The utility of initial staging PET-CT as a baseline scan for surveillance imaging in stage II and III melanoma

BackgroundThis study evaluates the utility of whole-body PET-CT for the initial staging and subsequent surveillance imaging of patients with completely resected stage II and stage III melanoma.MethodsA single-center, retrospective review of patients who received perioperative whole-body PET-CT from January 1, 2005 to December 1, 2019 within three months of initial melanoma diagnosis was performed.ResultsOf 258 total patients with completely resected melanoma who had a PET-CT within 3 months after their melanoma diagnosis, 113 had stage II and 145 had stage III melanoma. PET-CT detected distant metastasis in 3 (2.7%) of 113 stage II patients and 7 (4.8%) of 145 stage III patients.179 of 258 patients had adequate follow-up time to determine whether they received surveillance cross-sectional imaging and whether they had a melanoma recurrence. 143 (79.9%) received subsequent surveillance imaging, 74 of whom developed a recurrence. In 64 (86.5%) of 74 cases, recurrence was detected by routine surveillance. 26 (34.2%) of 76 stage II and 65 (63.1%) of 103 stage III patients developed a recurrence. The median time to recurrence among the 179 patients for stage II and III was 16.3 and 13.0 months, respectively.ConclusionsThese findings indicate that baseline staging with whole-body PET-CT rarely provides information that changes initial management. Rather, the value of the initial PET-CT is as a baseline for subsequent surveillance scans. Therefore, it may be premature to discourage cross-sectional imaging for patients with stage II and III melanoma without supportive evidence or a reliable biomarker of recurrent disease.     

Long-Term Results of 2 Adjuvant Trials Reveal Differences in Chemosensitivity and the Pattern of Metastases Between Colon Cancer and Rectal Cancer

BackgroundOur aim was to compare long-term results of adjuvant treatment of colon cancer (CC) and rectal cancer (RC). Adjuvant chemotherapy of CC improved overall survival (OS), whereas that of RC remained at the level achieved by 5-fluorouracil (5-FU).MethodsWe separately conducted 2 identically designed adjuvant trials in CC and RC. Patients were assigned to adjuvant chemotherapy with 5-FU alone, 5-FU + folinic acid (FA), or 5-FU + interferon-alfa. The first study enrolled patients with stage IIb/III CC, and the second study enrolled patients with stage II/III RC. All patients with RC received postoperative irradiation.ResultsMedian follow-up for all patients with CC (n = 855) and RC (n = 796) was 4.9 years. The pattern and frequency of recurrence differed significantly, especially lung metastases, which occurred more frequently in RC (12.7%) than in CC (7.3%; P < .001). Seven-year OS rates for 5-FU, 5-FU + FA, and 5-FU + IFN-alfa were 54.1% (95% confidence interval [CI], 46.5-61.0), 66.8% (95% CI, 59.4-73.1), and 56.7% (95% CI, 49.3-63.4) in CC and 50.6% (95% CI, 43.0-57.7), 56.3% (95% CI, 49.4-62.7), and 54.8% (95% CI, 46.7-62.2) in RC, respectively. A subgroup analysis pointed to a reduced local recurrence (LR) rate and an increased OS by the addition of FA in stage II RC (n = 271) but not in stage III RC (n = 525).ConclusionFA increased 7-year OS by 12.7 percentage points in CC but was not effective in RC. Based on these results and the pattern of metastases, our results suggest that the chemosensitivity of CC and RC may be different. Strategies different from those used in CC may be successful to decrease the frequency of distant metastases in RC in the future.     

Melanoma of unknown primary origin: A population-based study in the Netherlands

AimFew population-based studies have been published on melanoma of unknown primary origin (MUP). This study’s aim is to describe characteristics and survival of MUP patients in the Netherlands, based on nationwide data from the Netherlands Cancer Registry (NCR).MethodsPatient and tumour characteristics of MUP patients were retrieved from the NCR. Subgroups were made according to metastatic site: nodal or distant. Survival rates were calculated using the Kaplan–Meier method. To obtain a better insight in the composition and prognosis of the MUP group, the survival was compared to that of patients with melanoma of a known primary origin (MKP), tumour-node-metastasis (TNM) stage III and IV.ResultsOf all 33,181 melanoma patients diagnosed between 2003 and 2009, 2.6% (n = 857) were diagnosed with MUP. MUP patients with nodal metastases had a similar survival as MKP stage III with macroscopic nodal involvement. After stratification according to the number of involved lymph nodes, the survival of patients with nodal metastases with one involved lymph node was not significantly different between MUP and MKP. The survival of MUP patients with two or more involved lymph nodes was slightly worse than that of MKP stage III patients with macroscopic nodal involvement with two or more involved lymph nodes. MUP patients with distant metastases had a similar survival as MKP stage IV. After stratification according to number of metastatic sites and metastatic site category, the survival in MKP stage IV patients with (sub)cutaneous metastases was slightly worse than MUP distant patients with (sub)cutaneous metastases.ConclusionsThe results of this study imply that MUP patients form a heterogeneous group, and that MUP patients with nodal metastases could be classified as stage III melanoma with macroscopic nodal involvement, and MUP patients with distant metastases as stage IV melanoma.     

Ultrasound-based follow-up does not increase survival in early-stage melanoma patients: A comparative cohort study

IntroductionDifferent protocols have been used to follow up melanoma patients in stage I–II. However, there is no consensus on the complementary tests that should be requested or the appropriate intervals between visits. Our aim is to compare an ultrasound-based follow-up with a clinical follow-up.Patients and methodsAnalysis of two prospectively collected cohorts of melanoma patients in stage IB–IIA from two tertiary referral centres in Barcelona (clinical-based follow-up [C-FU]) and Turin (ultrasound-based follow-up [US-FU]). Kaplan–Meier curves were used to evaluate distant metastases-free survival (DMFS), disease-free interval (DFI), nodal metastases-free survival (NMFS) and melanoma-specific survival (MSS).ResultsA total of 1149 patients in the American Joint Committee on Cancer stage IB and IIA were included in this study, of which 554 subjects (48%) were enrolled for a C-FU, and 595 patients (52%) received a protocolised US-FU. The median age was 53.8 years (interquartile range [IQR] 41.5–65.2) with a median follow-up time of 4.14 years (IQR 1.2–7.6). During follow-up, 69 patients (12.5%) in C-FU and 72 patients (12.1%) in US-FU developed disease progression. Median time to relapse for the first metastatic site was 2.11 years (IQR 1.14–4.04) for skin metastases, 1.32 (IQR 0.57–3.29) for lymph node metastases and 2.84 (IQR 1.32–4.60) for distant metastases. The pattern of progression and the total proportion of metastases were not significantly different (P = .44) in the two centres. No difference in DFI, DMFS, NMFS and MSS was found between the two cohorts.ConclusionUltrasound-based follow-up does not increase the survival of melanoma patients in stage IB–IIA.     

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis

Background Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.Methods Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined.Results Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028).Conclusions Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.Subject terms: Targeted therapies, Melanoma, Melanoma     

Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas

BackgroundAlthough 90% of all melanomas are of cutaneous origin, some patients present with melanoma metastases of unknown origin (MUP). Commonly, in these patients an extensive search for the primary tumor is carried out. In the past, genetic analyses have shown substantial differences in pathogenetic mutations among cutaneous, acral and mucosal melanomas. The aim of this study was to assess the mutational status of MUP in order to better characterize the putative origin of the primary tumor and to evaluate potential prognostic factors.Patients and methodsThe medical records of 44 patients with MUP were analyzed and a survival analysis was conducted. In total, 66 paraffin samples of 44 patients were analyzed, and in 15 patients multiple metastases were tested. Mutational analysis of the BRAF, NRAS and KIT genes was carried out.ResultsTwenty-three patients (52.3%) had a mutation in the BRAF gene and 12 patients (23.8%) had a mutation in the NRAS gene. There were neither mutations in the KIT gene. In patients with multiple samples, there was 100% consistency regarding mutational status among the different metastases. The median overall survival (OS) was 86.4 months (39–134). The American Joint Committee on Cancer stage at first diagnosis of metastatic melanoma (stage III versus IV) was significantly associated with OS (P < 0.001), BRAF or NRAS mutation status had no significant prognostic impact on clinical outcomes.ConclusionsMUP resembles the genotype of cutaneous melanoma and not that of mucosal melanomas.     

Treatment patterns and outcomes among patients diagnosed with unresectable stage III or IV melanoma in Europe: A retrospective,longitudinal survey (MELODY study)

BackgroundMELanoma treatment patterns and Outcomes among patients with unresectable stage III or stage IV Disease: a retrospective longitudinal surveY (MELODY), the first multicountry, observational survey in patients with advanced melanoma, aimed to quantify the impact of existing treatment strategies by capturing information on treatment patterns and clinical outcomes.Patients and methodsPatients attending a participating site between 1st July 2005 and 30th June 2006 with ⩾2 months follow-up were eligible. Data were retrieved retrospectively from advanced melanoma diagnosis until 1st May 2008. Treatment data were collected by line of therapy and response and progression-free survival data by line of systemic treatment. Overall survival (OS) was evaluated for all treated patients.ResultsAmong all patients screened, 776 were eligible for this analysis. Median OS from the date of advanced disease diagnosis was 16.4 months. After excluding patients diagnosed prior to 1st July 2005 to account for any bias resulting from patient selection, the 12-month survival rate and median OS from the start date of second-line treatment was 28.8% and 6.8 months, respectively. Survival was lower in patients with brain metastases, elevated lactate dehydrogenase levels and more advanced disease. Rates of complete/partial tumour response were 15% and 7% in patients treated with first- and second-line systemic therapy, respectively.ConclusionsDespite receiving first- and second-line treatment, most patients with advanced melanoma have short survival times and poor prognoses, reinforcing the need for new treatments.     

Colorectal Cancer Survival: An Analysis of Patients With Metastatic Disease Synchronous and Metachronous With the Primary Tumor

BackgroundWhether metastatic colorectal cancer (mCRC) that presents synchronously with the primary lesion behaves differently from mCRC that appears metachronously to the primary disease is not clear.Patients and MethodsThe South Australian Clinical Registry for mCRC collects data for patients diagnosed after February 2006. Data from 2502 patients, available on October 22, 2012, were analyzed according to stage at initial diagnosis (SAID) to compare outcomes between metachronous tumors (MTs) (stages I, II, III) and synchronous tumors (STs) (stage IV). Overall survival (OS) was calculated from the date of mCRC diagnosis.ResultsPatients with ST had more liver-only metastases, and patients with MT had more lung-only, non-lung and non-liver, and non-lung metastases. The median time to recurrence differed significantly according to SAID: stage I, 49.3 mo (n = 29), stage II, 25.2 mo (n = 346) and stage III, 18.4 mo (n = 497). The median OS was longer for patients with MT than for those with ST (19.0 vs.14.9 mo, P = .003). For patients who received any treatment for mCRC, the OS was longer for patients with MT than for those with ST (19.2 vs. 15.3 mo, P = .005). In patients who received only chemotherapy for mCRC, the median OS was longer for patients with MT than for those with ST (15.2 vs. 9.9 mo, P < .0001). No difference in OS between the MT and ST groups for patients who did not receive treatment for mCRC (1.6 vs. 2.6 mo; P = .95).ConclusionPatients with MT have a longer OS than those with ST, independent of treatment. Classification of patients according to whether they have metachronous or synchronous presentation of mCRC is prognostic. These results may add further support for population screening with the aim to reduce de novo metastatic disease.     

The natural history and patterns of metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients

BackgroundWe examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would differ from primary mucosal melanomas at different anatomical sites.Patients and methodsClinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites.ResultsThe anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%,P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%,P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively.ConclusionsThe largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site.     

The effect of locoregional recurrence on survival and distant metastasis after conservative treatment for invasive breast carcinoma

AimsPatients with invasive breast cancer submitted to conservative treatment must be followed for a long period of time to study locoregional control. In this study, we analysed the outcome and relationships between locoregional recurrence (LRR), distant metastases and survival.Materials and methodsA 15-year study, including 470 women with early breast cancer, stage I and II, who underwent breast conservative treatment. Tumour size, nodal status, age, menopausal status, histological grade and LRR were analysed for their ability to predict overall survival, disease-specific survival and distant disease-free survival.ResultsWith a median follow-up time of 6.6 years (3 months to 19.1 years), there were 19 LRR at their first site of recurrence and 53 distant metastases. Tumour size greater than 2 cm, positive lymph nodes and histological grade III were significantly related to lower overall and distant metastases-free survival. On multivariate analysis, nodal status, histological grade III and LRR (coded as a time-dependent variable) were significantly related to overall, specific and distant metastases-free survival, whereas tumour size had only a borderline effect on specific and distant disease-free survival. Landmark analysis showed that women who presented an LRR within 2 years after surgery had significantly lower distant disease-free survival (hazard ratio [HR]: 8.39; 95% CI 2.56–27.47; P < 0.001), specific survival (HR: 8.19; 95% CI 2.45–27.41; P < 0.001) and overall survival (HR: 6.02; 95% CI 2.25–16.11; P < 0.005).ConclusionsLRR seems to be a significant predictor of distant metastases and survival, and patients who sustain early LRR tend to display a more aggressive clinical course.     

Male breast cancer: A retrospective analysis

BackgroundTo evaluate our results in the treatment of male breast cancer patients with respect to local control (LC), overall survival (OS) and possible prognosis factors for survival.Patients and methodsThirty-nine patients with male breast cancer have been retrospectively studied with the trial aim to evaluate the results of our practice. Among them, 94.8% had invasive ductal carcinoma (IDC), 2.6% invasive papillary carcinoma (IPC) and 2.6% invasive lobular carcinoma (ILC) and the distribution according to stage was found to be 12.8, 46.2, 30.7 and 10.3% in Stages I, II, III and IV, respectively. Among the patients, 7.7% received radiotherapy (RT) and hormonotherapy (HT), 22.8% received chemotherapy (CT), 61.8% received chemoradiotherapy (CRT) and HT and 7.7% received HT in addition to surgery.ResultsThe distant metastases rate was 36% and the local recurrence rate was 5%. All the local recurrences and the distant metastases had occurred after the first two years. The five-year disease free survival (DFS) and OS rates were 65.8 and 80.1% respectively. In our series, univariate analysis for OS demonstrated statistical significance for lymph node metastases (p = 0.00001), stage (p = 0.0098) and age (p = 0.03); while RT in the treatment modality (p = 0.6849), and tumor size (p = 0.4439) demonstrated no significance. The presence of lymph node metastases significantly impairs OS (p = 0.004) and DFS (p = 0.014) in multivariate analysis.ConclusionPostoperative radiotherapy was important in the management of male breast cancer to improve LC resulting in one local failure, but did not improve OS and DFS in our analysis. The presence of lymph node metastases significantly impaired OS and DFS.     

443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011

BackgroundMalignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents.Methods443 patients ⩽18 years of age with malignant melanoma were prospectively registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Cases were collected from 58 participating centres. 276 paediatric cases with a follow-up >3 months were evaluated for survival probabilities and prognostic factors by Kaplan–Meier method.ResultsAge of diagnosis ranged from 3 months to 18 years (median age 16 years). The male to female ratio was 0.8 (202 male, 240 female). Most melanoma were located at the trunk (n = 195) and the lower extremity (n = 114). Patients with >3 months of follow-up (median 55 months) showed an overall survival (OS) of 94.8% in 5 years. Survival according to tumour stage was 98.5% for stage I (n = 190), 91.1% for stage II (n = 39) and 53.0% for stage III/IV tumours (n = 11). Worse outcome was seen in patients with nodular melanoma (OS 77.9%, n = 42) compared to superficial spread histotype (OS 100%, n = 138) or other histotype (OS 96.9%, n = 88) (p < 0.0001), in case of thicker tumours (Clark level IV or V, OS 87.1%, n = 84) compared to thinner tumours (Clark level I, II, III, OS 99.1%, n = 164) (p = 0.0008) and in case of ulceration (OS 65.6%, n = 17) compared to no ulceration (OS 99.2%, n = 182).ConclusionPatient and tumour characteristics in paediatric melanoma patients show no evident differences to adult melanoma cases. The same clinical approach as in adults should be used.     

Incidence of brain metastases as a first site of recurrence among women with triple receptor-negative breast cancer

BACKGROUND:

This retrospective study sought to define the incidence of brain metastases as a first site of recurrence among women with triple receptor–negative breast cancer (TNBC).

METHODS:

A total of 2448 patients with stage I through III TNBC who were diagnosed between 1990 and 2010 were identified. We computed the cumulative incidence of developing brain metastases as a first site of recurrence at 2 and 5 years. Cox proportional hazards models were fitted to determine factors that could predict for the development of brain metastases as a first site of recurrence. The Kaplan‐Meier product limit method was used to compute survival following a diagnosis of brain metastases.

RESULTS:

At a median follow‐up of 39 months, 115 (4.7%) patients had developed brain metastases as a first site of recurrence. The cumulative incidence at 2 and 5 years was 3.7% (95% confidence interval [CI] = 2.9%‐4.5%) and 5.4% (95% CI = 4.4%‐6.5%), respectively. Among patients with stage I, II, and III disease, the 2‐year cumulative incidence of brain metastases was 0.8%, 3.1%, and 8%, respectively (P < .0001). The 5‐year cumulative incidence was 2.8%, 4.6%, and 9.6% among patients with stage I, II, and III disease, respectively (P < .0001). In the multivariable model, patients with stage III disease had a significant increase in the risk of developing brain metastases as a first site of recurrence (hazards ratio = 3.51; 95% CI = 1.85‐6.67; P = .0001) compared to patients with stage I disease. Those with stage II disease had a nonsignificant increased risk of developing brain metastases as a first site of recurrence (hazards ratio = 1.61; 95% CI = 0.92‐2.81; P = .10) compared with patients with stage I disease. Median survival following a diagnosis of brain metastases was 7.2 months (range, 5.7‐9.4 months).

CONCLUSIONS:

Patients with nonmetastatic TNBC have a high early incidence of developing brain metastases as a first site of recurrence, which is associated with subsequent poor survival. Patients with stage III TNBC in particular would be an ideal cohort in which to research preventive strategies. Cancer 2012. © 2012 American Cancer Society.     

Survival of patients with metastatic melanoma and brain metastases in the era of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies: A systematic review

BackgroundThe incidence of brain metastases (BM) in melanoma patients is common and associated with poor prognosis. MAP-kinase inhibitors and immunologic checkpoint blockade antibodies led to improved survival of metastatic melanoma patients; however, patients with BM are under-represented or excluded from the majority of clinical trials and the impact of new drugs on their survival is less clear. With the present systematic review, we aimed to analyze outcomes of patients with melanoma BM treated with the new drugs, both in the setting of phase I–II–III clinical trials and in the “real world”.MethodsAn electronic search was performed to identify studies reporting survival outcomes of patients with melanoma BM treated with MAP-kinase inhibitors and/or immunologic checkpoint blockade antibodies, regardless of study design.ResultsTwenty-two studies were included for a total of 2153 patients. Median OS was 7.9 months in phase I–II–III trials and 7.7 months in “real world” studies. In clinical trials, median OS was 7.0 months for patients treated with immunotherapy and 7.9 months for patients treated with BRAF inhibitors. In “real world” studies, median OS was 4.3 months and 7.7 months for patients treated with immunotherapy and BRAF inhibitors, respectively. Evidence of clinical activity exists for both immunotherapy and MAP-kinase inhibitors.ConclusionsMAP-kinase inhibitors and immunologic checkpoint blockade antibodies have clinical activity and may achieve improved OS in patients with metastatic melanoma and BM. These results support the inclusion of patients with BM in investigations of new agents and new treatment regimens for metastatic melanoma.     

Adjuvant treatment of in-transit melanoma: Narrowing the knowledge gap left by clinical trials

Few clinical trials address efficacy of adjuvant systemic treatment in patients with in-transit melanoma (ITM). This study describes adjuvant systemic therapy of ITM patients beyond clinical trials. In this study, we included stage III adjuvant-treated melanoma patients registered in the nationwide Dutch Melanoma Treatment Registry between July 2018 and December 2020. Patients were divided into three groups: nodal disease only, ITM only and ITM and nodal disease. Recurrence patterns, recurrence-free survival (RFS) and overall survival (OS) at 12-months were analyzed. In our study population of 1037 patients, 66.8% had nodal disease only, 16.7% had ITM only and 16.2% had ITM with nodal disease. RFS at 12-months was comparable in the nodal only and ITM only group (72.2% vs70.1%, P = .97) but lower in ITM and nodal disease patients (57.8%; P = .01, P < .01). Locoregional metastases occurred as first recurrence in 38.9% nodal disease only, 71.9% of ITM-only and 44.0% of ITM and nodal disease patients. Distant recurrences occurred in 42.3%, 18.8% and 36.0%, respectively (P = .02). 12-months OS was not significantly different for nodal disease only patients compared with ITM-only (94.4% vs 97.6%, P = .06) but was significantly higher for ITM-only compared with ITM and nodal disease patients (97.6% vs 91.0%, P < .01). In conclusion, we showed that in the adjuvant setting, RFS rates in ITM-only patients are similar to non-ITM, though better than in ITM and nodal disease patients. Adjuvant-treated ITM-only patients less often experience distant recurrences and have a superior OS compared with ITM and nodal disease patients.     

Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study

BackgroundThe clinical features and the prognostic relevance of vitiligo lesions in melanoma patients are still controversial. This prospective observational study was designed to characterise the clinical features of melanoma-associated vitiligo, to analyse the association with other autoimmune manifestations and to ascertain whether the development of vitiligo lesions carries a prognostic relevance on the clinical course of melanoma.Materials and methodsA total of 2954 consecutive patients have been included; multivariate analyses of distant metastasis-free survival (DMFS) and overall survival (OS) were carried out to ascertain the independent prognostic role of vitiligo as a time-dependent covariate.ResultsVitiligo was demonstrated in 83 of 2954 melanoma patients (2.8%). A significantly higher percentage of autoimmune diseases was demonstrated in vitiligo patients (7 of 83) with respect to patients without vitiligo (80 of 2871) (P = 0.004). Multivariate analyses selected the time-dependent covariate vitiligo as the favourable independent prognostic variable associated to a longer DMFS in stage III and a higher OS in both stage III and stage IV.ConclusionMelanoma-associated vitiligo should be considered as a distinct clinical entity, separate from vitiligo vulgaris, and identifies a subgroup of patients characterised by a high prevalence of immune-mediated diseases and by a favourable prognosis.     

Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy,anti-CTLA-4 therapy,BRAF/MEK inhibitors,BRAF inhibitor,or conventional chemotherapy

Novel targeted and immunotherapeutic agents have revolutionized systemic melanoma management. We note differing rates of distant brain control as well as overall survival following systemic treatment and stereotactic radiosurgery (SRS) in melanoma brain metastases management. These data support further research to determine the potential synergistic effect between these agents with SRS.BackgroundThe effect of immunologic and targeted agents on intracranial response rates in patients with melanoma brain metastases (MBMs) is not yet clearly understood. This report analyzes outcomes of intact MBMs treated with single-session stereotactic radiosurgery (SRS) and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAFi, or conventional chemotherapy.Patients and methodsPatients were included if MBMs were treated with single-session SRS within 3 months of receiving systemic therapy. The primary end point of this study was distant MBM control. Secondary end points were local MBM control defined as a >20% volume increase on follow-up MRI, systemic progression-free survival, overall survival (OS) from both SRS and cranial metastases diagnosis, and neurotoxicity. Images were reviewed alongside two neuro-radiologists at our institution.ResultsNinety-six patients were treated to 314 MBMs over 119 SRS treatment sessions between January 2007 and August 2015. No significant differences were noted in age (P = 0.27), gender (P = 0.85), treated gross tumor volume (P = 0.26), or the diagnosis-specific graded prognostic assessment (P = 0.51) between the treatment cohorts. Twelve-month Kaplan–Meier (KM) distant MBM control rates were 38%, 21%, 20%, 8%, and 5% (P = 0.008) for SRS with anti-PD-1 therapies, anti-CTLA-4 therapy, BRAF/MEKi, BRAFi, and conventional chemotherapy, respectively. No significant differences were noted in the KM local MBM control rates among treatment groups (P = 0.25). Treatment with anti-PD-1 therapy, anti-CTLA-4 therapy, or BRAF/MEKi significantly improved OS on both univariate and multivariate analyses when compared with conventional chemotherapy.ConclusionIn our institutional analysis of patients treated with SRS and various systemic immunologic and targeted melanoma agents, significant differences in distant MBM control and OS are noted. Prospective evaluation of the potential synergistic effect between these agents and SRS is warranted.     

Survival differences among women with de novo stage IV and relapsed breast cancer

BackgroundThe objective of this retrospective study was to determine whether differences in survival exist between women with de novo stage IV and relapsed breast cancer.Patients and methodsThree thousand five hundred and twenty-four women with de novo stage IV or relapsed breast cancer diagnosed from 1992 to 2007 were identified. Disease-free interval (DFI) was defined as the time from the diagnosis of primary nonmetastatic breast cancer to the date of the first distant metastases. Kaplan–Meier product limit method was used to estimate overall survival (OS). Cox proportional hazards model was fitted to determine the association between metastatic disease (relapsed versus de novo) and OS after controlling for other patient/tumor characteristics.ResultsSix hundred and forty-three (18.2%) women had de novo stage IV disease and 2881 (81.8%) had relapsed disease. Median follow-up was 19 months. Median OS among patients with de novo stage IV and relapsed disease was 39.2 and 27.2 months, respectively (P < 0.0001). In the multivariable model, women with relapsed disease had an increased risk of death compared with patients with de novo disease (HR = 1.75, 95% confidence interval 1.47–2.08, P < 0.0001). When the multivariable model was stratified by DFI, women with relapsed disease with DFI <6 months, ≥6 months to <2 years, or ≥2 to <5 years each had a significantly higher risk of death compared with women with de novo stage IV disease. The risk of death was not statistically different among patients with relapsed disease with DFI >5 years compared with those with de novo disease.ConclusionsThis large cohort study provides further insight into the natural history of relapsed and de novo stage IV breast cancer. DFI plays an important role in the prognosis for patients with relapsed breast cancer.     

Phosphorylated p38, a negative prognostic biomarker,complements TNM staging prognostication in colorectal cancer

Phosphorylated p38 (p-p38) played a pivotal role in the regulation of disease progression and correlated with tumor prognosis. Here, we characterized the prognostic effect of p-p38 in colorectal cancer (CRC). Three hundred and sixteen CRC patients in stages I–III were recruited in this study. P-p38 expression was semi-quantitatively evaluated using tissue microarrays and immunohistochemistry staining. Overall survival (OS), disease-free survival (DFS), local failure-free survival (LFFS), and distant metastasis-free survival (DMFS) of patient subgroups, segregated by p-p38 expression level and clinical stage, were compared using Kaplan–Meier analysis. We found that p-p38 was overexpressed in 48.1 % (152/316) CRC tissues, whereas low or deficiently expressed in normal adjacent epithelia. Overexpression of p-p38 predicted poor OS (P?P?=?0.002), LFFS (P?=?0.016), and DMFS (P?=?0.025) in CRC. Importantly, patient subgroups in the early stage (stages I?+?II) and with low p-p38 had similar OS, PFS, LFFS, and DMFS probabilities to that of stage I, whereas those with high p-p38 were similar to stage III disease. In addition, for stage III disease, the subgroup with low p-p38 had a similar survival probability to that of stage I, whereas the subgroup with high p-p38 had the worst survival. Multivariate Cox analysis confirmed that p-p38 was indeed a significantly independent factor for death, recurrence, and distant metastases in CRC. Our results demonstrated that p-p38 was a negative independent prognostic factor for CRC. Complementing TNM staging with p-p38 might refine the risk definition more accurately for a subset of patients.     

Locoregional Control,Overall Survival,and Disease-Free Survival in Stage IIIA (N2) Non–Small-Cell Lung Cancer: Analysis of Resected and Unresected Patients

IntroductionThe standard of care for stage IIIA (N2) non–small-cell lung cancer (NSCLC) includes concurrent definitive chemoradiation (dCRT) followed by durvalumab, thus challenging the role of surgery in resectable patients. We assessed locoregional disease control and survival in patients with surgically resected and unresected stage IIIA (N2) NSCLC disease.Patients and MethodsWe conducted a retrospective analysis from prospectively collected databases at MD Anderson Cancer Center. Patients undergoing neoadjuvant chemotherapy and surgery or dCRT for clinical stage IIIA (N2) disease (2004-2014) were evaluated. Primary outcomes included locoregional disease control, disease-free survival (DFS), and overall survival (OS). Kaplan-Meier outcome analyses were performed.ResultsOf the 159 resected patients, the majority had lobectomy (82.4%), followed by pneumonectomy (11.9%) and sublobar resection (5.7%). The 30- and 90-day mortality rates were 0.6% and 1.3%, respectively. At median follow-up of 52.8 months, recurrence was 55.3%, with 44.0% having distant and 15.1% locoregional recurrence. At 5 years, OS was 50.8% and DFS was 33.1% Median OS was 61.2 months. A total of 366 patients underwent dCRT, with intensity-modulated radiation in 64.5%, proton therapy in 26.0%, and 3-dimensional conformal radiotherapy in 9.6%. The mean dose was 68.1 Gy. At median follow-up of 20.8 months, recurrence was 53.6%, with distant and locoregional recurrence of 40.7% and 30.3%, respectively. At 5 years, OS was 29.2% and DFS was 20.5%. Median OS was 27.5 months.ConclusionStage IIIA (N2) NSCLC continues to be a heterogeneous disease, and patients with surgically resected and unresected disease represent different risk populations. Ongoing immunotherapy trials may further redefine treatment algorithms in this complex patient population.