Faculty Bibliography

Background: TAS-102 (trifluridine/tipiracil) is a novel oral antimetabolite for late line metastatic colorectal cancer (CRC) approved in 2018. Many patients are treated early in their course with oxaliplatin (OX), particularly adjuvant, and may benefit from re-treatment. In this trial we combine the typical late line use of TAS with OX (BEV [bevacizumab] added at investigator discretion) with goal of improved response.
Method(s): Eligibility included measurable CRC previously treated with all approved drugs per TAS package insert (irinotecan, oxaliplatin, 5FU, anti-VEGF, anti-EGF) as appropriate, PS = 0-1, labs within usual range, neuropathy < grade 2, ability to take oral meds, appropriate contraception. If no contraindication to BEV, this could be added at patient. TAS was dosed at 35 mg/m2 days 1-5 with OX 85/m2 d1 every 14 days (and BEV 5 mg/kg, if given). All supportive care was allowed including growth factors.
Result(s): 47 patients (pts, median age 55) were enrolled in a Simon mini-max design, including 45% female, 21% black, 11% Asian, 11% Hispanic and 5% mixed. 26 pts received BEV. For the first 40 pts, 385 cycles were given (mean = 7 cycles, median 8) with 18 pts (45%) requiring dose reductions (1 dose reduction = 9 pts, 2 = 6, 3 = 3), and 9 receiving (peg)/filgrastim. Toxicities leading to SAEs included gr 3 heme (2), heart failure, abd pain/n/v (6), sepsis (2), urinary (4); and related gr 3 included one gr 3 vomiting and one gr 3 neutropenia. Independently reviewed RECIST Response (N = 32) included PR 2(6%), SD 23 (72%), PD 7 (22%). Mean TTP was 4.5 m (median 4, range 1 - 18) with 9 (28%) pts more than 6 months.
Conclusion(s): In patients with late-line CRC and candidates for TAS (trifluridine/tipiracil), treatment with TAS plus OX is both well tolerated and active. RR is higher than single agent and 78% (95% CI, 60-91%) of patients had stable disease or response, with 60% receiving 8 or more cycles. Randomized trials comparing to single agent TAS are warranted in this setting

Previous studies demonstrate that Mycobacterium vaccae NCTC 11659 (M. vaccae), a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, is a potentially useful countermeasure against negative outcomes to stressors. Here we used male C57BL/6NCrl mice to determine if repeated immunization with M. vaccae is an effective countermeasure in a "two hit" stress exposure model of chronic disruption of rhythms (CDR) followed by acute social defeat (SD). On day -28, mice received implants of biotelemetric recording devices to monitor 24-h rhythms of locomotor activity. Mice were subsequently treated with a heat-killed preparation of M. vaccae (0.1 mg, administered subcutaneously on days -21, -14, -7, and 27) or borate-buffered saline vehicle. Mice were then exposed to 8 consecutive weeks of either stable normal 12:12 h light:dark (LD) conditions or CDR, consisting of 12-h reversals of the LD cycle every 7 days (days 0-56). Finally, mice were exposed to either a 10-min SD or a home cage control condition on day 54. All mice were exposed to object location memory testing 24 h following SD. The gut microbiome and metabolome were assessed in fecal samples collected on days -1, 48, and 62 using 16S rRNA gene sequence and LC-MS/MS spectral data, respectively; the plasma metabolome was additionally measured on day 64. Among mice exposed to normal LD conditions, immunization with M. vaccae induced a shift toward a more proactive behavioral coping response to SD as measured by increases in scouting and avoiding an approaching male CD-1 aggressor, and decreases in submissive upright defensive postures. In the object location memory test, exposure to SD increased cognitive function in CDR mice previously immunized with M. vaccae. Immunization with M. vaccae stabilized the gut microbiome, attenuating CDR-induced reductions in alpha diversity and decreasing within-group measures of beta diversity. Immunization with M. vaccae also increased the relative abundance of 1-heptadecanoyl-sn-glycero-3-phosphocholine, a lysophospholipid, in plasma. Together, these data support the hypothesis that shift toward a more proactive response to stress exposure, and promotes stress resilience.

Rab GTPases regulate membrane trafficking at the stages of vesicle formation, movement and fusion with target compartments. Rab11 GTPase coordinates trafficking at biosynthetic and endocytic recycling routes acting at the trans-Golgi network (TGN), post-Golgi vesicles and recycling endosomes. Rab11 Binding Protein (Rab11BP) has long been described as a potential Rab11 effector but its function remains unknown. The structure of Rab11BP includes a Rab11 binding domain and several domains presumably involved in protein-protein interactions, which include an FFAT-like domain, a proline rich domain and seven WD40 repeats typical of scaffold proteins. Here we used shRNA silencing experiments to first evaluate whether Rab11BP is involved in the Rab11-dependent endocytic recycling of transferring receptor (TfR) and then assessed the protein traffic between the endoplasmic reticulum (ER) and Golgi. We silenced Rab11BP expression with shRNA using lentiviral transduction or microinjection. Rab11BP-silenced cells showed normal TfR endocytosis and recycling analyzed by FACS. However, the distribution of KDELR-GFP and the retrograde-impaired mutant KDELR(D193N)-GFP indicated that Rab11BP functions in Golgi-to-ER retrograde trafficking. Rab11BP silencing led the KDELRGFP to change its distribution from a predominant ER location to an accumulation at the cis-Golgi, colocalizing with Giantin, while the Golgi-retained mutant KDELR(D193N)-GFP remained unaffected. This indicates an impaired retrograde Golgi-to-ER transport without affecting the anterograde transport from ER to Golgi, which likely impact on the ER function of KDEL-bearing chaperones. Rab11BP silencing decreased TGN46, furin, M6PR and calnexin protein levels and induced the characteristic fragmentation of the TGN associated with an impaired Golgi-to-ER transport. These results indicate that Rab11BP is required for retrograde transport from the Golgi-to-ER contributing to the maintenance of the Golgi structure and homeostasis. As to our knowledge Rab11 has not been involved in this step of the biosynthetic trafficking, our results suggest that Rab11BP might have functions independently of Rab11

Background/UNASSIGNED:Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. Patients and methods/UNASSIGNED:Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. Results/UNASSIGNED:Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. Conclusions/UNASSIGNED:Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

Objective: Niraparib is a highly selective PARP1/2 inhibitor that induces synthetic lethality in tumor cells with homologous recombination DNA repair deficiencies (HRD). Niraparib is administered orally once daily (QD) and may be taken without regard to meals, because food does not significantly affect the absorption or metabolism of niraparib. In a phase 1 study, niraparib was clinically active and well tolerated in patients with ovarian cancer. To address the need for novel therapies for recurrence, a randomized, doubleblind phase 3 study is evaluating niraparib as maintenance treatment in patients with stage III/IV ovarian, fallopian tube, or primary peritoneal cancer who responded to front-line platinum-based chemotherapy but are at high risk for progressive disease, based on one of the following: FIGO stage IV regardless of outcome of surgery, FIGO stage III and presence of macroscopic residual disease after primary surgery, or use of neoadjuvant chemotherapy regardless of residual disease after interval debulking surgery. Method: This multicenter trial is enrolling =305 patients with ovarian, fallopian tube, or peritoneal cancer. Eligible females are required to have histologically diagnosed stage III/IV cancer, tumor available for HRD test (myChoiceTM HRD test), normal or N90% decrease in CA-125 levels during front-line therapy, and no prior PARP inhibitor use. Patients who have undergone debulking surgery must have residual disease after primary surgery unless they received neoadjuvant therapy. Patients with a known history of myelodysplastic syndrome (MDS) or a baseline cytogenetic test result with a risk for a diagnosis of MDS or acute myeloid leukemia are excluded. Patients must have completed >=4 cycles of platinumbased therapy and had a complete or partial RECIST response. Patients are randomized (2:1) to receive niraparib 300 mg QD or matched placebo in 28-day cycles. Tumors are assessed every 12 weeks per RECIST v1.1. The primary endpoint is progression-free survival (PFS) by blinded central review. After 258 PFS events, the study will have 90% power (one-sided a = 0.025) to detect an improvement in median PFS with HR = 0.65. Secondary endpoints are evaluation of overall survival, patient-reported outcomes, safety and tolerability, and time to progression on next therapy. Results: Not applicable (trial in progress). Conclusion: Not applicable (trial in progress)

Background: In synucleinopathies, deposits of alpha-synuclein occur in sympathetic neurons innervating sweat glands, leading to impaired sudomotor function. Hence, measurement of sweat production may be relevant as a diagnostic biomarker. We hypothesized that patients with synucleinopathies have decreased electrodermal activity, and that this is associated with sympathetic adrenergic impairment.
Objective(s): To evaluate electrodermal activity in subjects with synucleinopathies.
Method(s): Cross-sectional study including 106 patients with synucleinopathies (55 with idiopathic Parkinson disease-PD-, 18 with probable multiple system atrophy-MSA-, 25 with pure autonomic failure-PAF-, and 8 with idiopathic REM behavior disorder-RBD-) and 57 healthy controls enrolled in New York University (New York, NY) and Hospital de Cruces (Bilbao, Spain). Electrodermal activity was assessed with a device (Sudoscan). Standard cardiovascular autonomic testing (in all subjects) and I¹²³metaiodobenzylguanidine myocardial scintigraphy (in 30 patients with PD) were performed to quantify sympathetic adrenergic dysfunction.
Result(s): Electrodermal activity both in the palms and in the soles was lower in patients than in controls (p<0.01). When considered separately, MSA, PAF and RBD had lower electrodermal activity in the palms than in controls (p<0.001), whereas electrodermal activity in the soles was lower in MSA, PAF and PD (p<0.05). Linear regressions showed that reduced electrodermal activity was associated with markers of sympathetic adrenergic impairment (p<0.05), but not with disease duration.
Conclusion(s): Decreased electrodermal activity in palms and soles is a frequent finding in synucleinopathies. Decreased electrodermal activity was associated with decreased sympathetic adrenergic function, suggesting a parallel degeneration of both adrenergic and cholinergic sympathetic fibers

BACKGROUND: Glycemic control of type 2 diabetes mellitus (T2DM) remains a dilemma to physicians. Although gastric bypass surgery undertaken for morbid obesity has been shown to resolve this disease well, data on the effectiveness of duodenojejunal bypass in improving or resolving T2DM and the metabolic syndrome (MS), especially in nonobese patients are scarce. This study was intended to evaluate the clinical effects of laparoscopic duodenojejunal bypass (LDJB) in patients with T2DM and a body mass index of <35 kg/m(2). METHODS: We conducted a 12-month prospective study on the changes in glucose homeostasis and the MS in seven T2DM subjects undergoing LDJB with similar DM duration, type of DM treatment, and glycemic control. Laboratory values including glycosylated hemoglobin A (HbA1c), fasting blood glucose, cholesterol, triglyceride, and C-peptide were followed throughout the 12 months. Serum levels of gastric inhibitory peptide and ghrelin were followed for 1 month. Serum levels of gastrin and glucagon-like peptide were followed for 3 months. RESULTS: At 12 months after surgery, all subjects consistently felt relief from fatigue, pain and/or numbness in the extremities, polyuria, and polydypsia. Clinical resolution was obtained for one patient, and the preoperative diabetic medication requirements decreased for most of the other patients. The subjects demonstrated an overall improved HbA1c (from 9.4% to 8.5%) and fasting blood glucose level (from 209 to 154 mg/dl). Although the change in fasting blood glucose approached statistical significance, these measures of glucose homeostasis did not achieve significance. Cholesterol and triglycerides increased slightly, and C-peptide decreased slightly over 1 year. These changes were not statistically significant. CONCLUSIONS: Although this is a small series, our data show that at 12 months after surgery, clinical improvement was obvious in all of our seven patients, but LDJB may not be effective at inducing remission of T2DM and the MS in certain patients undergoing this operation. This suggests that larger patient studies should be conducted, before concluding that surgery may offer clinical and biochemical resolution to a disease once treated only medically. Longer follow-up is required for better evaluation.

Given a stationary time series X and another stationary time series Y (with a different power spectral density), we describe an algorithm for constructing a stationary time series Z that contains exactly the same values as X permuted in an order such that the power spectral density of Z closely resembles that of Y. We call this method spectral mimicry. We prove (under certain restrictions) that, if the univariate cumulative distribution function (CDF) of X is identical to the CDF of Y, then the power spectral density of Z equals the power spectral density of Y. We also show, for a class of examples, that when the CDFs of X and Y differ modestly, the power spectral density of Z closely approximates the power spectral density of Y. The algorithm, developed to design an experiment in microbial population dynamics, has a variety of other applications.