Acute gastroenteritis is one of the most common diseases worldwide. In developed countries, viruses, particularly noroviruses, are recognized as the leading cause. In The Netherlands, the surveillance of gastroenteritis outbreaks with suspected viral etiologies (as determined by Kaplan criteria) was established by the National Institute for Public Health and the Environment in 1994. This paper presents an overview of viral gastroenteritis outbreaks reported from 1994 through 2005. A minimum epidemiological data set consisting of the associated setting(s), the probable transmission mode, the date of the first illness and the date of sampling, the number of persons affected, and the number of hospitalizations was requested for each reported outbreak. Stool samples were tested for the presence of norovirus, sapovirus, rotavirus, astrovirus, adenovirus, and Aichi virus by electron microscopy, enzyme-linked immunosorbent assay, and/or reverse transcription-PCR. A total of 6,707 stool samples from 941 gastroenteritis outbreaks were investigated. Noroviruses were detected as the causative agent in 735 (78.1%) of the outbreaks, and rotaviruses, adenoviruses, and astroviruses were found to be responsible for 46 (4.9%), 9 (1.0%), and 5 (0.5%) outbreaks, respectively. Among the gastroenteritis outbreaks in which a mode of transmission was identified, most outbreaks (38.1%) were associated with person-to-person transmission, and the majority (54.9%) of the outbreaks investigated were reported by residential institutions. Since 2002, the total number of outbreaks reported and the number of unexplained outbreaks have increased. Furthermore, the number of rotavirus-associated outbreaks has increased, especially in nursing homes. Despite thorough testing, 115 (12.2%) outbreaks suspected of having viral etiologies remain unexplained. Increases in numbers of reported outbreaks may indicate undefined changes in the criteria for reporting or the emergence of new pathogens.

The development of tumor-targeted therapies using monoclonal antibodies has been successful during the last 30 years. Nevertheless, the efficacy of antibody-based therapy is still limited and further improvements are eagerly awaited. One of the promising novel developments that may overcome the drawbacks of monoclonal antibody-based therapies is the employment of nanobodies. Current nanobody-based therapeutics can be divided into three different platforms with nanobodies functioning as: receptor antagonists; targeting moieties of effector domains; or targeting molecules on the surface of nanoparticles. In this article, we describe factors that affect their performance at three different stages: their systemic circulation upon intravenous injection; their extravasation and tumor penetration; and, finally, their interaction with target molecules.

Background Increasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first‐line maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose‐limiting toxicities (DLTs) during CAP‐B and CAPOX‐B. Methods Sarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs. Results One hundred eighty‐two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP‐B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX‐B. At the start of CAP‐B and CAPOX‐B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non‐sarcopenic at the start of CAP‐B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX‐B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m 2 ). Sarcopenia at the start of CAP‐B was not associated with DLTs [relative risk 0.87 (95% confidence interval 0.64–1.19)], whereas patients with >2% SMI loss had a significantly higher risk of DLTs [1.29 (1.01–1.66)]. At the start of subsequent CAPOX‐B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss [1.78 (1.06–3.01)] or sarcopenia [1.75 (1.08–2.86)]. After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX‐B [sarcopenia vs. non‐sarcopenic: 0.86 (0.69–1.08) and SMI loss vs. stable/gain: 0.83 (0.65–1.07)]. In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs. Conclusions In this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions)...

BackgroundObservational studies suggest that loss of skeletal muscle mass (SMM) is associated with chemotherapy‐related toxicity, poor quality of life, and poor survival in metastatic colorectal cancer (mCRC) patients. Little is known about the evolution of SMM during palliative systemic therapy. We investigated changes in SMM during various consecutive palliative systemic treatment regimens using repeated abdominal computed tomography scans of mCRC patients who participated in the randomized phase 3 CAIRO3 study.MethodsIn the CAIRO3 study, mCRC patients with stable disease or better after 6 cycles of first‐line treatment with capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) were randomized between maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation. Upon first disease progression, in both groups, CAPOX‐B or other treatment was reintroduced until the second disease progression, which was the primary study endpoint. We analysed 1355 computed tomography scans of 450 (81%) CAIRO3 patients (64 ± 9.0 years, CAP‐B n = 223; observation n = 227) for SMM at four time points (i.e. prior to the start of pre‐randomization initial treatment, at randomization, and at first and at second disease progression) using the Slice‐o‐matic software and single slice evaluation at the lumbar 3 level. By using accepted and widely used formulas, whole body SMM was calculated. A linear mixed effects model, adjusted for relevant confounders, was used to assess SMM changes for the total group and within and between study arms.ResultsDuring 6 cycles of initial treatment with CAPOX‐B prior to randomization, SMM decreased significantly in all patients [CAP‐B arm: −0.53 kg (95% CI −1.12; −0.07) and observation arm: −0.85 kg (−1.45; −0.25)]. After randomization, SMM recovered during CAP‐B treatment by 1.32 kg (0.73; 1.90) and observation by 1.20 kg (0.63; 1.78) (median time from randomization to first disease progression 8.6 and 4.1 months for CAP‐B arm and observation arm, respectively). After first progression and during reintroduction treatment with CAPOX‐B or other treatment, SMM again decreased significantly and comparable in both arms, CAP‐B: −2.71 kg (−3.37; −2.03), and observation: −2.01 kg (−2.64; −1.41) (median time from first progression until second progression CAP‐B arm: 4.7 months and observation arm: 6.6 months).ConclusionsThis longitudinal study provides a unique insight in SMM changes in mCRC patients during palliative systemic treatment regimens, including observation. Our data show that muscle loss is reversible and may be influenced by the intensity of systemic regimens. Although studies have shown prognostic capacity for SMM, the effects of subsequent changes in SMM are unknown and may be clues for new future therapeutic interventions.

PurposeThe aim of this work was to develop a CAIX-specific nanobody conjugated to IRDye800CW for molecular imaging of pre-invasive breast cancer.ProceduresCAIX-specific nanobodies were selected using a modified phage display technology, conjugated site-specifically to IRDye800CW and evaluated in a xenograft breast cancer mouse model using ductal carcinoma in situ cells (DCIS).ResultsSpecific anti-CAIX nanobodies were obtained. Administration of a CAIX-specific nanobody into mice with DCIS xenografts overexpressing CAIX showed after 2 h a mean tumor-to-normal tissue ratio (TNR) of 4.3 ± 0.6, compared to a TNR of 1.4 ± 0.2 in mice injected with the negative control nanobody R2-IR. In DCIS mice, a TNR of 1.8 ± 0.1 was obtained. Biodistribution studies demonstrated an uptake of 14.0 ± 1.1 %I.D./g in DCIS + CAIX tumors, 4.6 ± 0.8 %I.D./g in DCIS tumors, while 2.0 ± 0.2 %I.D./g was obtained with R2-IR.ConclusionsThese results demonstrate the successful generation of a CAIX-specific nanobody-IRDye800CW conjugate that can be used for rapid imaging of (pre-)invasive breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-015-0909-6) contains supplementary material, which is available to authorized users.