Hyperprogressive Disease (HPD) in Solid Tumours Receiving Immune Checkpoint Inhibitors in a Real-World Setting.

Introduction: Hyperprogressive disease (HPD) is a state of accelerated tumor growth from cancer immunotherapy, associated with poor outcome. The reported incidence is 6% to 29% among studies using varying definitions of HPD, with no predictive biomarkers. Tumor infiltrating lymphocytes (TILs) are prognostic and predictive for immunotherapy benefit in various tumor types, but have only been tested for correlation with HPD in one study. Objectives: The objective of the study was to determine the prevalence of HPD in solid tumor patients treated with immune checkpoint inhibitor therapy in a real-world setting, and to assess clinicopathological features as potential biomarkers for HPD. Methods: We conducted a retrospective analysis of solid tumor patients treated with immune checkpoint inhibitors at a single institution. Imaging pre-immunotherapy and postimmunotherapy were assessed for HPD, and correlated against clinicopathological factors, including TILs and programmed death-ligand 1 (PD-L1) status through archival tumor assessment. HPD was defined per Matos et al as response evaluation criteria in solid tumors (RECIST) progressive disease, minimum increase in measurable lesions of 10 mm, plus increase of ≥40% in sum of target lesions compared with baseline and/or increase of ≥20% in sum of target lesions compared with baseline plus new lesions in at least 2 different organs. Results: HPD occurred in 11 of 87 patients (13%), and associated with inferior overall survival (median 5.5 months vs 18.3 months, P = .002). However, on multivariate analysis, only liver metastases (hazard ratio [HR] 4.66, 95% confidence interval [CI] 2.27-9.56, P < .001) and PD-L1 status (HR 0.53, 95% CI 0.30-0.95, P = .03) were significantly associated with survival. Presence of liver metastases correlated with occurence of HPD (P = .01). Age, sex, and monotherapy versus combination immunotherapy were not predictive for HPD. PD-L1 status and TILs were not associated with HPD. Conclusions: We found 13% HPD among solid tumor patients treated with immunotherapy, consistent with the range reported in prior series. Assessment for HPD is feasible outside of a clinical trials setting, using modified criteria that require comparison of 2 imaging studies. Liver metastases were associated with risk of HPD, while TILs and PD-L1 status were not predictive for HPD.

Artefacts in geometric phase analysis of compound materials.

The geometric phase analysis (GPA) algorithm is known as a robust and straightforward technique that can be used to measure lattice strains in high resolution transmission electron microscope (TEM) images. It is also attractive for analysis of aberration-corrected scanning TEM (ac-STEM) images that resolve every atom column, since it uses Fourier transforms and does not require real-space peak detection and assignment to appropriate sublattices. Here it is demonstrated that, in ac-STEM images of compound materials with compositionally distinct atom columns, an additional geometric phase is present in the Fourier transform. If the structure changes from one area to another in the image (e.g. across an interface), the change in this additional phase will appear as a strain in conventional GPA, even if there is no lattice strain. Strategies to avoid this pitfall are outlined.

Electrolytic echo enhancement: a novel method to make needles more reflective to ultrasound.

INTRODUCTION: This study examines the effect of augmenting the ultrasound reflectivity of needles using a novel electrolytic echo enhancement method. METHODS: Needles were connected by a lead to the negative terminal of a 4.5 V direct current source. A grounding pad, connected to the positive terminal, was positioned on the undersurface of an ex vivo ox liver phantom. During needle insertion into the liver, electrolysis was induced creating a layer of gas on the needle electrode. RESULTS: Analysis of images showed a significant increase in needle brightness using electrolytic echo enhancement. Brightness was found to increase by a factor of ×3.6 compared with controls (P < 0.001). CONCLUSION: Electrolytic echo enhancement has the potential to make ultrasound-guided procedures safer and quicker for patients and increase the confidence of operators in their ability to see the whole needle including its tip.

Spectroscopic study of transparency current in mid-infrared quantum cascade lasers.

We report measurements which give direct insight into the origins of the transparency current for λ ~5 µm In0.6Ga0.4As/In0.42Al0.58As quantum cascade lasers in the temperature range of 80-280 K. The transparency current values have been found from broadband transmission measurements through the laser waveguides under sub-threshold operating conditions. Two active region designs were compared. The active region of the first laser is based on double-LO-phonon relaxation approach, while the second device has only one lower level, without specially designed resonant LO-phonon assisted depopulation. It is shown that transparency current contributes more than 70% to the magnitude of threshold current at high temperatures for both designs.

Intersubband gain-induced dispersion.

Time-resolved transmission spectroscopy of a mid-infrared quantum cascade laser emitting at 11.7 mum allows us to iteratively retrieve the effective refractive index and the extinction coefficient of the gain medium in a broad spectral range with an accuracy of +/-7x10(-3). Besides a 3% slowdown of the group velocity we find a large induced group-velocity dispersion with changing signs in the vicinity of the gain maximum, disclosing implications for self-pulse formation in quantum-cascade lasers. Additionally we measured the temperature in the active region by exploiting the thermo-optic effect. A linear behavior with respect to the current and the duty cycle was observed.

Vulval low-flow arteriovenous malformation.

This case report refers to a 26-year-old woman who attended a gynaecological clinic with a painful vulval swelling. She underwent surgical excision, was found to have a rare vulval low-flow arteriovenous malformation and was treated with embolisation therapy.

Bimodal electric tissue ablation: positive electrode studies.

BACKGROUND: Bimodal electric tissue ablation is a novel variation to standard radiofrequency ablation that produces significantly larger ablations by the addition of a direct electrical current. The negative electrode is attached to the radiofrequency current and the positive electrode is placed nearby. It has been identified that an electrolytic injury can occur at the positive electrode site. It is suggested that by increasing the surface area that is in contact with the positive electrode, the risk of tissue injury is reduced. This hypothesis was tested in a pig model. METHODS: Thirty-six ablations were carried out in the livers of six pigs (six ablations per pig). Two were standard radiofrequency ablation controls and two were carried out with positive electrode attached to a scalpel blade. Two were carried out with positive electrode attached to a grounding pad. After 48 h, liver was harvested and the ablation sizes were compared. Skin biopsies were taken from the scalpel site and one from the pad site and examined histopathologically. RESULTS: The scalpel blade ablations were significantly larger than controls and the grounding pad ablations (P < 0.001). The grounding pad ablation was significantly larger than controls. The scalpel blade skin site showed full-thickness tissue injury. The grounding pad site appeared microscopically normal. CONCLUSION: By increasing the surface area that connects to the positive electrode, significantly larger ablations can be carried out while minimizing the risk of associated tissue injury.

Training on a vascular interventional simulator: an observational study.

Radiology registrars were observed performing a left renal artery angioplasty using a proprietary training simulator up to five times during their first year of training. Total procedure time, fluoroscopy times, and metric information from the machine were recorded. Each step of the procedure was judged by an observer and a mistake profile was generated. Fifty-two runs were completed by 12 trainees. The mean procedure time decreased from 16.6 min to 9.8 min over the five runs. The number of mistakes ranged from zero to ten and the mean number of mistakes made varied from 0.7 to 2.6 per procedure without any particular trend. Our study demonstrates that training on the simulator does improve performance. The mistakes made throughout training indicates the potential benefit from further simulator training. It remains unclear how to integrate this form of training in current educational programs.

Bimodal electric tissue ablation-long term studies of morbidity and pathological change.

BACKGROUND: Radiofrequency ablation is a popular method of treating unresectable liver tumors but tumors greater than 3 cm in diameter have a much greater risk of local recurrence after treatment. Bimodal electric tissue ablation is a modified form of radiofrequency ablation that creates significantly larger ablations by the addition of extra direct current circuitry. This may help to reduce the risk of local recurrence in these larger tumors. Prior to use in a clinical setting, a long term study was performed to assess associated morbidity and the pathological changes in the ablations. METHODS: In eight pigs, six ablations were performed in each liver. Pigs were euthanized at 2 d, 2 wk, 2 mo, and 4 mo, and the ablations were assessed macroscopically and microscopically for pathological change. Regular blood tests were performed to assess changes in liver function. At death, any other abnormalities detected were reported. RESULTS: Histopathological examination of ablation zones revealed tissue death by coagulative necrosis and healing by fibrotic scarring. Transient rises in serum liver enzymes were seen in the postoperative period. Skin necrosis was noted at the site of the positive electrode of the direct electrical current but no other form of morbidity was seen associated with the procedure. CONCLUSIONS: Although the positive electrode placement requires further consideration, bimodal electric tissue ablation appears to be safe and behaves in a similar fashion to other thermal therapies such as standard radiofrequency ablation.

Bimodal electric tissue ablation-modified radiofrequency ablation with a le veen electrode in a pig model.

Radiofrequency ablation (RFA) is a method of treating non-resectable liver tumors by use of a high-frequency alternating electrical current. Concerns have been raised as the local recurrence rates following treatment have been reported to be as high as 47%. The size of the ablation is limited by charring of adjacent tissues. It is hypothesized that by hydrating the liver, we can reduce charring, thus producing larger ablations, and that this can be achieved by addition of a direct electrical current to the electrical circuit. Using a pig model, standard RFA control ablations were created in the left lobe of the liver. Ablations using the modified circuit were created in the right lobe. At the end of the procedure, the pig was killed by lethal injection and the liver harvested. From the explanted liver, the diameter of each ablation was measured and the modified ablations were compared with controls using restricted maximum likelihood variance analysis. From 4 pigs, 14 controls and 12 modified ablations were produced. The mean diameter of the controls was 27.78 mm (+/- SE 3.37 mm). The mean diameter of the modified ablation was 49.55 mm (+/- SE 3.46 mm), which was significantly larger than the controls (P < 0.001). This study has shown that by modification of the standard RFA circuit with the addition of a direct electrical current, significantly larger ablations can be produced. By using this technique, the number of ablations required to treat one tumor would be less and it is anticipated this could reduce the rate of local recurrence.

Mid-infrared optical coherence tomography.

A time domain optical coherence tomography (OCT) system is described that uses mid-infrared light (6-8 microm). To the best of our knowledge, this is the first OCT system that operates in the mid-infrared spectral region. It has been designed to characterize bioengineered tissues in terms of their structure and biochemical composition. The system is based upon a free-space Michelson interferometer with a germanium beam splitter and a liquid nitrogen cooled HgCdTe detector. A key component of this work has been the development of a broadband quantum cascade laser source (InGaAs/AlInAs containing 11 different active regions of the three well vertical transition type) that emits continuously over the 6-8 microm wavelength range. This wavelength range corresponds to the so called "mid-infrared fingerprint region" which exhibits well-defined absorption bands that are specifically attributable to the absorbing molecules. Therefore, this technology provides an opportunity for optical coherence molecular imaging without the need for molecular contrast agents. Preliminary measurements are presented.