Stereotactic Body Radiotherapy for Primary Renal Cell Carcinoma: A Case-Based Radiosurgery Society Practice Guide.

Traditionally, renal cell carcinoma (RCC) was considered a radioresistant tumor, thereby limiting definitive radiation therapy management options. However, several recent studies have demonstrated that stereotactic body radiotherapy (SBRT) can achieve high rates of local control for the treatment of primary RCC. In the setting of an expanding use of SBRT for primary RCC, it is crucial to provide guidance on practical considerations such as patient selection, fractionation, target delineation, and response assessment. This is particularly important in challenging scenarios where a paucity of evidence exists, such as in patients with a solitary kidney, bulky tumors, or tumor thrombus. The Radiosurgery Society endorses this case-based guide to provide a practical framework for delivering SBRT to primary RCC, exemplified by three cases. This article explores topics of tumor size and dose fractionation, impact on renal function and treatment in the setting of a solitary kidney, and radiation's role in the management of inferior vena cava tumor thrombus. Additionally, we review existing evidence and expert opinion on target delineation, advanced techniques like MRI-guided SBRT, and SBRT response assessment.

Association of low adherence to weekly cisplatin with outcomes in patients with head and neck squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guideline recommends consideration of weekly cisplatin as an alternative option for patients with head and neck cancer undergoing definitive chemoradiation. However, in a recent phase III trial (ConCERT), 20% of patients treated with weekly cisplatin could not receive a total of 200 mg/m2, and the association of low adherence to weekly cisplatin and cancer control outcomes remains unclear. To fill this knowledge gap, we performed an observational cohort study of patients with head and neck cancer undergoing definitive chemoradiation with weekly cisplatin. METHODS: Our institutional database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation with weekly cisplatin (40 mg/m2) between November 2007 and April 2023. Adherence to weekly cisplatin was defined as receiving at least 5 cycles with a total cumulative dose of 200 mg/m2. Survival outcomes were evaluated using Kaplan-Meier method, log-rank tests, Cox proportional hazard multivariable (MVA) analyses. Logistic MVA was performed to identify variables associated with low adherence to weekly cisplatin. Fine-Gray MVA was performed to analyze failure outcomes with death as a competing event. RESULTS: Among 119 patients who met our criteria, 51 patients (42.9%) had low adherence to weekly cisplatin. Median follow up was 19.8 months (interquartile range 8.8-65.6). Low adherence to weekly cisplatin was associated with worse overall survival (adjusted hazards ratio [aHR] 2.94, 95% confidence interval [CI] 1.58-5.47, p < 0.001) and progression-free survival (aHR 2.32, 95% CI 1.29-4.17, p = 0.005). It was also associated with worse distant failure (aHR 4.55, 95% CI 1.19-17.3, p = 0.03), but not locoregional failure (aHR 1.61, 95% CI 0.46-5.58, p = 0.46). KPS < 90 was the only variable associated with low adherence to weekly cisplatin (adjusted odds ratio [aOR] 2.67, 95% CI 1.10-6.65, p = 0.03). CONCLUSION: Our study suggested that over 40% of patients underwent fewer than 5 weekly cisplatin cycles and that low adherence to weekly cisplatin was an independent, adverse prognostic factor for worse survival and distant failure outcomes. Those with reduced adherence to weekly cisplatin were more likely to have poor performance status. Further studies are warranted to improve the adherence to chemotherapy and outcomes.

Vertebral body collapse after spine stereotactic body radiation therapy: a single-center institutional experience.

BACKGROUND: Spine stereotactic body radiation therapy (SBRT) for the treatment of metastatic disease is increasingly utilized owing to improved pain and local control over conventional regimens. Vertebral body collapse (VBC) is an important toxicity following spine SBRT. We investigated our institutional experience with spine SBRT as it relates to VBC and spinal instability neoplastic score (SINS). PATIENTS AND METHODS: Records of 83 patients with 100 spinal lesions treated with SBRT between 2007 and 2022 were reviewed. Clinical information was abstracted from the medical record. The primary endpoint was post-treatment VBC. Logistic univariate analysis was performed to identify clinical factors associated with VBC. RESULTS: Median dose and number of fractions used was 24 Gy and 3 fractions, respectively. There were 10 spine segments that developed VBC (10%) after spine SBRT. Median time to VBC was 2.4 months. Of the 11 spine segments that underwent kyphoplasty prior to SBRT, none developed subsequent VBC. No factors were associated with VBC on univariate analysis. CONCLUSIONS: The rate of vertebral body collapse following spine SBRT is low. Prophylactic kyphoplasty may provide protection against VBC and should be considered for patients at high risk for fracture.

Impact of Severe Winter Weather on Operations of a Radiation Oncology Department.

Purpose: During winter 2022, western New York faced 2 major storms with blizzard conditions and record-breaking snowfall. The severe weather resulted in power outages and travel bans. This study investigates the impact of these conditions on patient adherence to radiation therapy. Combining data from a large academic center and its satellite clinic, this single-center study sheds light on the challenges faced by cancer care facilities during severe weather and proposes suggestions to prevent and mitigate harm done by severe weather. Methods and Materials: In this study, data were collected using the MOSAIQ Record and Verify system (v. 2.81) to generate deidentified reports of scheduled and treated patients. The treatment adherence rate was calculated by dividing the number of patients treated by the total number of patients scheduled. Data were specifically collected for patients undergoing treatment on linear accelerators at a primary academic center and a satellite facility. The study focused on working days from November 1, 2022, to March 31, 2023, excluding weekends and holidays (as treatments are not routinely scheduled). Severe weather days were identified using advisories from the National Weather Service and the local institution, including specific periods in November, December, and January. Results: In the study, 15,010 scheduled treatment visits were recorded across the academic center and the satellite clinic. The mean daily treatment adherence rate was 91.7%. Severe weather conditions led to a significant reduction in adherence, with rates dropping to 77.8%. Adherence rates during nonsevere weather days were notably higher at 93.9%. Statistical analysis confirmed the substantial influence of severe weather on adherence (P < .001). Severe weather had a more pronounced impact on the satellite clinic during periods of severe weather, with absolute reduction in adherence rates of 21.9% versus 15% in the primary hospital. Moreover, adherence at the satellite clinic was lower than at the primary hospital site even under standard operating conditions (92.2% vs 94.0%, P < .001). Conclusion: As a part of operational planning, it is important to be aware how severe weather can impact treatment adherence. Study findings underscore the importance of proactive measures to ensure patient access to health care services during adverse weather events and highlight the broader significance of incorporating consideration of social determinants of health into contingency planning for maintaining treatment continuity.

Long-Term Survival and Failure Outcomes of Single-Fraction Stereotactic Body Radiation Therapy in Early Stage NSCLC.

Introduction: This study aims to report our 13-year institutional experience with single-fraction stereotactic body radiation therapy (SF-SBRT) for early stage NSCLC. Methods: A single-institutional retrospective review of patients with biopsy-proven peripheral cT1-2N0M0 NSCLC undergoing definitive SF-SBRT between September 2008 and May 2022 was performed. All patients were treated to 27 Gy with heterogeneity corrections or 30 Gy without. Primary outcomes were overall survival and progression-free survival. Secondary outcomes included local failure, nodal failure, distant failure, and second primary lung cancer. Results: Among 263 eligible patients, the median age was 76 years (interquartile range [IQR]: 70-81 y) and median follow-up time was 27.2 months (IQR: 14.25-44.9 mo). Median tumor size was 1.9 cm (IQR: 1.4-2.6 cm), and 224 (85%) tumors were T1. There were 92 patients (35%) alive at the time of analysis with a median follow-up of 34.0 months (IQR: 16.6-50.0 mo). Two- and five-year overall survival was 65% and 26%, respectively. A total of 74 patients (28%) developed disease progression. Rates of five-year local failure, nodal failure, distant failure, and second primary lung cancer were 12.7%, 14.7%, 23.5%, and 12.0%, respectively. Conclusions: Consistent with multiple prospective randomized trials, in a large real-world retrospective cohort, SF-SBRT for peripheral early stage NSCLC was an effective treatment approach.

Preoperative stereotactic radiosurgery as neoadjuvant therapy for resectable brain tumors.

PURPOSE: Stereotactic radiosurgery (SRS) is a method of delivering conformal radiation, which allows minimal radiation damage to surrounding healthy tissues. Adjuvant radiation therapy has been shown to improve local control in a variety of intracranial neoplasms, such as brain metastases, gliomas, and benign tumors (i.e., meningioma, vestibular schwannoma, etc.). For brain metastases, adjuvant SRS specifically has demonstrated positive oncologic outcomes as well as preserving cognitive function when compared to conventional whole brain radiation therapy. However, as compared with neoadjuvant SRS, larger post-operative volumes and greater target volume uncertainty may come with an increased risk of local failure and treatment-related complications, such as radiation necrosis. In addition to its role in brain metastases, neoadjuvant SRS for high grade gliomas may enable dose escalation and increase immunogenic effects and serve a purpose in benign tumors for which one cannot achieve a gross total resection (GTR). Finally, although neoadjuvant SRS has historically been delivered with photon therapy, there are high LET radiation modalities such as carbon-ion therapy which may allow radiation damage to tissue and should be further studied if done in the neoadjuvant setting. In this review we discuss the evolving role of neoadjuvant radiosurgery in the treatment for brain metastases, gliomas, and benign etiologies. We also offer perspective on the evolving role of high LET radiation such as carbon-ion therapy. METHODS: PubMed was systemically reviewed using the search terms "neoadjuvant radiosurgery", "brain metastasis", and "glioma". ' Clinicaltrials.gov ' was also reviewed to include ongoing phase III trials. RESULTS: This comprehensive review describes the evolving role for neoadjuvant SRS in the treatment for brain metastases, gliomas, and benign etiologies. We also discuss the potential role for high LET radiation in this setting such as carbon-ion radiotherapy. CONCLUSION: Early clinical data is very promising for neoadjuvant SRS in the setting of brain metastases. There are three ongoing phase III trials that will be more definitive in evaluating the potential benefits. While there is less data available for neoadjuvant SRS for gliomas, there remains a potential role, particularly to enable dose escalation and increase immunogenic effects.

Association of pre-treatment lymphocyte-monocyte ratio with survival outcome in patients with head and neck cancer treated with chemoradiation.

BACKGROUND: Given the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer. METHODS: A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan-Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias. RESULTS: A total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8-74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82-0.99, p = 0.03) and CSS (aHR 0.83, 95% CI 0.72-0.95, p = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12-2.26, p = 0.009) and CSS (HR 1.68, 95% CI 1.08-2.63, p = 0.02). CONCLUSION: Low LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.

Association of progesterone receptor status with 21-gene recurrence score and survival among patients with estrogen receptor-positive breast cancer.

BACKGROUND: Progesterone receptor (PR)-negative tumors have been shown to have worse prognosis and were underrepresented in recent trials on patients with estrogen receptor (ER)-positive breast cancer. The role of PR-negative status in the context of 21-gene recurrence score (RS) and nodal staging remains unclear. METHODS: The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1-3N0-1a breast cancer. Logistic and Cox multivariable analyses (MVA) were performed to identify association of PR status with high RS (> 25) and overall survival (OS), respectively. RESULTS: Among 143,828 women, 130,349 (90.6%) and 13,479 (9.4%) patients had PR-positive and PR-negative tumors, respectively. Logistic MVA showed that PR-negative status was associated with higher RS (> 25: aOR 16.15, 95% CI 15.23-17.13). Cox MVA showed that PR-negative status was associated with worse OS (adjusted hazards ratio [aHR] 1.20, 95% CI 1.10-1.31). There was an interaction with nodal staging and chemotherapy (p = 0.049). Subgroup analyses using Cox MVA showed the magnitude of the chemotherapy benefit was greater among those with pN1a, PR-negative tumors than pN1a, PR-positive tumors (PR-positive: aHR 0.57, 95% CI 0.47-0.67; PR-negative: aHR 0.31, 95% CI 0.20-0.47). It was comparable among those with pN0 tumors regardless of PR status (PR-positive: aHR 0.74, 95% CI 0.66-0.82; PR-negative: aHR 0.63, 95% CI 0.51-0.77). CONCLUSION: PR-negative tumors were independently correlated with higher RS and were associated with greater OS benefits from chemotherapy for pN1a tumors, but not pN0 tumors.

Association of Neighborhood-Level Household Income With 21-Gene Recurrence Score and Survival Among Patients With Estrogen Receptor-Positive Breast Cancer.

Importance: While low income has been associated with a higher incidence of triple-negative breast cancer, its association with 21-gene recurrence score (RS) among patients with estrogen receptor (ER)-positive breast cancer remains unclear. Objective: To evaluate the association of household income with RS and overall survival (OS) among patients with ER-positive breast cancer. Design, Setting, and Participants: This cohort study used data from the National Cancer Database. Eligible participants included women diagnosed between 2010 and 2018 with ER-positive, pT1-3N0-1aM0 breast cancer who received surgery followed by adjuvant endocrine therapy with or without chemotherapy. Data analysis was performed from July 2022 to September 2022. Exposures: Low vs high neighborhood-level household income levels defined as below vs above the median household income of $50 353 based on each patient's zip code. Main Outcomes and Measures: RS (a score ranged from 0 to 100 based on gene expression signatures indicating the risk of distant metastasis, with RS of 25 or below indicating non-high risk and RS above 25 indicating high risk) and OS. Results: Among 119 478 women (median [IQR] age, 60 [52-67] years; 4737 [4.0%] Asian and Pacific Islander, 9226 [7.7%] Black, 7245 [6.1%] Hispanic, 98 270 [82.2%] non-Hispanic White), 82 198 (68.8%) and 37 280 (31.2%) patients had high and low income, respectively. Logistic multivariable analysis (MVA) showed that, compared with high income, low income was associated with higher RS (adjusted odds ratio [aOR], 1.11; 95% CI, 1.06-1.16). Cox MVA showed that low income was also associated with worse OS (adjusted hazards ratio [aHR], 1.18; 95% CI, 1.11-1.25). Interaction term analysis showed a statistically significant interaction between income levels and RS (interaction P < .001). On subgroup analysis, significant findings were noted among those with RS below 26 (aHR, 1.21; 95% CI, 1.13-1.29), while there was no significant OS difference between income levels among others with RS of 26 or higher (aHR, 1.08; 95% CI, 0.96-1.22). Conclusions and Relevance: Our study suggested that low household income was independently associated with higher 21-gene recurrence scores and significantly worse survival outcomes among those with scores below 26, but not 26 or higher. Further studies are warranted to investigate the association between socioeconomic determinants of health and intrinsic tumor biology among patients with breast cancer.

Adjuvant chemotherapy versus observation following neoadjuvant therapy and surgery for resectable stage I-II pancreatic cancer.

Background: Neoadjuvant therapy (NT), either with systemic treatment alone or in combination with radiation, is often utilized in the management of pancreatic adenocarcinoma to increase the likelihood of margin-negative resection. Following NT and resection, additional adjuvant chemotherapy (AC) can be considered for select patients and has been shown to improve overall survival (OS). This National Cancer Data Base (NCDB) analysis was performed to evaluate the outcomes of AC versus observation for resected pancreatic adenocarcinoma treated with NT. Methods: The NCDB was queried for primary stage I-II cT1-3N0-1M0 resected pancreatic adenocarcinoma treated with NT (2004-2015). Baseline patient, tumor, and treatment characteristics were extracted. The primary endpoint was OS. With a 6-month conditional landmark, Kaplan-Meier analysis, multivariable Cox proportional hazards method, 1:1 propensity score matching were used to analyze the data. Results: A total of 1737 eligible patients were identified, of which 1247 underwent postoperative observation compared to 490 with AC. The overall median follow-up was 34.7 months. The addition of AC showed improved survival on the multivariate analysis (HR 0.78, p<0.001). Of 490 propensity-matched pairs, all variables were well balanced, including age (p=0.61), Charlson-Deyo comorbidity score (p=0.80), ypT stage (p=0.93), ypN stage (p=0.83), surgical margin (p=0.83), duration of postoperative inpatient admission (p=0.96), and 30-day unplanned readmission after resection (p=0.34). AC remained statistically significant for improved OS, with median OS of 26.3 months vs 22.3 months and 2-year OS of 63.9% vs 52.9% for the observation cohort (p<0.001). Treatment interaction analysis showed OS benefit of AC for patients with smaller tumors (HR 0.67, p<0.001 for <3.1 cm vs HR 0.93, p=0.48 for ≥3.1 cm). Conclusion: Using propensity score matched analysis, our findings suggest a survival benefit for adjuvant chemotherapy compared to observation following NT and surgery for resectable pancreatic adenocarcinoma, especially in patients with smaller tumors. Prospective studies are needed to identify subset of patients that would benefit from adjuvant chemotherapy.

Association of survival with stereotactic body radiation therapy following induction chemotherapy for unresected locally advanced pancreatic cancer.

Background: Induction chemotherapy (iC) followed by concurrent chemoradiation has been shown to improve overall survival (OS) for locally advanced pancreatic cancer (LAPC). However, the survival benefit of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy (CFRT) following iC remains unclear. Methods: The National Cancer Database (NCDB) was queried for primary stage III, cT4N0-1M0 LAPC (2004-2015). Kaplan-Meier analysis, Cox proportional hazards method, and propensity score matching were used. Results: Among 872 patients, 738 patients underwent CFRT and 134 patients received SBRT. Median follow-up was 24.3 months and 22.9 months for the CFRT and SBRT cohorts, respectively. The use of SBRT showed improved survival in both the multivariate analysis (HR 0.78, p=0.025) and 120 propensity-matched pairs (median OS 18.1 vs 15.9 months, p=0.004) compared to the CFRT. Conclusion: This NCDB analysis suggests survival benefit with the use of SBRT versus CFRT following iC for the LAPC.

The evolving role of radiation in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. Chemotherapy in resectable pancreatic cancer has improved survival by 10-20%. It only converted 10-30% of the borderline resectable and locally advanced pancreatic cancers to be surgically resectable. Radiation therapy has a documented role in managing localized pancreatic cancer, more so for borderline and locally advanced pancreatic cancer, where it can potentially improve the resectability rate of a given neoadjuvant treatment. The role of radiation therapy in resected pancreatic cancer is controversial, but it is used routinely to treat positive margins after pancreatic cancer surgery. Radiation therapy paradigms continue to evolve with advancements in treatment modalities, delivery techniques, and combination approaches. Despite the advances, there continues to be a controversy on the role of radiation therapy in managing this disease. In this review article, we discuss the recent updates, delivery techniques, and motion management in radiation therapy and dissect the applicability of this therapy in pancreatic cancer.

Embedding a genetic counselor into oncology clinics improves testing rates and timeliness for women with ovarian cancer.

OBJECTIVE: Germline genetic testing is crucial to the care of ovarian cancer patients, and as part of the guideline-based care for ovarian cancer patient's adherence to this recommendation has been low. We sought to determine whether embedding a genetic counselor (GC) within a medical and gynecologic oncology clinic would increase testing rates and improve the timeliness of testing. METHODS: Prospective cohort study of 358 ovarian cancer patients seen by medical and gynecologic oncologists between 2013 and 2015. Rates of referrals, completion of counseling, and genetic testing and timeliness of counseling were abstracted before and after a GC was embedded in the clinic in 2014. An additional year of data (2015) was collected to evaluate sustainability of the intervention. RESULTS: Between 2013 and 2015, 88-92% of women were referred for genetic testing, but in 2013 only 66% completed counseling and 61% were tested. After a GC was embedded in the clinic in 2014, more than 80% of referred women completed counseling and germline genetic testing. Time to genetic counseling also decreased from a median of 107 to 40 days, irrespective of age and cancer family history (p < 0.01). CONCLUSIONS: Embedding a GC into the workflow for ovarian cancer patients is an effective way of improving access to genetic counseling, testing rates, and the timeliness of testing.

A novel nonsense mutation in WNK1/HSN2 associated with sensory neuropathy and limb destruction in four siblings of a large Iranian pedigree.

BACKGROUND: Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is an autosomal recessive disorder with predominant sensory dysfunction and severe complications such as limb destruction. There are different subtypes of HSAN2, including HSAN2A, which is caused by mutations in WNK1/HSN2 gene. METHODS: An Iranian family with four siblings and autosomal recessive inheritance pattern whom initially diagnosed with HSAN2 underwent whole exome sequencing (WES) followed by segregation analysis. RESULTS: According to the filtering criteria of the WES data, a novel candidate variation, c.3718C > A in WNK1/HSN2 gene that causes p.Tyr1025* was identified. This variation results in a truncated protein with 1025 amino acids instead of the wild-type product with 2645 amino acids. Sanger sequencing revealed that the mutation segregates with disease status in the pedigree. CONCLUSIONS: The identified novel nonsense mutation in WNK1/HSN2 in an Iranian HSAN2 pedigree presents allelic heterogeneity of this gene in different populations. The result of current study expands the spectrum of mutations of the HSN2 gene as the genetic background of HSAN2A as well as further supports the hypothesis that HSN2 is a causative gene for HSAN2A. However, it seems that more research is required to determine the exact effects of this product in the nervous system.

The hormone-bound vitamin D receptor enhances the FBW7-dependent turnover of NF-κB subunits.

Signaling by hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D) has attracted increasing interest because of its non-classical actions, particularly its putative anticancer properties and its role in controlling immune system function. Notably, the hormone-bound vitamin D receptor (VDR) suppresses signaling by pro-inflammatory NF-κB transcription factors, although the underlying mechanisms have remained elusive. Recently, the VDR was shown to enhance the turnover of the oncogenic transcription factor cMYC mediated by the E3 ligase and tumor suppressor FBW7. As FBW7 also controls the turnover of the p100 (NF-κB2) subunit of the family, we determined whether the 1,25D enhanced FBW7-dependent turnover of NF-κB subunits p100, p105 (NF-κB1) and p65 (RELA). Protein levels of all three subunits declined markedly in the presence of 1,25D in multiple cell lines in the absence of substantial changes in mRNA expression. The VDR coimmunoprecipitated with all three subunits, and 1,25D treatment accelerated subunit turnover in cycloheximide-treated cells. Importantly, we observed an association of FBW7 with p105 and p65, as well as p100, and knockdown of FBW7 eliminated 1,25D-dependent subunit turnover. Moreover, expression of NF-κB target genes was elevated in FBW7-depleted cells. These results reveal that 1,25D signaling suppresses NF-κB function by enhancing FBW7-dependent subunit turnover.

Influence of muscarinic receptor modulators on interacerebroventricular injection of arachydonylcyclopropylamide induced antinociception in mice.

The interaction between antinociception induced by CB1 agonist and muscarinic receptor modulators has not been studied yet. In the present study, the effect of pilocarpine (a muscarinic agonist) and atropine (a muscarinic antagonist) on arachidonylcyclopropylamide (ACPA, a CB1 agonist) induced antinociception was studied in mice. In this study the antinociceptive effect of intracerebroventricular administration of ACPA (0.001-2 µg/mice) or intraperitoneal injection of pilocarpine (2.5-20mg/kg) or atropine (1 and 5mg/kg) were studied individually. Then the effect of co-administration of pilocarine (2.5mg/kg) or atropine (5mg/kg) and ACPA (0.001-2 µg/mice) were studied as well. ACPA and pilocarpine induced antinociception in mice but atropine did not. Pilocarpine potentiated but atropine antagonized the antinociceptive effect of ACPA. It is concluded that ACPA induced antinociception is influenced by muscarinic receptor modulators in mice.