Patients with melanoma of unknown primary show better outcome under immune checkpoint inhibitor therapy than patients with known primary: preliminary results.

Background: Melanoma of unknown primary (MUP) is an uncommon clinical subtype of melanoma of known primary (MKP). Objectives: We aimed to compare treatment outcomes of MUP and MKP patients who had undergone therapy with immune checkpoint inhibitors (ICPI). Methods: We studied 41 metastatic melanoma patients (32 with MKP and 9 with MUP) with an indication for ICPI. Results: Clinical characteristics such as age, gender, stage of disease, etc., did not significantly differ (P < .05) between MUP and MKP patients. 20/32 (62.5%) melanoma-specific deaths (MSD) were observed in the MKP group, whereas 2/9 (22.2%) were detected in the MUP group (P = .035). On logistic regression, the MUP status proved to be an independent predictor for a more favorable outcome under immunotherapy when compared to MKP (P = .030). Conclusion: Our preliminary results indicate that MUP patients show better clinical outcome under ICPI when compared to MKP.

A Brief Communication on Circulating PD-1-positive T-Regulatory Lymphocytes in Melanoma Patients Undergoing Adjuvant Immunotherapy With Nivolumab.

Upregulation of T-regulatory lymphocytes (Tregs) is one of numerous immune escape mechanisms of malignancies. In the present pilot study we aimed to study the effect of adjuvant nivolumab during the initiation of treatment on circulating Tregs subpopulations in patients with stage III melanoma. We subsequently recruited patients with stage III melanoma who had the indication for adjuvant anti-programmed death 1 (PD-1) treatment with nivolumab. Blood collections were performed before the initiation of nivolumab and before every 2-week therapy cycle. Flow cytometry was performed for the determination of circulating CD4CD25highCD127PD-1(PD-1Tregs) and CD4CD25highCD127CTLA-4 (CTLA-4Tregs) Treg populations. Circulating PD-1Tregs [18.1% (range, 2.9%-41.7%) vs. 4.2% (0.4%-9.8%), P=0.0001] significantly decreased after the first cycle of immunotherapy and maintained decreased during a 3-month course of treatment. By contrast, CTLA-4Tregs significantly increased after the first nivolumab dose when compared with CTLA-4Tregs before the second treatment [0.75 (0-45.5) vs. 2.1 (0.1-90.8), P=0.0002]. Blood levels of PD-1Tregs and CTLA-4Tregs remained more or less decreased and increased during a 3-month therapy with nivolumab, respectively. Data of PD-1Tregs as well as CTLA-4Tregs was not significantly associated with frequencies of immune-related adverse events (P<0.05). In conclusion, we have demonstrated that circulating PD-1Tregs of melanoma patients in stage III rapidly and continuously decline after the initiation of adjuvant treatment with the PD-1 blocking antibody nivolumab. By contrast, this decline is paralleled with an increase of CTLA-4Tregs. The expression of PD-1 and CTLA-4 on Tregs might be a potential biomarker for the efficacy of immune checkpoint blockade in melanoma.

Visual function and reading speed after bilateral implantation of 2 types of diffractive multifocal intraocular lenses: Add-on versus capsular bag design.

PURPOSE: To compare the functional outcomes of primary implantation of a monofocal intraocular lens (IOL) in the capsular bag and an add-on multifocal IOL in the sulcus with the functional results of a conventional multifocal posterior chamber IOL and to evaluate the multifocal add-on IOL as an effective alternative to a conventional multifocal IOL. SETTING: Ernst von Bergmann Eye Clinic, Potsdam, Germany. DESIGN: Prospective nonrandomized case series. METHODS: Cataract surgery patients were assigned to have bilateral implantation of a monofocal IOL (Aspira-aAY) in the capsular bag followed by a multifocal add-on IOL (Diff-sPB) in the sulcus (Group A) or with a conventional multifocal IOL (Diffractiva-s) in the capsular bag (Group B). The main study outcomes were assessed at the last follow-up visit (6 months postoperatively) and included refraction, intraocular pressure, visual acuity, reading speed, contrast sensitivity, defocus curve, and patient satisfaction. RESULTS: The study comprised 26 patients (52 eyes) Cataract surgery was uneventful in all cases. No severe complications were observed 6 months postoperatively. Visual performance with a multifocal diffractive add-on IOL was equivalent to that achieved with a conventional multifocal diffractive posterior chamber IOL. Similarly, there were no significant differences in patient satisfaction and reading speed for any type of letter size between groups (P > .05). CONCLUSION: Implanting a multifocal add-on IOL in the sulcus in addition to a monofocal IOL in the capsular bag produced outcomes similar to those of single implantation of a standard multifocal IOL in the capsular bag. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

The morphology, physiology and function of suboesophageal neck motor neurons in the honeybee.

We report some of the neural and muscular circuitry that allows honeybees to control head movements. We studied neck motor neurons with cell bodies in the suboesophageal ganglion, axons in the first cervical nerve (IK1) and terminals in neck muscles 44 and 51 (muscle classification: Snodgrass in Smithsonian Misc Coll 103:1-120, 1942). We show that muscle 44 actually comprises five separate bundles of muscle fibres (subunits), while muscle 51 is split into two subunits. Eight motor neurons innervate muscles 44 and 51. Two motor neurons have cell bodies in the ventral-median cell body group (one innervates a subunit in muscle 44, the other a subunit in muscle 51). One motor neuron has a ventrally located contralateral cell body (innervating a subunit in muscle 44) and five have laterally located ipsilateral cell bodies. Of the five lateral cells, one innervates a subunit in muscle 51, three selectively innervate subunits in muscle 44 and one co-innervates a subunit in muscle 44 with the contralateral cell. Extracellular recordings revealed three types of visually driven, direction-selective cell-types in each IK1 tuned for leftward, rightward and downward motion over the eyes. The spatiotemporal tuning of the units is similar to that of other visual interneurons in the bee brain.

Innervation pattern of suboesophageal ventral unpaired median neurones in the honeybee brain.

In honeybees (Apis mellifera), the biogenic amine octopamine has been shown to play a role in associative and non-associative learning and in the division of labour in the hive. Immunohistochemical studies indicate that the ventral unpaired median (VUM) neurones in the suboesophageal ganglion (SOG) are putatively octopaminergic and therefore might be involved in the octopaminergic modulation of behaviour. In contrast to our knowledge about the behavioural effects of octopamine, only one neurone (VUMmx1) has been related to a behavioural effect (the reward function during olfactory learning). In this study, we have investigated suboesophageal VUM neurones with fluorescent dye-tracing techniques and intracellular recordings combined with intracellular staining. Ten different VUM neurones have been found including six VUM neurones innervating neuropile regions of the brain and the SOG exclusively (central VUM neurones) and four VUM neurones with axons in peripheral nerves (peripheral VUM neurones). The central VUM neurones innervate the antennal lobes, the protocerebral lobes (including the lateral horn) and the mushroom body calyces. Of these, a novel mandibular VUM neurone, VUMmd1, exhibits the same branching pattern in the brain as VUMmx1 and responds to sucrose and odours in a similar way. The peripheral VUM neurones innervate the antennal and the mandibular nerves. In addition, we describe one labial unpaired median neurone with a dorsal cell body, DUMlb1. The possible homology between the honeybee VUM neurones and the unpaired median neurones in other insects is discussed.

A new ascending sensory tract to the calyces of the honeybee mushroom body, the subesophageal-calycal tract.

The mushroom bodies of the honeybee are important neuropils for learning and memory. Therefore, knowledge about their input and output connections is essential to understanding how these neuropils function. A newly described input tract to the mushroom body is presented here, which is called the subesophageal-calycal tract (SCT) and connects the subesophageal ganglion with the calyces of the mushroom bodies. The neuronal somata of the SCT neurons lie in one cluster between the lobula of the optic lobe and a neuropil area that is formed from the fusion of the tritocerebrum and the subesophageal ganglion. Within the subesophageal ganglion, the dendritic fibers of SCT neurons overlap with terminals of sensory neurons from the proboscis. Therefore, we conclude that the SCT neurons might process gustatory and mechanosensory information from the proboscis. Individual SCT neurons receive unilateral input within the subesophageal ganglion and may connect to either the ipsilateral or the contralateral mushroom body. On their way to the mushroom bodies, the SCT neuron axons meet the roots of the antennocerebralis tracts (ACTs) and from this point follow the same path as the median ACT neurons for a short distance. Within the calyces, the SCT neurons innervate two separate areas, a small area within the dorsal collar just below the lip and a part of the basal ring. Double-labeling experiments show that the projections of the SCT neurons do not overlap with the projections of the olfactory projection neurons and visual projection neurons from the dorsal medulla. The possible function of the SCT neurons and the relation of the SCT to known input tracts of the mushroom bodies in other insects are discussed.