The 2022 Assisi Think Tank Meeting: White paper on optimising radiation therapy for breast cancer.

The present white paper, referring to the 4th Assisi Think Tank Meeting on breast cancer, reviews state-of-the-art data, on-going studies and research proposals. <70% agreement in an online questionnaire identified the following clinical challenges: 1: Nodal RT in patients who have a) 1-2 positive sentinel nodes without ALND (axillary lymph node dissection); b) cN1 disease transformed into ypN0 by primary systemic therapy and c) 1-3 positive nodes after mastectomy and ALND. 2. The optimal combination of RT and immunotherapy (IT), patient selection, IT-RT timing, and RT optimal dose, fractionation and target volume. Most experts agreed that RT- IT combination does not enhance toxicity. 3: Re-irradiation for local relapse converged on the use of partial breast irradiation after second breast conserving surgery. Hyperthermia aroused support but is not widely available. Further studies are required to finetune best practice, especially given the increasing use of re-irradiation.

Toxicity after moderately hypofractionated versus conventionally fractionated prostate radiotherapy: A systematic review and meta-analysis of the current literature.

BACKGROUND: Moderately hypofractionated radiotherapy (RT) currently represents the standard RT approach for all prostate cancer (PCa) risk categories. We performed a systematic review and meta-analysis of available literature, focusing on acute and late genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) of moderate hypofractionation for localized PCa. MATERIALS AND METHODS: Literature search was performed and two independent reviewers selected the records according to the following Population (P) Intervention (I) Comparator (C) and Outcomes (O) (PICO) question: "In patients affected by localized PCa (P), moderately hypofractionated RT (defined as a treatment schedule providing a single dose per fraction of 3-4.5 Gy) (I) can be considered equivalent to conventionally fractionated RT (C) in terms of G > 2 GI and GU acute and late adverse events (O)?". Bias assessment was performed using Cochrane Cochrane Collaboration's Tool for Assessing Risk of Bias. RESULTS: Thirteen records were identified and a meta-analysis was performed. Risk of acute GI and GU > 2 adverse events in the moderately hypofractionated arm was increased by 9.8 % (95 %CI 4.8 %-14.7 %; I2 = 57 %) and 1.5 % (95 % CI -1.5 %-4.4 %; I2 = 0%), respectively. DISCUSSION: Overall, majority of trials included in our meta-analysis suggested that moderately hypofractionated RT is equivalent, in terms of GI and GU adverse events, to conventional fractionation. Pooled analysis showed a trend to increased GI toxicity after hypofractionated treatment, but this might be related to dose escalation rather than hypofractionation.

Stereotactic ablative radiotherapy in castration-resistant prostate cancer patients with oligoprogression during androgen receptor-targeted therapy

Objectives To report outcomes of stereotactic body radiotherapy (SBRT) in metastatic castration-resistant prostate cancer (mCRPC) patients with oligoprogression (≤ 5 metastases) during first-line treatment with androgen receptor-targeted therapy (ARTT). Patients and methods Retrospective multi-institutional analysis of mCRPC patients treated with SBRT to oligoprogressive lesions during ARTT. End-points were time to next-line systemic treatment (NEST), radiological progression-free survival (r-PFS) and overall survival (OS). Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Survival analysis was performed using the Kaplan–Meier method, univariate and multivariate analysis (MVA) were performed. Results Data from 34 patients were analyzed. Median NEST-free survival, r-PFS, and OS were 16.97, 13.47, and 38.3 months, respectively. At MVA, factors associated with worse NEST-free survival and r-PFS were polymetastatic burden at diagnosis of metastatic hormone-sensitive disease (hazard ratio [HR] 3.66, p = 0.009; HR 3.03, p = 0.034), PSA ≤ 7 ng/ml at mCRPC diagnosis (HR 0.23, p = 0.017; HR 0.19, p = 0.006) and PSADT ≤ 3 months at mCRPC diagnosis (HR 3.39, p = 0.026; HR 2.79, p = 0.037). Polymetastatic state at mHSPC diagnosis was associated with a decreased OS (HR 4.68, p = 0.029). No patient developed acute or late grade ≥ 2 toxicity. Conclusion Our results suggest that SBRT in oligoprogressive mCPRC is safe, effective and seems to prolong the efficacy of the ongoing systemic treatment positively affecting disease progression. Prospective trials are needed (AU)

Stereotactic ablative radiotherapy in castration-resistant prostate cancer patients with oligoprogression during androgen receptor-targeted therapy.

OBJECTIVES: To report outcomes of stereotactic body radiotherapy (SBRT) in metastatic castration-resistant prostate cancer (mCRPC) patients with oligoprogression (≤ 5 metastases) during first-line treatment with androgen receptor-targeted therapy (ARTT). PATIENTS AND METHODS: Retrospective multi-institutional analysis of mCRPC patients treated with SBRT to oligoprogressive lesions during ARTT. End-points were time to next-line systemic treatment (NEST), radiological progression-free survival (r-PFS) and overall survival (OS). Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Survival analysis was performed using the Kaplan-Meier method, univariate and multivariate analysis (MVA) were performed. RESULTS: Data from 34 patients were analyzed. Median NEST-free survival, r-PFS, and OS were 16.97, 13.47, and 38.3 months, respectively. At MVA, factors associated with worse NEST-free survival and r-PFS were polymetastatic burden at diagnosis of metastatic hormone-sensitive disease (hazard ratio [HR] 3.66, p = 0.009; HR 3.03, p = 0.034), PSA ≤ 7 ng/ml at mCRPC diagnosis (HR 0.23, p = 0.017; HR 0.19, p = 0.006) and PSADT ≤ 3 months at mCRPC diagnosis (HR 3.39, p = 0.026; HR 2.79, p = 0.037). Polymetastatic state at mHSPC diagnosis was associated with a decreased OS (HR 4.68, p = 0.029). No patient developed acute or late grade ≥ 2 toxicity. CONCLUSION: Our results suggest that SBRT in oligoprogressive mCPRC is safe, effective and seems to prolong the efficacy of the ongoing systemic treatment positively affecting disease progression. Prospective trials are needed.

Detection rate, pattern of relapse and influence on therapeutic decision of PSMA PET/CT in patients affected by biochemical recurrence after radical prostatectomy, a retrospective case series.

AIMS: 68Ga-Prostate-specific membrane antigen (PSMA) PET/CT is widely used in patients with biochemical recurrence (BCR) after radical prostatectomy. We collected data about patients staged with PSMA PET/CT after BCR (PSA < 1 ng/ml) in four different institutes. Impact of baseline features (Gleason score, risk classification, PSA at recurrence, PSA doubling time and time to recurrence) was explored to understand predictive factors of (PSMA) PET/CT positivity. Impact of restaging on following treatment approaches was reported. RESULTS: 92 patients were included. PSMA PET/CT detection rate was 56.5% and low-volume disease (≤ 3 non-visceral lesions) was detected in 52.2% of patients. After positive scan, 13.5% of patients still lies on observation, ADT alone was administered in 30.8% of cases, Stereotactic body RT (SBRT) alone was delivered to 44.2% of patients and 11.5% of patients underwent concomitant SBRT and ADT. Seven patients underwent conventional salvage prostate bed RT. Chi-squared test showed a higher rate of positive PSMA PET/CT for patients with Gleason score > 7 (p = 0.004) and TTR < 29.5 months (p = 0.003). CONCLUSIONS: PSMA PET/CT showed a high detection rate. This influenced clinical management in a significant percentage of patients, allowing treatment tailoring on the basis of imaging.

Breast-conserving treatment for ductal carcinoma in situ: Impact of boost and tamoxifen on local recurrences.

PURPOSE: Ductal carcinoma in situ represents 15 to 20% of all breast cancers. Breast-conserving surgery and whole breast irradiation was performed in about 60% of the cases. This study reports local recurrence rates in patients with ductal carcinoma in situ treated by breast-conserving surgery and whole breast irradiation with or without boost and/or tamoxifen and compares different therapeutic options in two European countries. PATIENTS AND METHODS: From 1998 to 2007, 819 patients with pure ductal carcinoma in situ were collected, both in France (266) and Italy (553). Median age was 56. All underwent breast-conserving surgery and whole breast irradiation; 391 (48%) received a boost (55% in France and 45% in Italy, P=0.017) and 173 (22.5%) tamoxifen (4.5% in France and 32% in Italy, P<0.0001). RESULTS: With a 90-month median follow-up, there were 51 local recurrences (6.2%), including 27 invasive (53%). The 5- and 10-year local recurrence rates were 4% and 8.6%. Two patients developed axillary recurrence and 12 (1.5%) metastases (seven after invasive local recurrence); 41 (5%) patients had contralateral breast cancer. In the multivariate analysis, high nuclear grade and lack of tamoxifen are the most powerful predictors of local recurrence, with 2.6 (95% confidence interval [95% CI]: 1.74-3.89, P=0.0012) and 2.85 (95% CI: 1.42-5.72, P=0.04) odds ratio (OR) estimates, respectively. Age, margin status and boost did not influence local recurrence rates. CONCLUSIONS: This study confirms the ductal carcinoma in situ treatment heterogeneity among countries and the unfavourable prognostic role of nuclear grade. Tamoxifen reduces local recurrence rates and might be considered for some subgroups of patients, but further confirmation is required. The boost usefulness still remains unclear.

Could machine learning improve the prediction of pelvic nodal status of prostate cancer patients? Preliminary results of a pilot study.

We tested and compared performances of Roach formula, Partin tables and of three Machine Learning (ML) based algorithms based on decision trees in identifying N+ prostate cancer (PC). 1,555 cN0 and 50 cN+ PC were analyzed. Results were also verified on an independent population of 204 operated cN0 patients, with a known pN status (187 pN0, 17 pN1 patients). ML performed better, also when tested on the surgical population, with accuracy, specificity, and sensitivity ranging between 48-86%, 35-91%, and 17-79%, respectively. ML potentially allows better prediction of the nodal status of PC, potentially allowing a better tailoring of pelvic irradiation.

Active surveillance for low-risk prostate cancer: diversity of practice across Europe.

BACKGROUND: Active surveillance (AS) is a recognised treatment option for low-risk prostate cancer (PCa). AIMS: To review AS criteria in terms of patient selection, follow-up and indications for intervention. METHODS: A total of 2,959 potential participants were identified and invited via email to complete an online survey. Only urologists practising in an EU country were eligible to participate. Statistical analyses were carried out using SPSS version 18.0. The χ (2) test was used to compare responses between those who do and do not follow an AS protocol. RESULTS: Response rate was 8% (n = 226). Ninety-seven per cent urologists offer AS; 25% (n = 53/215) within a clinical trial and a further 28% (n = 60/215) using an official AS protocol. Gleason score ≤ 3 + 3 = 6 (87 %, n = 173/200) and prostate-specific antigen (PSA) ≤ 10 ng/ml (86%, n = 170/198) are the commonest selection criteria. There was a statistically significant association between having an AS protocol and using PSA as an eligibility criterion (p = 0.03). For urologists not following a protocol, 11% do not consider PSA as an eligibility criterion and 81% consider PSA ≤ 10 ng/ml to decide on AS, compared to 2 and 90%, respectively, who adhere to a protocol. Twenty-four per cent of urologists without a protocol do not re-biopsy in comparison to 11% with a protocol (p = 0.026). Gleason score progression trigger the most intervention (n = 168/192, 87%). CONCLUSIONS: Urologists not adhering to an AS protocol or participating in a clinical trial appear to apply less rigorous criteria for both eligibility and monitoring in AS.

The impact of young age on breast cancer outcome.

AIMS: We conducted a retrospective analysis in order to evaluate the impact of age on women aged less than 35 years affected by breast cancer. MATERIALS AND METHODS: Between January 1972 and December 2006, 346 patients aged less than 35 years underwent adjuvant treatment at Florence University. The mean age of the patient population was 32 years (range 22-35): 76 patients were under 30 years old, the remaining were above 30 years old. RESULTS: In our series, 215 patients received adjuvant radiotherapy to whole breast after conservative surgery, 131 patients underwent mastectomy without subsequent radiation therapy and 323 patients had lymphadenectomy; 191 patients received adjuvant chemotherapy, 73 with anthracycline-containing regimen. With a median time of 2.5 years (range 6 months to 27.6 years) local relapses were observed in 67 cases (19.4%). At the multivariate analysis of local disease-free survival, ductal and ductal plus lobular histotypes, having more than 3 positive nodes, and age emerged as independent significant relapse predictors (p=0.018, p=0.0005, p=0.003 and p=0.024, respectively). For the DSS analysis, the median follow-up was 6.8 years (range 0.6-36.7 years). At the multivariate analysis, age (p=0.0038), positive nodes (p=0.0035) and distant metastases (p<0.0001) resulted to be independent death predictors. Patients younger than 30 had a worse prognosis. At the univariate analysis also local relapse resulted to be statistically significant (p=0.0004). CONCLUSIONS: Anthracycline-based chemotherapy seems to improve the outcome of these patients. However, there is an urgent need for tailored treatment investigations within the framework of randomized, controlled clinical trials.

The impact of young age on breast cancer outcome.

AIMS: We conducted a retrospective analysis in order to evaluate the impact of age on women aged less than 35 years affected by breast cancer. MATERIALS AND METHODS: Between January 1972 and December 2006, 346 patients aged less than 35 years underwent adjuvant treatment at Florence University. The mean age of the patient population was 32 years (range 22-35): 76 patients were under 30 years old, the remaining were above 30 years old. RESULTS: In our series, 215 patients received adjuvant radiotherapy to whole breast after conservative surgery, 131 patients underwent mastectomy without subsequent radiation therapy and 323 patients had lymphadenectomy; 191 patients received adjuvant chemotherapy, 73 with anthracycline-containing regimen. With a median time of 2.5 years (range 6 months to 27.6 years) local relapses were observed in 67 cases (19.4%). At the multivariate analysis of local disease-free survival, ductal and ductal plus lobular histotypes, having more than 3 positive nodes, and age emerged as independent significant relapse predictors (p = 0.018, p = 0.0005, p = 0.003 and p = 0.024, respectively). For the DSS analysis, the median follow-up was 6.8 years (range 0.6-36.7 years). At the multivariate analysis, age (p = 0.0038), positive nodes (p = 0.0035) and distant metastases (p < 0.0001) resulted to be independent death predictors. Patients younger than 30 had a worse prognosis. At the univariate analysis also local relapse resulted to be statistically significant (p = 0.0004). CONCLUSIONS: Anthracycline-based chemotherapy seems to improve the outcome of these patients. However, there is an urgent need for tailored treatment investigations within the framework of randomized, controlled clinical trials.

Adjuvant trastuzumab in breast cancer: experience from the University of Florence.

The objective of this study was to evaluate the efficacy and tolerability profile of sequential trastuzumab in the adjuvant treatment of non-metastatic breast cancer. We analyzed 94 patients with non-metastatic breast cancer who underwent postoperative treatment between November 2003 and December 2008 at the University of florence. All patients received one year of sequential trastuzumab after adjuvant chemotherapy. Cardiac monitoring in our study consisted of assessment of left ventricular ejection fraction (lVef) by echocardiography at baseline, after the completion of chemotherapy, then every 3 months during trastuzumab treatment and every 6 months thereafter. 91.6% of patients were alive without evidence of distant or local relapse, while 8.4% developed disease recurrence. The cumulative incidence of cardiotoxicity was 14.5%. In our experience trastuzumab given postoperatively with adjuvant chemotherapy was well tolerated and produced optimal clinical results in terms of disease-free survival.

[Development of the agricultural sector in Italy: need to harmonize production and health protection]. / Lo sviluppo dell'agricoltura in Italia oggi: necessità di armonizzare aspetti produttivi e di tutela della salute.

Epidemiological data show excess of respiratory, dermatological, infectious, carcinogenic and musculoskeletal disorders among agricultural workers. Nevertheless, the national rates of reported cases do not correspond to the expected epidemiological data. In 2009, 3.914 cases of occupational diseases were reported to the national work compensation Institute (INAIL), as related to 1,200.000 agricultural workers employed in Italy. About 71% of these cases were related to musculoskeletal disorders. This shows a relevant difference between observed and expected cases, even more evident than in other sectors like constructions. More efficient preventive intervention is needed to improve this situation of under-reporting, through the implementation of epidemiological surveillance based on multiple sources of information. These sources should include the periodical health surveillance of active workers, the databank of General Practitioners, the hospital admission charts, and the case-lists of patients admitted to the Institutes of Occupational Health, according to a systematic active search of occupational cases.

Doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil as adjuvant chemotherapy in breast cancer.

This study evaluated whether doxorubicin and cyclophosphamide are superior to cyclophosphamide, methotrexate and 5-fluorouracil as adjuvant chemotherapy in breast cancer patients. Between July 1976 and December 2004, 1045 breast cancer patients received adjuvant chemotherapy at the Radiotherapy Unit of the University of florence. 927 were administered i.v. CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2) and 5-fluorouracil 600 mg/m(2) on days 1 and 8, repeated every 28 days for a total of six cycles) and 118 i.v. DC (doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) on day 1 repeated every 21 days for a total of four cycles). All patients underwent adjuvant radiotherapy as well. The survival analysis, stratified according to treatment, did not show any significant difference in metastasis occurrence between the two groups (log rank test p=0.42). According to multivariate analysis four parameters emerged as independent prognostic factors for distant metastases in patients treated with the Cmf regimen: pt (p=0.0005), number of positive axillary lymph nodes (p=<0.0001), tamoxifen use (p=0.0109) and local relapses (p=<0.0001). Only number of positive axillary lymph nodes and local relapses were significant predictors of metastases occurrence according to multivariate analysis in the DC group, 17 and p=0.028, respectively. No significant difference between the two regimens was observed with regards to number of involved nodes. DC and CMF produced similar outcome in breast cancer patients.

Oesophagectomy after definitive chemoradiation in patients with locally advanced oesophageal cancer.

AIMS: The clinical benefit of salvage oesophagectomy in patients who recur after radical chemoradiotherapy (CRT) is not clearly defined. This study retrospectively evaluated the outcome in patients who underwent salvage oesophagectomy having failed primary CRT. MATERIALS AND METHODS: Between March 1999 and October 2005, 181 patients with oesophageal cancer were treated at the Royal Marsden Hospital with definitive CRT. Ten patients underwent salvage oesophagectomy. All of them had locally advanced cancer of the oesophagus at presentation (adenocarcinoma in three patients and squamous cell carcinoma in seven patients) and received combined CRT, consisting of 12 weeks of cisplatin and 5-fluorouracil-based chemotherapy followed by CRT. Radiotherapy was delivered with a computed tomography-planned technique to a dose of 54 Gy with daily 5-fluorouracil. RESULTS: An Ivor-Lewis procedure was carried out in all cases. The median time between the end of CRT and surgery was 5 months (range 1-67). Curative resection was achieved in three patients, seven had microscopic positive circumferential margins. One patient died postoperatively and complications occurred in four cases: anastomotic leak in two patients, pneumonia in one patient, empyema and sepsis in one patient. The median critical care unit stay was 7 days (range 4-26) and hospitalisation was 21 days (range 15-84). With a median follow-up period of 45.5 months (range 5-89) the 1-, 2- and 3-year survival calculated from the completion of CRT was 70, 50 and 30%, respectively. Median survival was 21.5 months (range 8-90). CONCLUSIONS: Salvage oesophagectomy may prolong survival in carefully selected patients with local relapse. Patients fit for surgery at presentation benefit from a more intensive follow-up protocol to detect early recurrence.

Adjuvant hypofractionated radiation therapy for breast cancer after conserving surgery.

AIMS: To evaluate the incidence of locoregional recurrence (LRR) and the cosmetic results in a group of patients with breast cancer treated with a hypofractionated schedule of adjuvant radiotherapy after conservative surgery. MATERIALS AND METHODS: In total, 539 patients with pTis-pT1-pT2 breast cancer underwent radiotherapy treatment after conservative surgery at the University of Florence and at the Pistoia Hospital. The dose delivered was 44 Gy (2.75 Gy daily fraction). The tumour bed boost (10 Gy) was given by electrons. RESULTS: At the time of the analysis, 1.8% of patients (10/539) had breast relapse. No patients developed nodal recurrence (supraclavicular, axillary and internal mammary nodes). The 3- and 5-year actuarial rates for LRR were 1.2% (+/- 0.5% standard error) and 2.1% (+/- 0.6% standard error), respectively. Considering the late toxicity, we found that 412 (76.4%) patients had grade 0 or grade 1 late toxicity, 113 patients (20.9%) had grade 2 late toxicity and 14 patients (2.5%) had grade 3 late toxicity. No patients developed grade 4 toxicity. CONCLUSION: This type of approach resulted in an effective treatment in terms of local control in patients with negative or one to three positive axillary nodes and negative surgical margins. Patients treated with a hypofractionated schedule showed very good cosmesis.

[Upper limb work-related disorders: description of an Italian hospital based case study]. / Patologie muscoloscheletriche dell'arto superiore lavoro-correlate: analisi di una casistica ospedaliera.

Using the Hospital computerized database, individual variables including referral source, gender; age, life style, work sector, clinical and work history, final clinical diagnosis and work-relatedness evaluation were retrieved and analysed. The results of this survey showed a significant increase of number of cases, especially from 1999 to 2006. Shoulder disorders showed a significant increase in the latest years of the observation period, while the other upper limb districts remained constant. The work sectors mostly affected were textile, construction, metalmechanical and food industry. The findings of this study indicates an increasing demand for clinical assessment of work-related musculoskeletal disorders of the upper limb. Therefore, it is important that a standardized diagnostic procedure is applied together with an accurate evaluation of biomechanical overload.

[Work-related musculoskeletal disorders of the upper extremity in spinning: lack of risk or of adequate methods for assessing risk?]. / Patologie muscoloscheletriche dell'arto superiore in addetti alla filatura: assenza di rischio o carenza di metodi per valutare in modo adeguato il rischio?

The existence of a risk of musculoskeletal disorders work-related of the upper extremity (UEWMSDs) in the textile industry, specifically in particular working phases as spinning, appears today controversial. The upper limb disorders, sometimes described, have not a location ever plausible with the level of the biomechanical overload, as when carpal tunnel syndromes are signalled during activities in which the shoulder is the only segment eventually interested. Moreover these findings are shown in workers appointed at tasks or actions not clearly identified at risk. For example the spinning activity, that requires the movement of shuttles of modest weight, sometimes on levels above the shoulder line, is organized with cyclical cadences sometimes as repetitive tasks concentrated in a short period, sometimes in longer during the entire shift. Distribution and number of the actions, would however allow a sufficient biomechanical recovery. The identification of the single technical action may result difficult, due to interindividual variability of actions, of their speed and complexity. Furthermore the other possible activities, alternate with specific spinning activities, can require strength or not correct posture even if they may have short duration. In this paper we present and discuss the results of the ergonomic survey for risk assessment of musculoskeletal disorders work-related of the upper limb. These analysis have been carried out in two textile plants, in which some cases of disorders of the upper limb in workers employed in spinning activities have been described by occupational health physicians. In addition to assessment of possible risk for UEWMSDs in spinning activities, we founded the capability of usual methods for ergonomic analysis to adequately examine work situations like spinning, in which the hazardous actions are diluted over the entire shift or concentrate in a short period and in which there is a specific biomechanically overloaded segment i.e. the shoulder. Finally attention was paid to evaluate psychosocial factors which appear to be important when biomechanical factors are low-lying.

[Exposure to neurotoxic metals and prevalence of parkinsonian syndrome in the area of Brescia]. / Esposizione a metalli neurotossici e prevalenza di sindromi parkinsoniane nel territorio bresciano.

The prevalence of parkinsonian syndromes was studied in the province of Brescia (Northern Italy), in order to verify its possible increase in the surroundings of ferroalloy plants located in a valley of the pre-Alps. A case-list of subjects affected by these disturbances was identified using four different sources of information: a) registers from local medical clinics; b) admission charts from local hospitals; c) consumption of levodopa; d) NHS list of exemption from prescription payment, due to the illness. Exploratory data show a frequency of parkinsonian disturbances among the residents in the surroundings of the ferroalloy plants and downwind (crude prevalence = 358/100,000 population, standardized for age and sex = 438) significantly higher (s.m.r, = 1.58; C.I. = 1.41-1.76) than the entire Province (crude prevalence 246/100,000). This preliminary result could indicate the interaction of prolonged environmental exposure to heavy metals, such as manganese, and genetic factors, potentially relevant in this mountain population.