BackgroundAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has shown remarkable results in malignant melanoma (MM), while studies on the potential in other cancer diagnoses are sparse. Further, the prospect of using checkpoint inhibitors (CPIs) to support TIL production and therapy remains to be explored.Study designTIL-based ACT with CPIs was evaluated in a clinical phase I/II trial. Ipilimumab (3 mg/kg) was administered prior to tumor resection and nivolumab (3 mg/kg, every 2 weeks ×4) in relation to TIL infusion. Preconditioning chemotherapy was given before TIL infusion and followed by low-dose (2 10e6 international units (UI) ×1 subcutaneous for 14 days) interleukin-2 stimulation.ResultsTwenty-five patients covering 10 different cancer diagnoses were treated with in vitro expanded TILs. Expansion of TILs was successful in 97% of recruited patients. Five patients had sizeable tumor regressions of 30%–63%, including two confirmed partial responses in patients with head-and-neck cancer and cholangiocarcinoma. Safety and feasibility were comparable to MM trials of ACT with the addition of expected CPI toxicity. In an exploratory analysis, tumor mutational burden and expression of the alpha-integrin CD103 (p=0.025) were associated with increased disease control. In vitro tumor reactivity was seen in both patients with an objective response and was associated with regressions in tumor size (p=0.028).ConclusionHigh success rates of TIL expansion were demonstrated across multiple solid cancers. TIL ACTs were found feasible, independent of previous therapy. Tumor regressions after ACT combined with CPIs were demonstrated in several cancer types supported by in vitro antitumor reactivity of the TILs.Trial registration numbersNCT03296137, and EudraCT No. 2017-002323-25.

To validate micro-lightguide spectrophotometry (O2C) in patients with lower limb ischemia and to compare results with those obtained from toe blood pressure. Methods: We prospectively examined 59 patients, 24 of whom complained of claudication, 31 had critical ischemia, and four were asymptomatic. Diabetes was present in 19 (32%) patients. Saturation (SO 2) and flow measured with O2C were determined with the limb in the horizontal position followed by a 55-cm elevation. Toe pressures were determined in the horizontal position only. In addition, 13 patients were examined before and, on average, 3 days after revascularization. Results: Median SO 2 was 62% (25%-75% percentile: 37%-75%) with the limb in the horizontal position and 16% (3%-41%) with the limb elevated. Comparing the individual toe pressures with SO 2 values measured in the horizontal position and elevated position revealed a significant correlation (r s ‫؍‬ 0.40; P < .01 and r s ‫؍‬ 0.56; P < .01, respectively). A low SO 2 (ie, <40% in the horizontal position and <20% in the elevated position) was highly predictive of a toe pressure of 40 mm Hg or less. In the horizontal position, the positive predictive value was 100%, whereas the negative predictive value was 47%. The similar figures in the elevated position were a positive predictive value of 97% and a negative predictive value of 68%. Postoperatively, SO 2 increased significantly from 27% (P25%-75%: 11%-75%) to 79% (68%-87%) in the horizontal position (P ‫؍‬ .008) and from 14% (P25%-75%: 2%-39%) to 55% (30%-73%) in the elevated position (P ‫؍‬ .011), respectively. Looking at the individual 13 cases in which revascularization was performed, three patients had a partial reconstruction (ie, superficial femoral artery occlusion distal to a central reconstruction or reconstruction to a popliteal blind segment). These patients had significantly lower postoperative SO 2 as well as toe pressure compared with the 10 patients with unobstructed flow to the foot. Conclusions: O2C was easy to use, fast, and painless. The most useful finding was the high predictive value of a low saturation and the rise in O2C values after successful revascularization.

Background and objectives. In fresh blood, tissue hypoxia increases microcirculatory acidosis, which enhances erythrocyte O2 unloading and increases the amount of available O2. Storage of eryfhrocytes increases the HbO2 affinity and reduces O2 unloading. We examined the development of the affinity change during a period of 5 weeks of storage by present blood bank standards, and investigated to what extent acidosis offsets the affinity change. Materials and methods. Blood from volunteer donors was processed and stored as erythrocyte concentrates (EC). At 2–5 day intervals, EC were drawn from the bags and suspended in plasma and crystalloids to an Hb ≈ 10 g/dL. The suspensions were adjusted to give a pH of 7.40, 7.10, 6.80 or 6.30 and equilibrated with different gas mixtures to SO2 0, 25, 50, 75 and 100%. Measurements of the PO2/SO2 pairs at each pH were used to calculate the position of the HbO2 curve and its P50 value. Results. A significant leftward shift in the HbO2 curve was established after 1 week of storage; after 2.5 weeks only minor further changes were observed. Acidification right-shifted the HbO2 curve, after 2.5 weeks of storage the curve at pH 7.10 was similar to that for fresh blood at pH 7.40. Calculations of extractable O2 showed that the left-shifted HbO2 curve of stored EC could be advantageous at a low arterial PO2. Conclusions. The rightward shift of the HbO2 curve due to acidosis is well maintained in stored eryfhrocytes, a moderate pH decrease offsets the storage-induced increased HbO2 affinity.

Background Exercise walking has improved walking capacity in patients with intermittent claudication without affecting the macrocirculation reflected in ankle pressures. We wanted to investigate microcirculation in the skin related to exercise walking by using Micro-Lightguide Spectrophotometry (O2C). Materials and Methods Twenty-eight patients with intermittent claudication—bilateral in 17—were included in a 12 weeks of structured home-based exercise program. The pain-free and maximal walking distances were determined on a treadmill. Saturation and flow, monitored by O2C, were examined immediately before and after the treadmill test. O2C examination took place before as well as after completion of the exercise program. Ankle–brachial index was obtained before treadmill testing. Results As expected, walking performance improved significantly without affecting ankle pressures. Neither oxygen saturation nor flow, assessed at 2 mm depth, was affected following a 12 weeks of exercise program. We observed a significant decrease in oxygen saturation and flow upon treadmill testing in the both limbs in patients with bilateral peripheral arterial disease (PAD). In contrast, the treadmill test elicited no changes in the opposite and asymptomatic limb in patients with only unilateral PAD. Conclusion The findings suggest that O2C may be used to study microcirculatory changes. However, it is best suited for the study of phenomena resulting in major changes as it eliminates some inherent variability.