Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.

Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.

Background The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. Methods We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient’s age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. Results The median age in the sample of 7487 consecutive patients was 84 years (IQR 81–87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). Conclusion Knowledge about a patient’s frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Objective— To investigate the prevalence of sinusoidal and pseudo‐sinusoidal fetal heart rate (FHR) patterns in labour and the relation between the characteristics of the FHR pattern and fetal outcome. Design— A prospective observational study over a 6 month period in which all women who had continuous FHR monitoring in labour had their intrapartum cardiotocographs (CTGs) scrutinized for the presence of sinusoidal or pseudosinusoidal FHR patterns. Setting— John Radcliffe Hospital, Oxford. Subjects— 1520 women who had fetal monitoring during labour for various reasons. Main outcome measures— Both internal (electrocardiographic) and external (ultrasound) recordings of the FHR were analysed. Abnormal FHR patterns were related to obstetric characteristics and fetal outcome in terms of Apgar scores, umbilical artery pH and admission to the special care unit. Results— No true sinusoidal FHR patterns were observed, but pseudoinusoidal FHR patterns were found in 230 of the 1520 CTGs examined (15%) Of these, 219 were classified as minor (amplitude 5–15 beatdmin) and 11 as intermediate (amplitude 16–24 beatdmin). Major pseudo‐sinusoidal FHR pat‐terns (amplitude >24 beats/min) were not observed. Minor pseudo‐sinusoidal FHR patterns had a mean duration of 21 (SD 13) min and typically occurred once or twice early in labour. Using logistic regression analysis a significant, independent relation was demonstrated between the presence of minor pseudo‐sinusoidal FHR patterns and the use of pethidine (RR 1.84,95% CI 1.3 to 2.59, P < 0.0001) and epidural analgesia (RR 1.85,95% CI 1.24 to 2.76, P < 0.001). Intermediate pseudo‐sinusoidal FHR patterns were found in association with both in utero fetal sucking and transient episodes of fetal hypoxia such as that caused by periodic umbilical cord compression. Conclusion— Pseudo‐sinusoidal FHR patterns in labour will usually be associated with a normal fetal outcome but a careful fetal assessment is mandatory.

Objective--To investigate the prevalence of sinusoidal and pseudo-sinusoidal fetal heart rate (FHR) patterns in labour and the relation between the characteristics of the FHR pattern and fetal outcome. Design-A prospective observational study over a &month period in which all women who had continuous FHR monitoring in labour had their intrapartum cardiotocographs (CTGs) scrutinized for the presence of sinusoidal or pseudosinusoidal FHR patterns. Setting-John Radcliffe Hospital, Oxford. Subjects-1520 women who had fetal monitoring during labour for various reasons, Main outcome measures-Both internal (electrocardiographic) and external (ultrasound) recordings of the FHR were analysed. Abnormal FHR patterns were related to obstetric characteristics and fetal outcome in terms of Apgar scores, umbilical artery pH and admission to the special care unit. Results-No true sinusoidal FHR patterns were observed, but pseudosinusoidal FHR patterns were found in 230 of the 1520 CTGs examined (15%). Of these, 219 were classified as minor (amplitude 5-15 beatdmin) and 11 as intermediate (amplitude 16-24 beatdmin). Major pseudo-sinusoidal FHR patterns (amplitude >24 beatdmin) were not observed. Minor pseudo-sinusoidal FHR patterns had a mean duration of 21 (SD 13) min and typically occurred once or twice early in labour. Using logistic regression analysis a significant, independent relation was demonstrated between the presence of minor pseudosinusoidal FHR patterns and the use of pethidine (RR 1-84,95% CI 1.3 to 2.59, P