A mixed-method study evaluating an innovative care model for rural patients undergoing outpatient breast surgery.

BACKGROUND: The Delta Oasis program was launched in New Brunswick in 2006 to offer patients from rural areas who were undergoing breast cancer surgery and their families 1 night of free accommodations and a postoperative consultation with an extramural nurse. We sought to investigate patient experiences with this program. METHODS: This mixed-method retrospective study took place from 2020 to 2022 and compared the preoperative anxiety and quality of recovery of program participants and control patients who were discharged home over 100 km from hospital. We conducted 2 × 2 analysis of variance to evaluate the effects of intervention group and surgery type. We conducted semistructured interviews with intervention participants, which we then thematically analyzed. Two patient partners were engaged during data synthesis to support the interpretation of results. RESULTS: We included 34 patients who participated in the program and 18 control patients. No statistically significant differences were found between treatment groups in preoperative anxiety and quality of recovery, regardless of surgery type. Thematic analysis of interviews with 17 intervention participants revealed that they were highly satisfied with the program and that the experience helped reduce stress and discomfort related to their surgery. INTERPRETATION: The Delta Oasis program is a cost-effective alternative to inpatient care after breast cancer surgery and is highly regarded by rural patients; expansion to other regions with the inclusion of additional low-risk surgeries could help address hospital capacity issues. This study contributes to our understanding of the patient experience with the Delta Oasis program and informs the development of similar programs elsewhere.

Immune-related adverse events and kidney function decline in patients with genitourinary cancers treated with immune checkpoint inhibitors.

BACKGROUND: In patients with genitourinary cancers, the effect of immune checkpoint inhibitors (ICIs) on kidney function is unknown. PATIENTS AND METHODS: This is a retrospective cohort study of patients with renal cell carcinoma (RCC) and urothelial carcinoma who received ICIs at two major cancer centers between 2012 and 2018. Cumulative incidence and Fine and Gray subdistribution hazard models were performed to determine predictors of the co-primary outcomes, (1) acute kidney injury (AKI) and (2) sustained estimated glomerular filtration rate (eGFR) loss, defined as a >20% decline in eGFR sustained ≥90 days. We also determined the association between immune-related adverse events (irAE) and adverse kidney outcomes among patients surviving ≥1 year. RESULTS: 637 patients were included; 320 (50%) patients had RCC and 317 (50%) patients had urothelial carcinoma. Half of the cohort had eGFR<60 mL/min/1.73 m2 at baseline. irAEs, AKI, and sustained eGFR loss were common, occurring in 33%, 25% and 16%, respectively. Compared to patients with urothelial carcinoma, patients with RCC were more likely to develop irAEs (aHR 1.61, 95% CI 1.20-2.18) and sustained eGFR loss (aHR 1.97, 95% CI 1.24-3.12), but not AKI (aHR 1.53, 95% CI 0.97-2.41). Among patients surviving ≥1 years, experiencing a non-renal irAE was associated with a significantly higher risk of sustained eGFR loss (aHR 1.71, 95% CI 1.14-2.57). CONCLUSION: AKI and sustained eGFR loss are common in patients with genitourinary cancers receiving ICIs. irAEs may be a novel risk factor for kidney function decline among patients receiving ICIs.

Renal Cell Cancer and Chronic Kidney Disease.

The association between chronic kidney disease (CKD) and renal cell carcinoma (RCC) is bidirectional and multifactorial. Risk factors such as hypertension, diabetes mellitus, obesity, and smoking increase the risk of both CKD and RCC. CKD can lead to RCC via an underlying cystic disease or oxidative stress. RCC can cause CKD because of the tumor itself, surgical reduction of renal mass (either partial or radical nephrectomy), and perioperative acute kidney injury. Medical therapies such as immune checkpoint inhibitors and vascular endothelial growth factor inhibitors can lead to acute kidney injury and resultant CKD. Clinicians need to be aware of the complex, bidirectional interplay between both diseases.

TNAP and Pain Control.

Chronic pain is one of the most debilitating and expensive diseases, yet current therapies are often insufficient in bringing about long-term relief. Further, many treatments for chronic pain also carry significant side effects. The molecule adenosine has long been identified as a potent inhibitor of nociceptive circuits in the spinal cord; however, the widespread expression of adenosine receptors in many organ systems has limited its use as an analgesic. Recently several 5' ectonucleotidases, including tissue non-specific alkaline phosphatase (TNAP), have been characterized for their ability to generate endogenous adenosine in nociceptive circuitry of the dorsal spinal cord. These ectonucleotidases have the ability to hydrolyze the endogenous pronociceptive nucleotides like adenosine triphosphate (ATP) into the antinociceptive nucleoside adenosine. This chapter discusses the role of TNAP and other ectonucleotidases in nociceptive circuits, and their potential as future targets of new therapeutics to treat chronic pain.

Deletion of ENTPD3 does not impair nucleotide hydrolysis in primary somatosensory neurons or spinal cord.

Ectonucleotidases are membrane-bound or secreted proteins that hydrolyze extracellular nucleotides.  Recently, we identified three ectonucleotidases that hydrolyze extracellular adenosine 5'-monophosphate (AMP) to adenosine in primary somatosensory neurons.  Currently, it is unclear which ectonucleotidases hydrolyze ATP and ADP in these neurons.  Ectonucleoside triphosphate diphosphohydrolases (ENTPDs) comprise a class of enzymes that dephosphorylate extracellular ATP and ADP.  Here, we found that ENTPD3 (also known as NTPDase3 or CD39L3) was located in nociceptive and non-nociceptive neurons of the dorsal root ganglion (DRG), in the dorsal horn of the spinal cord, and in free nerve endings in the skin.  To determine if ENTPD3 contributes directly to ATP and ADP hydrolysis in these tissues, we generated and characterized an Entpd3 knockout mouse.  This mouse lacks ENTPD3 protein in all tissues examined, including the DRG, spinal cord, skin, and bladder.  However, DRG and spinal cord tissues from Entpd3 (-/-) mice showed no reduction in histochemical staining when ATP, ADP, AMP, or UTP were used as substrates.  Additionally, using fast-scan cyclic voltammetry (FSCV), adenosine production was not impaired in the dorsal spinal cord of Entpd3 (-/-) mice when the substrate ADP was applied.  Further, Entpd3 (-/-) mice did not differ in nociceptive behaviors when compared to wild-type mice, although Entpd3 (-/-) mice showed a modest reduction in ß-alanine-mediated itch.  Taken together, our data indicate that deletion of Entpd3 does not impair ATP or ADP hydrolysis in primary somatosensory neurons or in dorsal spinal cord.  Moreover, our data suggest there could be multiple ectonucleotidases that act redundantly to hydrolyze nucleotides in these regions of the nervous system.

Tissue-nonspecific alkaline phosphatase acts redundantly with PAP and NT5E to generate adenosine in the dorsal spinal cord.

Prostatic acid phosphatase (PAP) and ecto-5'-nucleotidase (NT5E) hydrolyze extracellular AMP to adenosine in dorsal root ganglia (DRG) neurons and in the dorsal spinal cord. Previously, we found that adenosine production was reduced, but not eliminated, in Pap⁻/⁻/Nt5e⁻/⁻ double knock-out (dKO) mice, suggesting that a third AMP ectonucleotidase was present in these tissues. Here, we found that tissue-nonspecific alkaline phosphatase (TNAP, encoded by the Alpl gene) is expressed and functional in DRG neurons and spinal neurons. Using a cell-based assay, we found that TNAP rapidly hydrolyzed extracellular AMP and activated adenosine receptors. This activity was eliminated by MLS-0038949, a selective pharmacological inhibitor of TNAP. In addition, MLS-0038949 eliminated AMP hydrolysis in DRG and spinal lamina II of dKO mice. Using fast-scan-cyclic voltammetry, we found that adenosine was rapidly produced from AMP in spinal cord slices from dKO mice, but virtually no adenosine was produced in spinal cord slices from dKO mice treated with MLS-0038949. Last, we found that AMP inhibited excitatory neurotransmission via adenosine A1 receptor activation in spinal cord slices from wild-type, Pap⁻/⁻, Nt5e⁻/⁻, and dKO mice, but failed to inhibit neurotransmission in slices from dKO mice treated with MLS-0038949. These data suggest that triple elimination of TNAP, PAP, and NT5E is required to block AMP hydrolysis to adenosine in DRG neurons and dorsal spinal cord. Moreover, our data reveal that TNAP, PAP, and NT5E are the main AMP ectonucleotidases in primary somatosensory neurons and regulate physiology by metabolizing extracellular purine nucleotides.

PAP and NT5E inhibit nociceptive neurotransmission by rapidly hydrolyzing nucleotides to adenosine.

BACKGROUND: Prostatic acid phosphatase (PAP) and ecto-5'-nucleotidase (NT5E, CD73) produce extracellular adenosine from the nucleotide AMP in spinal nociceptive (pain-sensing) circuits; however, it is currently unknown if these are the main ectonucleotidases that generate adenosine or how rapidly they generate adenosine. RESULTS: We found that AMP hydrolysis, when measured histochemically, was nearly abolished in dorsal root ganglia (DRG) neurons and lamina II of spinal cord from Pap/Nt5e double knockout (dKO) mice. Likewise, the antinociceptive effects of AMP, when combined with nucleoside transport inhibitors (dipyridamole or 5-iodotubericidin), were reduced by 80-100% in dKO mice. In addition, we used fast scan cyclic voltammetry (FSCV) to measure adenosine production at subsecond resolution within lamina II. Adenosine was maximally produced within seconds from AMP in wild-type (WT) mice but production was reduced >50% in dKO mice, indicating PAP and NT5E rapidly generate adenosine in lamina II. Unexpectedly, we also detected spontaneous low frequency adenosine transients in lamina II with FSCV. Adenosine transients were of short duration (<2 s) and were reduced (>60%) in frequency in Pap-/-, Nt5e-/- and dKO mice, suggesting these ectonucleotidases rapidly hydrolyze endogenously released nucleotides to adenosine. Field potential recordings in lamina II and behavioral studies indicate that adenosine made by these enzymes acts through the adenosine A1 receptor to inhibit excitatory neurotransmission and nociception. CONCLUSIONS: Collectively, our experiments indicate that PAP and NT5E are the main ectonucleotidases that generate adenosine in nociceptive circuits and indicate these enzymes transform pulsatile or sustained nucleotide release into an inhibitory adenosinergic signal.

Prostatic acid phosphatase reduces thermal sensitivity and chronic pain sensitization by depleting phosphatidylinositol 4,5-bisphosphate.

Prostatic acid phosphatase (PAP) is expressed in nociceptive dorsal root ganglion (DRG) neurons, functions as an ectonucleotidase, and generates adenosine extracellularly. Here, we found that PAP inhibits noxious thermal sensitivity and sensitization that is associated with chronic pain through sustained activation of the adenosine A(1) receptor (A(1)R) and phospholipase C-mediated depletion of phosphatidylinositol 4,5-bisphosphate (PIP(2)). In mice, intrathecal injection of PAP reduced PIP(2) levels in DRGs, inhibited thermosensation through TRPV1, and enduringly reduced thermal hyperalgesia and mechanical allodynia caused by inflammation, nerve injury, and pronociceptive receptor activation. This included inhibitory effects on lysophosphatidic acid, purinergic (ATP), bradykinin, and protease-activated (thrombin) receptors. Conversely, PIP(2) levels were significantly elevated in DRGs from Pap(-/-) mice, and this correlated with enhanced thermal hyperalgesia and mechanical allodynia in Pap(-/-) mice. To directly test the importance of PIP(2) in nociception, we intrathecally injected PIP(2) into mice. This transiently (2 h) elevated PIP(2) levels in lumbar DRGs and transiently (2 h) enhanced thermosensation. Additionally, thermal hyperalgesia and mechanical allodynia were enduringly enhanced when PIP(2) levels were elevated coincident with injury/pronociceptive receptor stimulation. Nociceptive sensitization was not affected if PIP(2) levels were elevated in the absence of ongoing pronociceptive receptor stimulation. Together, our data suggest that PIP(2) levels in DRGs directly influence thermosensation and the magnitude of nociceptive sensitization. Moreover, our data suggest there is an underlying "phosphoinositide tone" that can be manipulated by an adenosine-generating ectonucleotidase. This tone regulates how effectively acute nociceptive insults promote the transition to chronic pain.

Bullous pemphigoid presenting as dry gangrene in a revascularized limb.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, and has been associated with many diseases; most autoimmune. It has never previously been associated with a reperfused limb. A 74-year-old female underwent a right femoroanterior tibial polytetrafluoroethylene (PTFE) bypass for tissue loss and rest pain in the right foot. After surgery she was treated for recurrent infection which exacerbated tissue loss and was eventually diagnosed as BP. There was a delay in diagnosis due to the similarity to dry gangrene. This case highlights the potential difficulties of BP diagnosis in a revascularized limb and the importance of multidisciplinary management of atypical infection.