"One more chance to survive": the experiences of patients with advanced melanoma and their partners with tumor-infiltrating lymphocyte therapy-a qualitative study and recommendations for future care.

PURPOSE: Patients with advanced melanoma refractory to first-line treatment have a need for effective second-line treatment options. A recent phase 3 trial showed promising results for adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) as second-line therapy in patients with advanced melanoma. However, it remains unknown how patients and their partners experience TIL therapy, which is key to evaluate and improve the quality of care. METHODS: Semi-structured interviews about the experience of TIL therapy were conducted with patients with advanced melanoma and their partners 2-4 weeks post-treatment (short term) and >6 months after treatment (long term). RESULTS: In total, 25 interviews were conducted with advanced melanoma patients treated with TIL (n=13) and their partners (n=12), with the majority being short-term interviews (n=17). Overall, patients and partners experienced TIL therapy as intense (uncertainty of successful TIL culture, multiple treatment-related toxicities, and extensive hospitalization). Patients and partners with young children or other caregiving responsibilities encountered the most challenges during TIL therapy. All patients, however, reported a recovery of all treatment-related toxicities within 2-4 weeks (except fatigue). CONCLUSION: Clinical data justify the role of TIL therapy in the treatment of advanced melanoma. With the distinct nature of TIL therapy compared to the current standard of care, we have provided patient-centered recommendations that will further enhance the quality of TIL therapy. IMPLICATIONS FOR CANCER SURVIVORS: As more patients with advanced melanoma are expected to receive TIL therapy in the future, our findings could be incorporated into survivorship care plans for this novel group of advanced melanoma survivors treated with TIL.

Fluorescent Dye Paper-Based Method for Assessment of Pesticide Coverage on Leaves and Trees: A Citrus Grove Case Study.

Crop disease management depends on efficient and adequate pesticide distribution to reduce pest population. Instrument-based methods to evaluate the spatial distribution of pesticides are available, but they are not field-compatible because of instrument size, cost, and extensive sample preparation. The current gold standard of water-sensitive papers is field-compatible; however, these papers often produce false positives due to reaction with water from sources other than the pesticide mixture. Thus, we developed a novel method in which a fluorescent dye is sprayed over a crop with circles of filter paper (samplers) attached to the leaves. After collection, a lightbox is used to take pictures of the samplers, and an algorithm analyzes each image for percent coverage to visualize the pesticide distribution within the crop. Our method produces results quickly and inexpensively compared to current methods and can be applied to any crop to inform best pesticide application strategies.

T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression.

Background: Almost half of the patients with metastatic melanoma obtain only short-term or no benefit at all from checkpoint inhibitor (CPI) immunotherapy. In this study, we investigated whether the immune system of patients progressing following CPI treatment was able to generate functional tumor-specific immune responses. Materials and methods: Tumor-infiltrating lymphocytes (TILs) were isolated and expanded from metastatic melanoma lesions which progressed during or after anti-programmed cell death protein 1 (PD)-1 and anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) treatment. Tumor-specific immune responses were assessed with co-culture assays of TILs and autologous tumor cells. Results: TILs from 23 metastases of individual patients could be assessed for T cells recognition of autologous tumor cells. All metastases were progressive on or following anti-PD-1 (23/23, 100%), and the majority also after anti-CTLA-4 (17/23, 74%). Functional antitumor immune responses were detected in 19/23 patients (83%). Both CD8+ (in 18/23 patients, 78%) and CD4+ (in 16/23 patients, 70%) TILs were able to recognize autologous tumors. A large fraction of CD8+ TILs (median 23%, range 1.0%-84%) recognized tumor cells. This is similar to the cohorts of unselected patient populations with metastatic melanoma presented in previous studies. The localization of intratumoral immune infiltrates was heterogeneous among samples. In a phase I/II clinical trial, TILs were administered with lymphodepleting chemotherapy, pegIFNα2b and interleukin-2 to 12 patients with CPI-resistant melanoma. Out of 12 patients who previously failed CPI therapy, treatment with TILs resulted in two partial responses, of which one is ongoing. Conclusions: Tumor-reactive T cells appear to heavily infiltrate the tumor microenvironment of patients who failed previous CPI treatment. These patients can still respond to an infusion of unselected autologous TILs. Our results warrant further testing of novel immune re-activation strategies in melanoma patients who failed multiple CPI therapy.

Microbial acceleration of aerobic pyrite oxidation at circumneutral pH.

Pyrite (FeS2 ) is the most abundant sulfide mineral on Earth and represents a significant reservoir of reduced iron and sulfur both today and in the geologic past. In modern environments, oxidative transformations of pyrite and other metal sulfides play a key role in terrestrial element partitioning with broad impacts to contaminant mobility and the formation of acid mine drainage systems. Although the role of aerobic micro-organisms in pyrite oxidation under acidic-pH conditions is well known, to date there is very little known about the capacity for aerobic micro-organisms to oxidize pyrite at circumneutral pH. Here, we describe two enrichment cultures, obtained from pyrite-bearing subsurface sediments, that were capable of sustained cell growth linked to pyrite oxidation and sulfate generation at neutral pH. The cultures were dominated by two Rhizobiales species (Bradyrhizobium sp. and Mesorhizobium sp.) and a Ralstonia species. Shotgun metagenomic sequencing and genome reconstruction indicated the presence of Fe and S oxidation pathways in these organisms, and the presence of a complete Calvin-Benson-Bassham CO2 fixation system in the Bradyrhizobium sp. Oxidation of pyrite resulted in thin (30-50 nm) coatings of amorphous Fe(III) oxide on the pyrite surface, with no other secondary Fe or S phases detected by electron microscopy or X-ray absorption spectroscopy. Rates of microbial pyrite oxidation were approximately one order of magnitude higher than abiotic rates. These results demonstrate the ability of aerobic microbial activity to accelerate pyrite oxidation and expand the potential contribution of micro-organisms to continental sulfide mineral weathering around the time of the Great Oxidation Event to include neutral-pH environments. In addition, our findings have direct implications for the geochemistry of modern sedimentary environments, including stimulation of the early stages of acid mine drainage formation and mobilization of pyrite-associated metals.

Long-term potential of in situ chemical reduction for treatment of polychlorinated biphenyls in soils.

Polychlorinated biphenyls (PCBs) are well-known for being hydrophobic and persistent in the environment. Although many treatment approaches have been demonstrated to result in degradation of PCBs in water or water/cosolvent systems, few examples exist where such approaches have been applied successfully for PCB degradation in soil-water systems. A possible explanation for the limited treatment of PCBs in soil-water systems is that reactants that are capable of degrading PCBs in the aqueous phase are unlikely to persist long enough to achieve meaningful treatment of slowly-desorbing PCBs associated with the soil phase. To investigate this explanation, laboratory studies were conducted to evaluate chemical reductants, including zero valent metals, palladium (Pd) catalyst, and emulsified zero valent iron (EZVI), for dechlorination of PCBs in the presence and absence of soil. In the absence of soil, Pd-catalyzed treatments (Pd with electrolytic ZVI or iron/aluminum alloy) achieved rapid destruction of a model PCB congener, 2-chlorobiphenyl, with half-lives ranging from 43 to 110 min. For treatment of soils containing Aroclor 1248 at an initial concentration of approximately 1,500 mg kg(-1), Pd-catalyzed treatments achieved no measurable enhancement over the background PCB depletion rate (i.e., that measured in the untreated control) of 5.3 mg kg(-1)week(-1). In the presence of soils, EZVI was the only approach evaluated that resulted in a clear enhancement in PCB dechlorination rates. EZVI achieved PCB concentration reductions of greater than 50% at an average rate of 19 mg kg(-1)week(-1). The results suggest that slow PCB desorption limits treatment effectiveness in soils.

In vitro cytokine responses to periodontal pathogens: generalized aggressive periodontitis is associated with increased IL-6 response to Porphyromonas gingivalis.

Generalized aggressive periodontitis (GAgP) is an inflammatory condition resulting in destruction of tooth-supporting tissues. We examined the production of IL-1beta, IL-6, tumour necrosis factor (TNF)-alpha, IL-12 and IL-10 in cultures of peripheral mononuclear cells (MNC) from 10 patients with GAgP and 10 controls stimulated with periodontal pathogens or a control antigen, tetanus toxoid (TT) in the presence of autologous serum. The pathogens used were Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum, either as type strains or bacteria isolated from the participants' inherent oral flora. The P. gingivalis -induced production of IL-6 was approximately 2.5-fold higher in patients with GAgP than in healthy controls (P < 0.05), while the corresponding TNF-alpha production was non-significantly elevated. IL-1beta production induced by P. gingivalis, as all cytokine responses induced by Pr. intermedia, F. nucleatum and TT was similar in the two groups. A reduced IL-12p70 response to Pr. intermedia and F. nucleatum was observed in smokers compared to non-smoking patients (P < 0.02). To assess the role of serum factors in the elevated IL-6 response to P. gingivalis, MNC from two donors free of disease were stimulated with this bacterium in the presence of the various patient and control sera. An elevated IL-6 and TNF-alpha response was observed in the presence of patient sera (P < 0.01 and P < 0.04, respectively). The data suggest that an exaggerated production of IL-6 occurs in GAgP, and that pro-inflammatory serum factors play an essential role in the response.