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Most animals display multiple behavioral states and control the time allocation to each of their activity phases depending on their environment. Here we develop a new quantitative method to analyze Caenorhabditis elegans behavioral states. We show that the dwelling and roaming two-state behavior of C. elegans is tightly controlled by the concentration of food in the environment of the animal. Sensory perception through the amphid neurons is necessary to extend roaming phases while internal metabolic perception of food nutritional value is needed to induce dwelling. Our analysis also shows that the proportion of time spent in each state is modulated by past nutritional experiences of the animal. This two-state behavior is regulated through serotonin as well as insulin and TGF-beta signaling pathways. We propose a model where food nutritional value is assessed through internal metabolic signaling. Biogenic amines signaling could allow the worm to adapt to fast changes in the environment when peptide transcriptional pathways may mediate slower adaptive changes.

Radioembolization of liver cancers using 90 Y-loaded microspheres is experiencing more widespread use. However, few data are available concerning the doses delivered to the tumors and the healthy liver. This retrospective study was conducted to calculate the tumor dosimetry (planned tumor dose [T plan D]) and nontumor dosimetry in patients treated by 90 Y-loaded glass microspheres and determine whether tumor dosimetry could predict response and survival. Methods: Thirty-six patients with hepatocellular carcinoma (HCC), including 16 with portal vein thrombosis (PVT), were treated with 90 Y-loaded glass microspheres. The T plan D and the dose delivered to the injected healthy liver were calculated using a quantitative analysis of the 99m Tc-macroaggregated albumin ( 99m Tc-MAA) SPECT/CT exam. Responses were assessed after 3 mo, using the criteria of the European Association for the Study of the Liver. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier tests. Results: The response rate was 69% for the overall population and 75% for the PVT patients. The dose delivered to the tumor was the only parameter associated with response with multivariate analysis (P 5 0.019). A threshold T plan D value of 205 Gy was predictive of response, with a sensitivity of 100% and an accuracy of 91%. Quantitative 99m Tc-MAA SPECT/CT allowed us to increase the injected activity for 4 patients with large lesions. PFS was only 5.2 mo and OS 9 mo when using a T plan D of less than 205 Gy versus 14 mo (P 5 0.0003) and 18 mo (P 5 0.0322), respectively, with a T plan D of 205 Gy or more. Conclusion: Quantitative 99m Tc-MAA SPECT/ CT is predictive of response, PFS, and OS. Dosimetry based on 99m Tc-MAA SPECT/CT can be used for the selection of patients and for an adaptation of treatment planning, especially in selected patients (particularly in the case of large tumors). These results also confirm the efficacy and safety of 90 Y-loaded microspheres in treating HCC, even in the presence of PVT (and especially when 99m Tc-MAA uptake is seen inside the PVT).

PurposeTo evaluate the impact of dosimetry based on MAA SPECT/CT for the prediction of response, toxicity and survival, and for treatment planning in patients with hepatocellular carcinoma (HCC) treated with 90Y-loaded glass microspheres (TheraSphere®).MethodsTheraSphere® was administered to 71 patients with inoperable HCC. MAA SPECT/CT quantitative analysis was used for the calculation of the tumour dose (TD), healthy injected liver dose (HILD), and total injected liver dose. Response was evaluated at 3 months using EASL criteria. Time to progression (TTP) and overall survival (OS) were evaluated using the Kaplan-Meier method. Factors potentially associated with liver toxicity were combined to construct a liver toxicity score (LTS).ResultsThe response rate was 78.8 %. Median TD were 342 Gy for responding lesions and 191 Gy for nonresponding lesions (p < 0.001). With a threshold TD of 205 Gy, MAA SPECT/CT predicted response with a sensitivity of 100 % and overall accuracy of 90 %. Based on TD and HILD, 17 patients underwent treatment intensification resulting in a good response rate (76.4 %), without increased grade III liver toxicity. The median TTP and OS were 5.5 months (2–9.5 months) and 11.5 months (2–31 months), respectively, in patients with TD <205 Gy and 13 months (10–16 months) and 23.2 months (17.5–28.5 months), respectively, in those with TD >205 Gy (p = 0.0015 and not significant). Among patients with portal vein thrombosis (PVT) (n = 33), the median TTP and OS were 4.5 months (2–7 months) and 5 months (2–8 months), respectively, in patients with TD <205 Gy and 10 months (6–15.2 months) and 21.5 months (12–28.5 months), respectively, in those with TD >205 Gy (p = 0.039 and 0.005). The median OS was 24.5 months (18–28.5 months) in PVT patients with TD >205 Gy and good PVT targeting on MAA SPECT/CT. The LTS was able to detect severe liver toxicity (n = 6) with a sensitivity of 83 % and overall accuracy of 97 %.ConclusionDosimetry based on MAA SPECT/CT was able to accurately predict response and survival in patients treated with glass microspheres. This method can be used to adapt the injected activity without increasing liver toxicity, thus defining a new concept of boosted selective internal radiation therapy (B-SIRT). This new concept and LTS enable fully personalized treatment planning with glass microspheres to be achieved.

The objective of this study was to evaluate the response rate and survival of hepatocellular carcinoma portal vein thrombosis (PVT) patients treated with 90 Y-loaded glass microspheres using a personalized dosimetry and intensification concept. Methods: The microspheres were administered to 41 hepatocellular carcinoma PVT patients (main 5 12; lobar/segmental 5 29). 99m Tc-macroaggregated albumin SPECT/CT quantitative analysis was used to calculate the tumor dose (TD), healthy injected liver dose (HILD), and injected liver dose (ILD). Response was evaluated at 3 mo using the criteria of the European Association for the Study of the Liver, with CT follow-up lasting until disease progression or death. Survival was assessed using the Kaplan-Meier method. Results: The mean injected activity was 3.1 ± 1.5 GBq, and mean ILD was 143 ± 49 Gy. When a TD threshold of 205 Gy was applied, 99m Tc-macroaggregated albumin SPECT/CT achieved a 100% sensitivity and 90% overall accuracy (0 false-negatives; 4 false-positives) in response prediction. On the basis of TD and HILD values, 37% of patients received an intensification of the treatment (increased injected activity with the aim of achieving a TD $ 205 Gy and HILD , 120 Gy, applying an ILD . 150 Gy). This intensification resulted in a high response rate (85%) without increased liver toxicity of grade 3 or higher (6% vs. 12% in the patients who did not receive treatment intensification; not statistically significant). For the total 41 patients, median overall survival (OS) was 18 mo (95% confidence interval, 11-25 mo). For patients with a TD of less than 205 Gy, median OS was 4.3 mo (3.7-5 mo), versus 18.2 mo (8.5-28.7 mo) for those with a TD of 205 Gy or more (P 5 0.005). Median OS was 20.9 mo for patients with a TD of 205 Gy or more and good PVT targeting (n 5 36). OS was 12 mo (3 mo to N) for patients with main PVT, versus 21.5 mo (12-28.7 mo) for those with segmental or lobar PVT (not statistically significant). For the 5 patients with complete portal vein revascularization who underwent lobar hepatectomy, median OS was not reached yet exceeded 24.5 mo and was significantly higher than that of other patients (P 5 0.0493). Conclusion: Using a 99m Tc-macroaggregated albumin SPECT/CT personalized dosimetry and intensification concept with 90 Y-loaded glass microspheres induced prolonged OS for PVT patients as compared with the standard of care (sorafenib), without increasing liver toxicity. Prospective randomized studies are therefore warranted.

Radioembolization with 90Y-loaded microspheres is increasingly used in the treatment of primary and secondary liver cancer. Technetium-99 m macroaggregated albumin (MAA) scintigraphy is used as a surrogate of microsphere distribution to assess lung or digestive shunting prior to therapy, based on tumoral targeting and dosimetry. To date, this has been the sole pre-therapeutic tool available for such evaluation. Several dosimetric approaches have been described using both glass and resin microspheres in hepatocellular carcinoma (HCC) and liver metastasis. Given that each product offers different specific activities and numbers of spheres injected, their radiobiological properties are believed to lightly differ. This paper summarizes and discusses the available studies focused on MAA-based dosimetry, particularly concentrating on potential confounding factors like clinical context, tumor size, cirrhosis, previous or concomitant therapy, and product used. In terms of the impact of tumoral dose in HCC, the results were concordant and a response relationship and tumoral threshold dose was clearly identified, especially in studies using glass microspheres. Tumoral dose has also been found to influence survival. The concept of treatment intensification has recently been introduced, yet despite several studies publishing interesting findings on the tumor dose-metastasis relationship, no consensus has been reached, and further clarification is thus required. Nor has the maximal tolerated dose to the liver been well documented, requiring more accurate evaluation. Lung dose was well described, despite recently identified factors influencing its evaluation, requiring further assessment. Conclusion: MAA SPECT/CT dosimetry is accurate in HCC and can now be used in order to achieve a fully customized approach, including treatment intensification. Yet further studies are warranted for the metastasis setting and evaluating the maximal tolerated liver dose.

Biphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor.

Background & AimsEfficacy of radioembolization is derived from radioinduced damage, whereas tumour dosimetry is not considered as yet in prospective clinical trials.ObjectivesThis study evaluates the impact of tumour dose (TD), based on 99mTc macroaggregated albumin (MAA) quantification, on response and overall survival (OS).Materials and MethodsWe consecutively included 85 patients with hepatocellular carcinoma treated with 90Y‐loaded glass microspheres. TD was calculated using a quantitative analysis of the MAA SPECT/CT. Responses were assessed after 3 months using the European Association for the Study of the Liver criteria. OS was assessed using Kaplan–Meier tests.ResultsResponse rate was 80.3% on lesion‐based analysis (n=132), and 77.5% on patient‐based analysis. The response rate was only 9.1% for patients with TD <205 Gy against 89.7% for those with TD ≥205 Gy (P<10−7). Non‐portal vein thrombosis (PVT) patients exhibited a median OS of 11.75 m (95% CI: 3–30.7 m) for TD <205 Gy, and 25 m (95% CI: 15–34.7 m) for TD ≥205 Gy (P=.0391). PVT patients exhibited a 4.35 m median OS (95% CI: 2–8 m) for TD<205 Gy, and 15.7 m (95% CI: 9.5–25.5 m) for TD ≥205 Gy, (P=.0004), with HR of 6.99. PVT patients exhibited a median OS of 3.6 m (95% CI: 2–8 m) when PVT MAA targeting was poor or with TD <205 Gy (poor candidate), vs 17.5 m (95% CI: 11–26.5 m) for the others identified as good candidates (P<.0001), with HR of 12.85.ConclusionThis study confirms the highly predictive value of MAA‐based TD evaluation for response and OS. TD evaluation and PVT MAA targeting should be further evaluated in ongoing trials, whereas personalized dosimetry should be implemented in new trial designs.