Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFß/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma.

Importance: While smoking is associated with a decreased incidence of cutaneous melanoma, the association of smoking with melanoma progression and death is not well defined. Objective: To determine the association of smoking with survival in patients with early-stage primary cutaneous melanoma. Design, Setting, and Participants: This cohort study performed a post hoc analysis of data derived from the randomized, multinational first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II). Participants were accrued for MSLT-I from January 20, 1994, to March 29, 2002; MSLT-II, from December 21, 2004, to March 31, 2014. Median follow-up was 110.0 (IQR, 53.4-120.0) months for MSLT-I and 67.6 (IQR, 25.8-110.2) months for MSLT-II. Patients aged 18 to 75 years with clinical stages I or II melanoma with a Breslow thickness of 1.00 mm or greater or Clark level IV to V and available standard prognostic and smoking data were included. Analyses were performed from October 4, 2022, to March 31, 2023. Exposure: Current, former, and never smoking. Main Outcomes and Measures: Melanoma-specific survival of patients with current, former, and never smoking status was assessed for the entire cohort and for nodal observation and among subgroups with sentinel lymph node biopsy (SLNB)-negative and SLNB-positive findings. Results: Of 6279 included patients, 3635 (57.9%) were men, and mean (SD) age was 52.7 (13.4) years. The most common tumor location was an extremity (2743 [43.7%]), and mean (SD) Breslow thickness was 2.44 (2.06) mm. Smoking status included 1077 (17.2%) current, 1694 (27.0%) former, and 3508 (55.9%) never. Median follow-up was 78.4 (IQR, 30.5-119.6) months. Current smoking was associated with male sex, younger age, trunk site, thicker tumors, tumor ulceration, and SLNB positivity. Current smoking was associated with a greater risk of melanoma-associated death by multivariable analysis for the entire study (hazard ratio [HR], 1.48 [95% CI, 1.26-1.75]; P < .001). Former smoking was not. The increased risk of melanoma-specific mortality associated with current smoking was greatest for patients with SLNB-negative melanoma (HR, 1.85 [95% CI, 1.35-2.52]; P < .001), but also present for patients with SLNB-positive melanoma (HR, 1.29 [95% CI, 1.04-1.59]; P = .02) and nodal observation (HR, 1.68 [95% CI, 1.09-2.61]; P = .02). Smoking at least 20 cigarettes/d doubled the risk of death due to melanoma for patients with SLNB-negative disease (HR, 2.06 [95% CI, 1.36-3.13]; P < .001). Conclusions and Relevance: The findings of this cohort study suggest that patients with clinical stage I and II melanoma who smoked had a significantly increased risk of death due to melanoma. Smoking status should be assessed at time of melanoma diagnosis and may be considered a risk factor for disease progression.

A Look at the Other Side: High-Risk Lesions and Occult Contralateral Malignancy in Symmetry Procedures for Patients Undergoing Oncoplastic Breast-Conserving Surgery.

BACKGROUND: The incidence of occult breast cancer among patients undergoing reduction mammoplasty or risk-reducing mastectomies ranges from 1% to approximately 10%, respectively. Identification of incidental cancer often mandates subsequent mastectomy due to ambiguous margins. This study aimed to determine the incidence of contralateral malignancy among patients undergoing oncoplastic breast-conserving surgery (OBCS) with concurrent symmetry procedures. METHODS: The authors reviewed their prospectively maintained institutional database of patients with unilateral breast cancer who underwent OBCS. Patients who underwent excisional biopsy on the contralateral breast were analyzed separately. Patient demographics, pathologic features, and subsequent disease management were evaluated. RESULTS: Between March 2018 and July 2022, 289 patients underwent OBCS with a symmetry procedure, and 100 patients yielded contralateral breast tissue specimens. For 14 patients, a planned excisional biopsy was performed with their symmetry procedure, and five lesions (36%) were found to be malignant. Of the remaining 86 patients, 92% underwent preoperative breast magnetic resonance imaging (MRI). Four patients (4.7%) had occult malignancies identified on the contralateral breast pathology; three patients with ductal carcinoma in situ and one patient with invasive lobular carcinoma. Three patients had undergone preoperative MRI without suspicious findings. No patients required mastectomy for treatment of the contralateral breast cancer. CONCLUSION: The incidence of occult malignancy among OBCS symmetry procedures approaches 5%. The final pathology of excisional biopsies had a higher upgrade rate than previously reported. All identified malignancies were early-stage disease. The higher incidence of occult breast cancer in this population warrants the routine orientation of all specimens, which allows patients with incidental early-stage cancer the option of breast preservation.

Simultaneous Symmetry Procedure in Patients Undergoing Oncoplastic Breast-Conserving Surgery: An Evaluation of Patient Desire and Revision Rates.

INTRODUCTION: In the era of oncoplastic breast conserving-surgery (OBCS), cosmetic outcomes and the desire for symmetry have become essential elements of the surgical management of breast cancer (BC). The timing of contralateral symmetry procedures remains a controversial topic. Simultaneous symmetry procedures (SSP) in OBCS have not been routinely offered due to the perceived risk of delayed asymmetry, potentially increasing the need for delayed cosmetic revision. This study evaluates the rate of revision after SSP in patients undergoing OBCS. METHODS: We reviewed our institutional prospectively maintained database identifying all BC patients treated surgically since our introduction of oncoplastic surgery in 2018. We routinely offer SSP when appropriate. Descriptive statistics evaluated oncoplastic surgical techniques, SSP offerings and procedures, perioperative complications, and revision rates after treatment completion. RESULTS: Between 2018 and 2022, 485 breast cancer patients underwent partial mastectomy, and 396 (82%) underwent OBCS. Of the 313 patients offered SSP, 272 (87%) accepted. The margin reexcision rate of this cohort was 20%. Of the 272 patients with SSP, 152 (56%) underwent intraoperative radiation therapy (IORT), and 105 (39%) had adjuvant external beam radiation therapy. Three patients (1%) experienced complications involving the symmetry side. No patients with complications experienced a delay in adjuvant therapies or requested cosmetic revisions. Three patients (1%) desired surgical revisions due to asymmetry. CONCLUSIONS: Symmetry procedures at the time of OBCS are widely accepted by patients and rarely require delayed cosmetic revision. Simultaneous symmetry procedures should be routinely discussed with patients during the surgical planning of OBCS.

GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity.

OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Here, we show that tumour-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and the host bone marrow is central for monopoiesis and potentiation of TAMs, and abrogation of this signalling axis facilitates antitumour immunity in a novel model of iCCA. METHODS: Blood and tumours were analysed from iCCA patients and controls. Treatment and correlative studies were performed in mice with autochthonous and established orthotopic iCCA tumours treated with anti-GM-CSF monoclonal antibody. RESULTS: Systemic elevation in circulating myeloid cells correlates with poor prognosis in patients with iCCA, and patients who undergo resection have a worse overall survival if tumours are more infiltrated with CD68+ TAMs. Mice with spontaneous iCCA demonstrate significant elevation of monocytic myeloid cells in the tumour microenvironment and immune compartments, and tumours overexpress GM-CSF. Blockade of GM-CSF with a monoclonal antibody decreased tumour growth and spread. Mice bearing orthotopic tumours treated with anti-GM-CSF demonstrate repolarisation of immunosuppressive TAMs and MDSCs, facilitating T cell response and tumour regression. GM-CSF blockade dampened inflammatory gene networks in tumours and TAMs. Human tumours with decreased GM-CSF expression exhibit improved overall survival after resection. CONCLUSIONS: iCCA uses the GM-CSF-bone marrow axis to establish an immunosuppressive tumour microenvironment. Blockade of the GM-CSF axis promotes antitumour T cell immunity.

Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model.

Metastatic melanoma portends a poor prognosis and patients may present with multiple, simultaneous tumors. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond, or exhibit lesion-specific responses wherein some metastases respond as others progress within the same patient. While intertumoral heterogeneity has been clinically associated with these mixed lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates this intertumoral genetic and microenvironmental heterogeneity. We show that genetic differences between tumors are sufficient to generate distinct tumor immune microenvironments (TIME) simultaneously in the same mouse. Furthermore, these TIMEs lead to the independent regulation of PD-1/PD-L1 (programmed cell death protein 1/PD-1 ligand), a popular axis targeted by immune checkpoint therapy, in response to ongoing anti-tumor immunity and the presence of interferon-gamma. Currently, therapeutic selection for metastatic melanoma patients is guided by a single biopsy, which may not represent the immune status of all tumors. As a result, patients can display heterogeneous lesion-specific responses. Further investigations into this synchronous melanoma model will provide mechanistic insight into the effects of intertumoral heterogeneity and guide therapeutic selection in this challenging patient population.

From bench to bedside: updates in basic science, translational and clinical research on muscle fatigue in cancer cachexia.

PURPOSE OF REVIEW: Cancer cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here, we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers and potential therapies. RECENT FINDINGS: Both in mice and humans, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in precachexia. Inflammatory pathways, mitochondrial dysfunction and gut microbiota have recently been studied to play an important role in muscle fatigue in preclinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue. SUMMARY: Heightened inflammation within muscle, altered muscle function and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.

Narcotic Free Cervical Endocrine Surgery: A Shift in Paradigm.

BACKGROUND AND OBJECTIVE: The opioid epidemic has stimulated initiatives to reduce the number of unnecessary narcotic prescriptions. We adopted an opt-in prescription system for patients undergoing ambulatory cervical endocrine surgery (CES). We hypothesized that empowering patients to decide whether or not to receive narcotics for pain control would result in fewer unnecessary opioid prescriptions. METHODS: We enrolled all patients scheduled for outpatient CES between July 2017 and June 2018 in a narcotic opt-in program. Patient demographics, procedure characteristics, and postoperative pain scores were collected prospectively. Statistical analyses were performed to correlate clinical predictors with narcotic request. Results were compared against a historical control group. The study was approved by the University IRB. RESULTS: A total of 216 consecutive patients underwent outpatient CES following implementation of the program. Only nine (4%) requested prescription narcotic medication at discharge, and no patient called after discharge to request analgesic medications. Compared with our prior treatment paradigm, we achieved a 96.6% reduction in the number of narcotic tablets prescribed, and a 98% reduction in unconsumed tablets. Univariate analysis suggested history of substance abuse (P < 0.001), anxiety (P = 0.01), depression (P < 0.001), baseline narcotic use (P = 0.004), highest pain postoperatively (P = 0.004), and incision length (P = 0.007) as predictive for narcotic request. Multivariate analysis retained significance with incision length and history of substance abuse. CONCLUSION: By empowering patients undergoing ambulatory CES to accept or decline a prescription, we reduced the number of prescribed narcotic tablets by 96.6%. Although longer incisions and prior substance abuse predict higher likelihood of requesting pain medication on discharge, 207 of 216 patients were treated with acetaminophen alone.

Open adrenalectomy through a makuuchi incision: A single institution's experience.

BACKGROUND: Surgical techniques for adrenalectomy have evolved substantially over the last century. Although minimally invasive approaches are favored for benign disease, open adrenalectomy remains the gold standard for large tumors and those concerning for malignancy. Most reports describe the use of midline, subcostal, or thoracoabdominal incisions for open adrenalectomy. We studied our experience with the Makuuchi incision, designed to optimize exposure and minimize denervation of the abdominal wall. METHODS: All open adrenalectomies at the University of Rochester from 2009 to 2017 were retrospectively reviewed. Patient demographic characteristics, intraoperative details, and postoperative complications were investigated. Surgical site infection and hernia rates of Makuuchi incision were compared with non-Makuuchi incision patients and with published standards. The study was approved by the university Institutional Review Board. RESULTS: A total of 41 adrenalectomies were performed via Makuuchi incision. Population statistics included a mean age of 51.7 (19-86) years, a mean body mass index of 29.7 (17.3-45.8), and a mean tumor diameter of 8 cm (3.1-26 cm). Fourteen (34%) required multivisceral resection. Twenty-one (51%) were previous or current smokers, and 9 (22%) had hypercortisolemia. Median duration of stay was 6 days (4-73). Incisional hernia occurred in 5 patients (12%) and surgical site infection in 3 patients (7%), 2 patients had Cushing syndrome and 1 was immunosuppressed. Pain was managed with patient-controlled epidural anesthesia or patient-controlled anesthesia with postoperative day 1 daily morphine equivalents equating to 0.5 mg of hydromorphone q2h. Among 15 non-Makuuchi incision patients, there were 2 hernias (13%), 2 surgical site infections (13%), and 1 case of postoperative pneumonia. CONCLUSION: The Makuuchi incision is well tolerated and affords outstanding exposure of the adrenals and adjacent viscera. Incisional hernia and surgical site infection rates were favorable compared with published rates for midline or subcostal incisions, despite an obese population with a high incidence of hypercortisolism and immunosuppression.