received adjuvant radiotherapy and five hundred thirty-four (53%) adjuvant systemic therapy. Two hundred ninety-three (29%) patients had a family history of breast cancer (FH). Contralateral breast cancer (CBC) occurred more frequently in women with FH (P range 0.042-0.008). Local recurrence (LR) was 37% and 73% at 10 years in those treated by BCS with and without radiotherapy, respectively. At 10 years, disease-free survival (DFS) was 30% and overall patient survival 48%. CONCLUSIONS: In this cohort, breast cancer was usually self-diagnosed and tumors were &gt; 2 cm at presentation in approximately two-thirds of cases, suggesting the possibilities of a delay in diagnosis, more aggressive tumors or both. Our results are compatible with the known association of breast cancer FH with increased CBC. Our data also corroborates the suggestion that positive genetic testing in this age group should lead to consideration of more aggressive ipsilateral and contralateral breast management. In those receiving adjuvant irradiation after BCS, the LR rate was high, but did not impact on overall survival

Real-life experience with IV fosfomycin in Canada: Results from the Canadian LEadership on Antimicrobial Real-life usage (CLEAR) registry

ABSTRACT: Objectives: Data on the use of intravenous (IV) fosfomycin in Canada are limited. Using data captured by the Canadian LEadership on Antimicrobial Real-life usage (CLEAR) registry, we report the use of IV fosfomycin in Canadian patients. Methods: The CLEAR registry uses the web-based data management program, REDCapTM (https://rcsurvey.radyfhs.umanitoba.ca/surveys/?s=F7JXNDFXEF) to facilitate clinicians’ entering of details associated with their clinical experiences using IV fosfomycin. Results: Data were available for 59 patients treated with IV fosfomycin. The most common infections treated were: bacteraemia or sepsis (25.4% of patients), complicated urinary tract infection (20.3%), ventilator-associated bacterial pneumonia (18.6%), and hospital-acquired pneumonia (13.6%). IV fosfomycin was used to treat Gram-negative (88.1%) and Gram-positive (10.2%) infections. The most common pathogens treated were carbapenem-resistant Enterobacterales (44.1%), multidrug-resistant Pseudomonas aeruginosa (18.6%), vancomycin-resistant Enterococcus faecium (5.1%), and methicillin-resistant Staphylococcus aureus (3.4%). IV fosfomycin was primarily used due to resistance to initially prescribed therapies (69.5%), frequently in combination with other agents (86.4%). Microbiological success (eradication/presumed eradication) occurred in 77.4% of patients, and clinical success (clinical cure/improvement) occurred in 62.5%. Overall, 15.3% of patients died because of their infection. Adverse effects were not documented in 73.1% of patients, and no patient discontinued therapy because of an adverse effect. Conclusions: In Canada, IV fosfomycin is used primarily as directed therapy to treat a variety of severe infections caused by Gram-negative and Gram-positive bacteria. It is primarily used in patients infected with bacteria resistant to other agents and as part of combination therapy. Its use is associated with relatively high microbiological and clinical cure rates, and it has an excellent safety profile

Trial Design and Results for Adjuvant AS02A.

<p><i>Aotus</i> monkeys vaccinated antigens in combination with AS02A. Groups of six animals were vaccinated. Day 11 is c-day 11 parasitemia. Tx is treatment outcome: noTx, no treatment required; TxA treatment for anemia; TxP, treatment for uncontrolled parasitemia. GIA is <i>in vitro</i> growth/invasion inhibition against FVO or 3D7 strain <i>P. falciparum.</i> ELISA Ab units were determined with 3D7 or FVO strain MSP1₄₂ expressed in baculovirus. ELISA Ab titers were determined with 3D7 or FVO strain MSP1₄₂, p19, EGF1 or EGF2 expressed in <i>E. coli</i>, and assays were run only using Ag homologous to the vaccine strain.</p><p>n/d is not done. ^*, no sample available.</p

Correlation between log(c-day 11 parasitemia) and serologic response in animals vaccinated with FVO strain Ag.

<p>Animals were vaccinated with either <i>E. coli</i> or baculovirus expressed MSP1₄₂ in combination with FA, ISA-720 or AS02A. Growth/Invasion inhibition is against FVO (Panel A) or 3D7 (Panel B) strain targets. ELISA was performed with recombinant FVO (Panel C) or 3D7 (Panel D) strain MSP1₄₂ expressed in baculovirus. Correlations were determined with Pearson's test after testing data distributions for normality.</p

Trial Design and Results for Adjuvant CFA/FA

<p><i>Aotus</i> monkeys vaccinated with Ag in combination with FA. Groups of six animals were vaccinated. Day 11 is c-day 11 parasitemia. Tx is treatment outcome: noTx, no treatment required; TxA treatment for anemia; TxP, treatment for uncontrolled parasitemia. GIA is <i>in vitro</i> growth/invasion inhibition against FVO or 3D7 strain <i>P. falciparum.</i> ELISA Ab units were determined with 3D7 or FVO strain MSP1₄₂ expressed in baculovirus. ELISA Ab titers were determined with 3D7 or FVO strain MSP1₄₂, p19, EGF1 or EGF2 expressed in <i>E. coli</i>, and assays were run only using Ag homologous to the vaccine strain. Some results from regimens 1, 3 and 7 were reported previously <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002830#pone.0002830-Darko1" target="_blank">[24]</a>. n/d is not done. ^*, no sample available.</p

Individual value plots showing strain-specific Ab responses by ELISA for vaccine recipients.

<p>Responses are grouped by vaccine strain received and then by the Ag strain use for ELISA. Panel A includes all 3D7 strain vaccine recipients in the trial. Panel B includes all FVO strain vaccine recipients in the trial. Connect lines join each individual animal's ELISA Ab response measured with the FVO Ag to that measured with the 3D7 Ag. Both Ag were expressed in baculovirus.</p

C-day 11 parasitemias for regimens 3, 7, 8, and 9 grouped by adjuvant and antigen.

<p>Open circles, individual responses; filled circles, means; bar is the 95% confidence interval for the mean. Panel A compares grouped log(c-day 11 parasitemia) levels. Panel B shows the estimated marginal means from the GLM used to analyze the responses.</p