Prognostic value of Gustave Roussy immune score in operable pancreatic adenocarcinoma.

Background: The Gustave Roussy immune score (GRIm score) is a laboratory index developed to predict survival in nonsmall cell lung cancer patients undergoing immunotherapy and has shown that the pretreatment value is an independent prognostic factor for survival. In this study, we aimed to determine prognostic significance of GRIm score for pancreatic adenocarcinoma that have not been determined in the literature for pancreatic cancer before. The reason for choosing this scoring is to show that the immune scoring system works as a prognostic marker in pancreatic cancer known as immune-desert tumor via immune properties of microenvironment. Methods: Medical records of patients with histologically confirmed pancreatic ductal adenocarcinoma, who were treated and followed up between December 2007 and July 2019 at our clinic, were reviewed retrospectively. GRIm scores of each patient were calculated at the time of diagnosis. Survival analysis were performed according to risk groups. Results: A total of 138 patients were included in the study. While 111 (80.4%) patients were in the low-risk group; 27 (19.6%) were in high-risk group according to GRIm score. Median OS was 36.9 months (95% Confidence interval (CI): 25.42-48.56) in lower GRIm scores, and it was 11.1 months (95% CI: 6.83-15.44) in higher GRIm scores (P = 0.002). One-two-three-year OS rates were 85% versus 47%, 64% versus 39%, 53% versus 27% for low versus high GRIm scores, respectively. The multivariate analysis revealed that high GRIm score was an independent poor prognostic factor. Conclusion: GRIm can be used as a noninvasive, easily applicable, practical prognostic factor in pancreatic cancer patients.

Can assessment of disease burden and quality of life based on mobility level in patients with end-stage cancer provide an insight into unmet needs? An exploratory cross-sectional study.

PURPOSE: The purpose of this study was to: 1) investigate the differences in the needs of end-stage cancer who can move independently, using mobility aids (MA), or are bedridden; and 2) determine the effects of these different mobility levels on the patients' current quality of life (QoL), fatigue, and mental conditions. METHODS: The study employed an exploratory prospective cross-sectional study design, which was carried out in two hospitals. The study included 99 end-stage cancer. The mobility levels of the patients were evaluated in three groups: Group 1: bedridden; Group 2: mobile with MA; and Group 3: ambulatory (under supervision or fully independent). A core cancer-specific questionnaire-integrating system for assessing health-related QOL (EORTC-QLQ-C15-PAL), the Piper Fatigue Scale (PFS), and the Hospital Anxiety-Depression scale were utilized.The median age was 60years (31-83). Cancer types were as follows: gastrointestinal (45.5%), lung (38.4%), breast (4%), genitourinary system (4%), and others (8%). Forty-two percent of the patients were completely bedridden, 42.2% used MA, and 15.2% were independently ambulatory. The EORTC QLQ-C15-PAL physical (=.000) and emotional function values (=.029) differed among mobilization statuses. There was a significant difference among mobilization groups, in terms of behavioral values, in the PFS (=.006). The depression rate in the independent ambulatory group was lower than in the bedridden and MA groups (=0.011; =0.004).  p p p p1  p2 . CONCLUSION: Health-related QoL, fatigue level, and emotional state vary in end-stage cancer who undergo evaluations according to their mobility levels. These patients should be assessed comprehensively, and treatment plans should be organized carefully, with a multidisciplinary approach.

Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

Real-world assessment of quality-of-life in patients with breast cancer treated with adjuvant endocrine therapy.

Objective: The aim of this study was to investigate quality-of-life (QoL) in breast cancer (BC) patients treated with adjuvant endocrine therapy (AET). Methods: We designed a cross-sectional study of 233 BC patients treated with AET and used the Functional Assessment of Cancer Therapy - Breast questionnaire. Results: No significant difference was observed between endocrine agents. Duration of AET did not affect QoL. In the entire cohort, multivariate analysis determined age (p = 0.034) and switching treatment from tamoxifen to aromatase inhibitors (p = 0.049) as significant positive coefficients of QoL, while comorbidity (p = 0.072) tended to be associated with lower scores. Education level (p = 0.001) and chemotherapy (p = 0.04) were significant predictors of QoL in the tamoxifen group, while comorbidity (p = 0.04), surgery type (p = 0.02), radiotherapy (p = 0.006) and stage (p = 0.009) had a significant impact on QoL in aromatase inhibitors group. Conclusion: Evaluating the well-being of BC patients by QoL questionnaires is of great importance to identify particular subgroups that may require supportive care.

Breast cancer (BC) remains the most common cancer among women worldwide. Hormone receptor-positive (estrogen receptor- and/or progesterone receptor-positive) BC represents 70% of all cases. Advances in the treatment of disease lead to improved patient survival. As a result, quality-of-life (QoL) becomes a major concern in clinical practice. This study aimed to assess the impact of socio-demographic, clinical and treatment-related factors on QoL among patients with BC treated with adjuvant endocrine therapy. We used the Functional Assessment of Cancer Therapy ­ Breast questionnaire to evaluate QoL. In the entire cohort, multivariate analysis determined age and switching treatment from tamoxifen to aromatase inhibitors to be significant positive coefficients of QoL, while comorbidity tended to be associated with lower scores. Education level and chemotherapy were significant determinants of QoL in the tamoxifen group, while comorbidity, surgery type, radiotherapy and disease stage had a significant impact on QoL in the aromatase inhibitor group. These findings can be utilized to identify certain subgroups that may need greater supportive care.

Prognostic Value of Tissue-Resident Memory T Cells and Tumor Microenvironmental Features in Resected Pancreatic Adenocarcinoma

Background: Pancreatic ductal adenocarcinoma differs from other solid tumors with its unique immunosuppressive microenvironment and non-immunogenic feature. There are not many studies in the literature investigating the effect of these features on prognosis. Aims: To investigate the prognostic value of tissue-resident memory T cells, tumor microenvironment features, and tumor-associated immune cells in resected pancreatic ductal adenocarcinomas. Study Design: Retrospective cross-sectional study. Methods: Of 138 patients diagnosed with pancreatic ductal adenocarcinoma between 2011 and 2018, 81 were included in the study. Specimens from operated patients were reassessed separately as peritumoral and intratumoral areas for tissue resident memory cells and tumor microenvironmental elements (tumor infiltrating lymphocytes, tumor stroma, CD204+ macrophages, PDL1+ immune cells). Disease-free survival and overall survival were defined from the date of operation to the date of recurrence and the date of first diagnosis to the date of death, respectively. If the patient was alive, the last visit date was taken into account. Results: The median age at diagnosis was 63 (range: 40-78). The median follow-up period was 18.9 months (range: 1.4-80.4 months). Median overall survival was 23.7 months (1.4-80.4 months) and median disease-free survival was 10.8 months (1.4-74.4 months). Patients with higher intra-tumoral tissue-resident memory cell counts had a longer survival trend than those having lower values (25.6 months vs. 18 months, respectively, P = .84). According to microenvironmental evaluations, lower stromal score (defined as stroma having less desmoplasia and rich in cells) and presence of peritumoral Crohn's-like inflammatory response were associated with higher survival (29.2 months vs. 19.7 months for low vs. high stromal scores, respectively, P = .16 and 30.2 months vs. 18.1 months for the presence of Crohn's-like inflammatory response P = .13). Decreased survival was observed in tumors with increased CD204+ tumor-associated macrophages which were immunosuppressive elements of the microenvironment (12 months vs. 26.3 months for intra-tumoral assessment, P = .29). Conclusion: Tissue-resident memory T cells and other microenvironmental features may be prognostic in resectable pancreatic ductal adenocarcinomas. Further studies with larger cohorts are needed for validation.

Merkel cell carcinoma in Turkey: A multicentric study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin. In this study, we aimed to evaluate the clinicopathologic characteristics, treatment outcomes, and survival of MCC cases in Turkey. MATERIALS AND METHODS: The patients diagnosed with MCC between 1999 and 2018 at twenty different centers in Turkey were included in the study. Patient and tumor characteristics and adjuvant and metastatis treatment outcomes were analyzed retrospectively. RESULTS: The median age of totally 89 patients was 70 (26-93). The most common primary location was lower limbs (n = 29, 32.5%). Immunohistochemically, CK20 positivity was present in 59 patients (66.3%). Only two patients had secondary malignancy. The majority of the patients (n = 76, 85.4%) were diagnosed at the localized stage. Surgery was performed for all patients in the early stage, and adjuvant radiotherapy or/and chemotherapy was applied to 52.6% (n = 40) of nonmetastatic patients. The median follow-up was 29 months. Recurrence developed in 21 (27.6%) of the 76 patients who presented with local or regional disease. Two-year disease-free survival (DFS) was 68.1% and 5-year DFS was 62.0% for localized stage. The 5-year DFS was similar for patients receiving adjuvant treatment (chemotherapy, radiotherapy, or sequential chemoradiotherapy) and without adjuvant therapy (P > 0.05). Two-year overall survival in patients who presented with localized disease was 71.3% and 18.5% in metastatic patients (P < 0.001). In the metastatic stage, platinum/etoposide combination was the most preferred combination regimen. Median progression-free survival (PFS) in first-line chemotherapy was 7 months (95% confidence interval: 3.5-10.5 months; standart error: 1.78). CONCLUSIONS: Although MCC is rare in Turkey, the incidence is increasing. Gender, CK20 status, tumor size, lymph node involvement, and adjuvant treatment were not associated with recurrence.

BRAF Inhibitor Therapy-Related Encephalitis in a Patient with Metastatic Melanoma.

INTRODUCTION: BRAF inhibitors such as encorafenib and vemurafenib in combination with MEK inhibitors are commonly used for the treatment of patients with BRAF V600-mutant melanoma. CASE PRESENTATION: A patient with relapsed metastatic melanoma with a BRAF V600 mutation was started on treatment with vemurafenib and cobimetinib. Within 2 weeks of treatment start, he was hospitalized and diagnosed with encephalitis through a lumbar puncture and treated with corticosteroids, with subsequent normalization of cerebrospinal fluid (CSF) findings. When he recovered and was switched to encorafenib treatment, the same symptoms recurred, and the patient was treated with high-dose steroids and intravenous immunoglobulin, again with improvement in his CSF. He has not had a relapse of his symptoms since BRAF inhibitor treatment was permanently discontinued. CONCLUSION: This is the first known report of a patient who has developed encephalitis because of treatment with BRAF inhibitors.

Prognostic factors in progressive high-grade glial tumors treated with systemic approach: A single center experience.

PURPOSE: Malignant high-grade gliomas are the most common and aggressive type of primary brain tumor, and the prognosis is generally extremely poor. In this retrospective study, we analyzed the outcome of systemic treatment in recurrent high-grade glioma patients and the impact of prognostic factors on survivals. METHODS: Data from 114 patients with recurrent high-grade glioma who received systemic treatment and followed in our clinic between 2012 and 2018 were retrospectively analyzed. Eastern Cooperative Oncology Group (ECOG) performance status, age, gender, histology, type of surgical resection, side effects after systemic treatment (deep vein thrombosis, hypertension, proteinuria), IDH1 and alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutation status were investigated as prognostic factors for progression-free survival and overall survival. RESULTS: At the time of diagnosis, the median age was 48 (17-77) and 68% of the patients were male. Most common pathologic subtype was glioblastoma multiforme (68%). Median follow-up duration was 9.1 months (1-68 months). Median progression-free survival and overall survival were 6.2 months and 8 months, respectively. In multivariate analysis, ECOG PS, deep venous thrombosis and the presence of ATRX and IDH1 mutation were found to be independent prognostic factors for progression-free survival (p < 0.05) and, ECOG PS, the presence of ATRX and IDH1 mutation for overall survival (p < 0.05). CONCLUSION: Our study is real life data and the median progression-free survival and overall survival rates are similar to the literature. We have found ECOG PS, presence of ATRX and IDH1 mutation to be independent prognostic factors for both progression-free survival and overall survival.

Modified Glasgow Prognostic Score, Prognostic Nutritional Index and ECOG Performance Score Predicts Survival Better than Sarcopenia, Cachexia and Some Inflammatory Indices in Metastatic Gastric Cancer.

Background: Gastric carcinoma (GC) patients usually present with locally advanced or metastatic disease; therefore treatment aim is mainly palliation. In this study our purpose is to analyze the prognostic values of the sarcopenia index (SI), cachexia index (CIn) and other inflammatory indexes (advanced lung cancer inflammation index [ALI], modified Glasgow Prognostic Score [mGPS], prognostic index [PI], prognostic nutritional index [PNI] and neutrophil-to-lymphocyte ratio [NLR]) in metastatic GC patients.Methods: Data from the files of metastatic GC patients, who applied to Medical Oncology outpatient clinic in Marmara University Pendik Education and Research Hospital between January 2011 and June 2016, were retrospectively reviewed. Five hundred seventy patients with gastric cancer were detected. Exclusion criteria were the inability to reach the patient surveys for prognostic index calculations, the presence of additional comorbidities to affect the laboratory parameters, and the absence of metastatic disease. Finally, 87 of these patients were included in this study. For SI calculation L3 level muscle area was measured from patients' computed tomography (CT) by a radiologist. SI reference value was obtained from western-EGWSOP (The European Working Group on Sarcopenia in Older People) and eastern (Harada Y, et al.) sources separately, as Turkey doesn't have a reference value for SI. NLR cutoff value was accepted as the median value of patients' NLR measurements. Statistical analysis was conducted using SPSS. Kaplan-Meier and Cox regression models were used to assess independent prognostic factors. The area under the curve was used to compare the prognostic value of indexes.Results: The median length of follow-up of 87 patients was nine months (1-64 mo,/s), and 78 patients died during follow-up. Fifty-nine patients were male (63%), and the median age was 62 (range, 23-88). According to univariate analysis high mGPS and PI score, PNI level <45, NLR level ≥ 3.41, ALI level <18, CI level under 35, SI (Harada Y, et al) ≤44.5 for males and ≤36.5 for females, ECOG score ≥ 2, weight loss more than 10% during last 6 mo, BMI under 24 were poor prognostic factors. Age, gender, having multiple organ metastasis, history of gastric surgery, positivity C-erb-B2, SI (EGWSOP) ≤52.4 for males, and ≤38.4 for females did not have any impact on survival. According to multivariate analysis, high mGPS (score 2) (HR 2,494, 95% CI 1.25-4 .94, p = 0.02), PNI (score 1) (HR 4.2, 95% CI 1.73-10.1, p < 0.001) and ECOG score (≥2) (HR 1.541, 95% CI 1,089-4,214, p = 0.004) have been found to be independent prognostic factors which are determining the survival. mGPS was found to be more valuable than other indexes for predicting mortality by measuring the AUC with ROC analysis.Conclusions: In our study, mGPS, PNI and ECOG score were independent indicators for shorter survival in metastatic gastric cancer patients. mGPS and PNI, which can be done by using only serum CRP, albumin level and complete blood count, might be inexpensive, practical and beneficial to use in routine clinical practice to determine survival.

Differences in PET/CT standardized uptake values involvement and survival compared to histologic subtypes of lung adenocarcinoma.

PURPOSE: Lung adenocarcinoma is histologically diverse but has distinct histologic growth patterns. There is no consensus on the clinical benefit of this histologic model. We aimed to evaluate the differences in the distribution of the preoperative primary tumor positron emission tomography (PET)/computed tomography (CT) standardized uptake values (SUVs) and survival in the lung adenocarcinoma subtypes. METHODS: We retrospectively evaluated the data of 107 patients with resected lung adenocarcinoma who had preoperative PET/CT between 2005 and 2017 in a single center. Patients had lepidic, acinar, papillary, micropapillary, and solid histologic subtypes. We compared fluorodeoxyglucose SUVs and survival data of histologic subtypes. RESULTS: The median age of the patients was 62 years (40-75), 76.4% were male, the median SUVmax was 9.4 (1-36.7), and the median follow-up time was 29 months (3-135 months). The median overall survival (OS) was 71 months and the median progression-free survival (PFS) was 33 months. SUVmax was significantly different in histologic subtypes: values for papillary, micropapillary, solid, acinar, and lepidic subtypes were 9.7, 8, 12, 9.1, and 3.9, respectively (p = 0.000). Solid predominant adenocarcinoma had significantly higher SUVmax than the other subtypes (p = 0.001). Lepidic predominant adenocarcinoma had significantly lower SUVmax than the other subtypes (p = 0.000). There was no significant difference in OS between histologic subtypes (p = 0.66), but PFS was significantly different between the groups (p = 0.017), and the solid subtype had a shorter PFS than the other histologic subtypes. CONCLUSION: Lung adenocarcinoma consists of a diverse group of diseases. Different SUVmax values are seen in different histologic subtypes of nonmetastatic lung adenocarcinoma. Solid predominant types have high SUVmax values while lepidic predominant types have lower SUVmax values. The solid subtype had a shorter PFS than the other histologic subtypes.

Results of treating primary pulmonary sarcomas and pulmonary carcinosarcomas.

OBJECTIVE: Primary pulmonary sarcomas (PPS) and pulmonary carcinosarcomas (PCS) are rare aggressive lung malignancies. We reviewed our 21-year experience with the surgical and nonsurgical treatment of both tumors, comparing their clinical, histopathologic, and treatment results. METHODS: All patients with PPS or PCS who underwent surgical and nonsurgical treatment between 1998 and 2019 at our cancer center were retrospectively reviewed. Multivariable Cox proportional hazards model was constructed. RESULTS: In total, 100 patients were analyzed: 45 with PPS and 55 with PCS. Among patients with PPS, 31 of 45 (69%) underwent surgery with 1 (3%) operative mortality. For patients with PCS, 29 of 55 (53%) underwent surgery with no operative mortality. Patients with PPS were younger than PCS (P < .01). Fewer patients were smokers among PPS (58%) versus PCS (93%) (P < .01). For resected PPS, mean tumor size was 8.2 ± 4.1 cm (range 2.2-18.0) compared with 10.1 ± 5.0 cm (range 3.9-17.0) for unresected PPS. Tumor size for resected PCS was 6.2 ± 2.6 cm (range 2.0-10.5) versus 6.8 ± 3.5 cm (range 1.2-13.5) for unresected PCS. Of resected patients, 5 of 31 (16%) with PPS and 9 of 29 (31%) with PCS were node positive. Overall survival estimates were as follows: for PPS, median survival and 5-year overall survival for resected versus unresected cases were 39.6 months/28.7% versus 4.9 months/7.8%. For PCS, survival estimates were 23.6 months/31.0% versus 14.9 months/28.2%, respectively. In multivariable analyses (N = 100), age, smoking history, histology, and surgery were risk factors of survival. CONCLUSIONS: At initial evaluation, PPS and PCS presented with large-sized tumors and usually were not stage I. Surgery had a positive impact on survival among patients with PPS. Whenever feasible, surgical resection, even in locally advanced disease, may yield long-term survival in these aggressive lung tumors, although the level of evidence is low.

Is insulin resistance a predictor for complete response in breast cancer patients who underwent neoadjuvant treatment?

PURPOSE: Neoadjuvant chemotherapy is the standard front-line treatment modality in locally advanced breast cancer. Achieving pathological complete response (pCR) is a significant prognostic factor for prolonged disease-free and overall survival. Insulin resistance is defined as a pathological condition in which insulin effect is impaired in peripheral target tissues such as the skeletal muscle, liver, and adipose tissue. The relationship between breast cancer and insulin resistance is controversial. In this study, our aim is to evaluate the role of insulin resistance, body mass index (BMI), metabolic syndrome, and inflammation markers to predict complete response in breast cancer patients who underwent neoadjuvant treatment. METHODS: Data from 55 locally advanced non-diabetic breast cancer patients, treated with neoadjuvant chemotherapy between 2015 and 2017, were retrospectively evaluated. Homeostatic model assessment, IR = insulin resistance (HOMA-IR) was calculated by using the obtained insulin and fasting blood glucose values before neoadjuvant chemotherapy (fasting insulin × fasting glucose/405). We considered a cut-off of 2.5 for insulin resistance. The systemic inflammatory index (SII), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) were calculated. RESULTS: Twenty-five patients had no insulin resistance. The most common pathologic subtype (56%) was hormone receptor (HR) positive and human epidermal growth factor receptor-2 (Her-2)-negative invasive ductal carcinoma. Sixteen (29%) patients had a pathological complete response (pCR). We found that the probability of pCR in patients with insulin resistance was 4.7 times lower than that in patients without insulin resistance [OR: 4.7 (95%CI 1.7-17.2), p = 0.01]. CONCLUSION: Our results revealed that insulin resistance may have a negative effect on pathological complete response (pCR) following neoadjuvant therapy particularly with hormone-positive and Her-2-negative cases of non-diabetic breast cancer.

Relationship Between Programmed Death Receptor-Ligand 1 Expression and Response to Checkpoint Inhibitor Immunotherapy in Pulmonary Sarcomatoid Carcinoma: A Pooled Analysis.

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) or pleomorphic carcinoma is a rare subtype of non-small cell lung cancer. Some reports have suggested the efficacy of checkpoint inhibitor immunotherapy for PSC. However, owing to the small number of patients in each report, it remains unclear whether programmed death receptor-ligand 1 (PD-L1) expression is predictive of tumor response or survival. PATIENTS AND METHODS: The English literature was systematically searched for articles published from 2015 to 2019 and reported on tumor response or progression-free survival (PFS) after immunotherapy for advanced PSC. In addition, our institutional electronic medical records were searched for eligible cases to be included. Pooled analyses were performed. RESULTS: Analyses included 90 patients. Best tumor response was partial or complete response in 54.5%, stable disease 15.9%, and progressive disease in 29.6%. The median PFS was 7.0 months. Among 66 patients with reported PD-L1 expression, the level was <1% in 7 patients (10.6%), 1%-49% in 10 patients (15.2%), and ≥50% in 49 patients (74.2%). A positive relationship between PD-L1 level and tumor response was observed. Among 47 patients with a PD-L1 of ≥50%, 33 patients (70.2%) achieved response, compared with 5 of 10 patients (50%) with a PD-L1 of 1%-49% and 2 of 7 patients (28.6%) with a PD-L1 of <1% (P = .026). PFS was superior among patients with a PD-L1 of ≥1% compared with those with a PD-L1 of <1% (14.4 months vs. 2.7 months respectively; P = .04). CONCLUSIONS: Among patients with advanced PSC, PD-L1 expression is significantly associated with increased tumor responses and improved PFS after checkpoint inhibitor immunotherapy.

Treatment Options for Advanced Melanoma After Anti-PD-1 Therapy.

PURPOSE OF REVIEW: While anti-PD-1 antibodies have been a breakthrough in the treatment of patients with advanced melanoma, a substantial proportion of patients are still refractory to or progress after treatment with anti-PD-1 immunotherapy. Here, we review the post anti-PD-1 therapy alternatives that may be possible for patients with unresectable or metastatic stage 3 or 4 melanoma. RECENT FINDINGS: Currently available treatment options include BRAF-targeted and MEK inhibitor-targeted therapies for those with BRAFV600 mutant melanoma, while for patients with BRAF-WT melanoma or those who have already received prior BRAF-targeted therapy, options include anti-CTLA-4 therapy, alone or in combination with anti-PD-1 therapy, or for selected patients, clinical trials that may incorporate other immune checkpoint inhibitors or co-stimulatory agonists, oncolytic virotherapies, adoptive cellular therapies, or other novel agents. Participation in clinical trials is critical in order to delineate what more effective treatment options are and which group of patients after receiving prior anti-PD-1 therapy.

A rare case of primary rectal choriocarcinoma and review of the literature.

INTRODUCTION: Primary choriocarcinoma of the colon is an extremely rare neoplasm which has a poor prognosis. Only 18 cases have been previously reported in English medical literature. Here we present a case of primary rectal choriocarcinoma with a good response to chemotherapy and review the literature on this uncommon tumor. CASE REPORT: A 36-year-old woman presented with abdominal pain and vaginal bleeding. Abdominal magnetic resonance imaging revealed 6.9 × 5.3 × 6.4 cm hypervascular mass posterior to uterus very close to rectum. Beta-human chorionic gonadotropin (ß-hCG) level was markedly elevated. Low anterior resection of the rectum with lymph node dissection and total abdominal hysterectomy with bilateral salpingo-oophorectomy were performed. Pathologic diagnosis was reported as colonic choriocarcinoma with a focal component of adenocarcinoma. Post-operative magnetic resonance imaging detected multiple metastatic lesions throughout the liver. The patient was treated with systemic chemotherapy using bleomycin, etoposide and cisplatin (BEP protocol). After three cycles, ß-hCG level decreased to normal and magnetic resonance imaging showed regression of liver metastasis. However, the patient died of respiratory failure due to bleomycin toxicity and pneumonia accompanied by rapid disease progression. DISCUSSION: This is an extremely rare case of primary rectal choriocarcinoma. Due to poor prognosis of the disease, it seems very important to start prompt treatment to improve patient's survival.

Neoadjuvant BRAF-targeted therapy in regionally advanced and oligometastatic melanoma.

Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible. A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging, and clinical outcomes were evaluated. Results: Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST response based on preoperative imaging and pathologic response. After a median of 43-month follow-up, only 1 patient (10%) with a pCR recurred, while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapse-free (RFS) and overall survival (OS) compared to patients with residual tumor. Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS.

How long should we continue crizotinib in ALK translocation-positive inflammatory myofibroblastic tumors? Long-term complete response with crizotinib and review of the literature.

INTRODUCTION: Inflammatory myofibroblastic tumor is a rare disease which is typically seen in children and young adults. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in over-expression of anaplastic lymphoma kinase gene. Herein, we present two anaplastic lymphoma kinase-positive cases with long-term remission with crizotinib. We do not know how long these therapies need to be continued. CASE REPORTS: We present two cases of inflammatory myofibroblastic tumor treated with anaplastic lymphoma kinase inhibitor therapies: an 8-year-old Turkish boy and a 21-year-old Caucasian man. MANAGEMENT AND OUTCOME: Two cases, both with good tumor control under crizotinib, but one who progressed on drug holiday, responded again to the same drug, and had a very short period of response after restarting crizotinib. CONCLUSION: A molecular-targeted drug (anaplastic lymphoma kinase inhibitor) was found to be extremely effective as selective therapy for inflammatory myofibroblastic tumor with anaplastic lymphoma kinase translocation. Here, we want to emphasize the continuation of this treatment after achieving a good response until progression or a major side effect.

Impact of the Charlson Comorbidity Index on dose-limiting toxicity and survival in locally advanced and metastatic renal cell carcinoma patients treated with first-line sunitinib or pazopanib.

BACKGROUND: Anti-angiogenic tyrosine kinase inhibitors, sunitinib and pazopanib, have proven efficacy in advanced renal cell carcinoma, with specific adverse events occurring during treatment process. Comorbidities can reflect functional status and have prognostic value in oncology patients. We aimed to assess the association of the Charlson Comorbidity Index with severe toxicities and mortality in renal cell carcinoma cases treated with front-line sunitinib or pazopanib. METHODS: Files of locally advanced and metastatic renal cell carcinoma patients who received first-line sunitinib or pazopanib were retrospectively examined. Charlson Comorbidity Index of each patient was calculated. Patients were also stratified into Memorial Sloan-Kettering Cancer Center risk groups. Predictors of dose-limiting toxicity were evaluated with binomial logistic regression analysis. Univariate and multivariate Cox regression models were utilized to determine prognostic factors for survival. RESULTS: The study included 102 patients, 64 were treated with first-line sunitinib and 38 with pazopanib. In 42 patients (41.9%), Charlson Comorbidity Index was 9 or more. Dose-limiting toxicities were significantly more frequent in Charlson Comorbidity Index ≥9 group (69% vs. 40%, p = 0.004), and Charlson Comorbidity Index independently predicted dose-limiting toxicity (Hazard ratio (HR) = 4.30, p = 0.002). After adjusting for other variables, a Charlson Comorbidity Index of ≥9 is also a significant prognostic factor for progression-free (HR = 1.76, p = 0.02) and overall survival (HR = 1.75, p = 0.03). CONCLUSIONS: Charlson Comorbidity Index may be a valuable method to estimate prognosis and optimize therapy in patients with advanced renal cell carcinoma receiving first-line sunitinib or pazopanib.

Assessment of survival and prognostic factors in metastatic colorectal cancer patients treated with first-line bevacizumab-based therapy.

PURPOSE: Colorectal cancer (CRC) is a significant cause of cancer mortality worldwide. Survival has improved with bevacizumab in metastatic CRC treatment. Our purpose was to analyse survival and prognostic factors in metastatic CRC patients treated with first-line bevacizumab-based treatment. METHODS: Files of CRC patients were examined retrospectively and 360 patients treated with first-line bevacizumab were included. Objective response rates (ORRs), median progression-free and overall survival (PFS and OS) of the patients were calculated. Survival was analyzed with the Kaplan-Meier method. Log-rank test and Cox regression model were used for univariate and multivariate analyses, respectively. RESULTS: Median age at diagnosis was 59.5 years. Of the patients 74.4% had initially stage IV disease. Median PFS was 8.5 months, median OS 25.3 months and ORR was 51.4%. ORRs, median PFS and OS of KRAS mutant and wild-type or unknown patients were statistically similar. In left-sided disease, median PFS and OS (9.6 and 27.1 months) were superior compared to right-sided disease (7.3 and 19.4 months) (p=0.005 and 0.02, respectively). Primary disease location, histopathologic grade, primary surgery and metastasectomy affected OS significantly. Histopathologic grade (hazard ratio=1.77, p=0.002) and metastasectomy (hazard ratio=0.48, p=0.001) were independent prognostic factors. CONCLUSIONS: Our study confirmed that after bevacizumab-based treatment, KRAS status might not be a prognostic factor. We have also shown that left CRC have more favorable outcomes than right CRC in bevacizumab therapy. Additionally, even in metastatic setting histopathologic grade of the primary CRC together with metastasectomy are independent prognostic factors.

Leveraging transcriptional dynamics to improve BRAF inhibitor responses in melanoma.

BACKGROUND: Melanoma is a heterogeneous tumour, but the impact of this heterogeneity upon therapeutic response is not well understood. METHODS: Single cell mRNA analysis was used to define the transcriptional heterogeneity of melanoma and its dynamic response to BRAF inhibitor therapy and treatment holidays. Discrete transcriptional states were defined in cell lines and melanoma patient specimens that predicted initial sensitivity to BRAF inhibition and the potential for effective re-challenge following resistance. A mathematical model was developed to maintain competition between the drug-sensitive and resistant states, which was validated in vivo. FINDINGS: Our analyses showed melanoma cell lines and patient specimens to be composed of >3 transcriptionally distinct states. The cell state composition was dynamically regulated in response to BRAF inhibitor therapy and drug holidays. Transcriptional state composition predicted for therapy response. The differences in fitness between the different transcriptional states were leveraged to develop a mathematical model that optimized therapy schedules to retain the drug sensitive population. In vivo validation demonstrated that the personalized adaptive dosing schedules outperformed continuous or fixed intermittent BRAF inhibitor schedules. INTERPRETATION: Our study provides the first evidence that transcriptional heterogeneity at the single cell level predicts for initial BRAF inhibitor sensitivity. We further demonstrate that manipulating transcriptional heterogeneity through personalized adaptive therapy schedules can delay the time to resistance. FUNDING: This work was funded by the National Institutes of Health. The funder played no role in assembly of the manuscript.