Multiplexed immunohistochemical analysis of the immune microenvironment of biliary tract cancers pre- & post-neoadjuvant chemotherapy: case series.

Background: Neoadjuvant chemotherapy (NACT) is increasingly being used in the management of locally advanced biliary tract cancer (BTC). The evidence suggests a contributing role of tumor infiltrating immune cells in the prognosis and response. We set out to characterize immune modulation of tumor immune microenvironment in BTC following NACT. Case Description: Patients with BTC who underwent diagnostic biopsy, then NACT then resection between 2014-2018 were identified. Multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis was performed with a series of immune markers to characterize T-cells, immune checkpoints etc. on pre- & post-NACT tumor tissue. Density was calculated for each marker. The final analysis included five patients. Median age was 48 (range, 41-56) years, with 4 female, 4 intrahepatic cholangiocarcinoma and 1 gallbladder. All patients received gemcitabine/cisplatin as NACT (median of 5 cycles). Median time from diagnosis to surgery was 4.3 (range, 1.4-7.8) months. All patients were mismatch repair proficient (pMMR). NACT on average produced a depletion of all immune markers. Given small sample size, each patient was considered their own control and changes in mean cell densities post-NACT were calculated. Patient #2 with a 40-fold increase in PD-L1 expression & 5-fold decrease in CD8:FOXP3 ratio after NACT notably had the shortest disease-free interval (DFI). Patient #3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold with a decrease in PD-L1. Conclusions: Preliminary results suggest NACT may differentially modulate various compartments of the immune tumor contexture despite overall cell depletion. Future studies should focus on strategies to expand immune modulation of tumor microenvironment, including immune-oncology agents to augment the effects of chemotherapy.

Adjuvant Chemotherapy Is Not Guided by Pathologic Treatment Effect After Neoadjuvant Chemotherapy in Pancreatic Cancer.

OBJECTIVES: Currently, there is no guidance for optimal adjuvant chemotherapy selection after pancreatectomy with a partial or poor response to neoadjuvant therapy. This study seeks to describe an institution's practice patterns of adjuvant chemotherapy selection after neoadjuvant therapy. METHODS: Patients at a single institution receiving neoadjuvant chemotherapy followed by pancreatectomy for pancreatic cancer were reviewed. Patients enrolled in trials or without follow-up were excluded. Types of chemotherapy, the College of American Pathologists pathologic tumor response, and medical oncology plans were recorded. RESULTS: Forty-one patients met inclusion criteria. Pathologic review of treatment effect demonstrated that 3 patients (7.3%) had complete pathologic response, 3 (7.3%) had near complete pathologic response, 16 (39%) had partial response, and 14 (34.1%) had poor/no response to neoadjuvant chemotherapy. Fourteen of the 30 patients with partial or poor response (46.7%) received an alternate adjuvant regimen. Pathologic response to neoadjuvant chemotherapy specifically guided therapy in 11 (30.5%) patients. CONCLUSIONS: Despite 73.1% of patients with partial or poor response to neoadjuvant chemotherapy, only 46.7% received a different adjuvant regimen. Medical oncologists infrequently considered treatment effect when choosing adjuvant therapy. Pathologic response to neoadjuvant chemotherapy should be considered when selecting adjuvant chemotherapy.

Impact of High-Quality Goals-of-Care Discussions on Oncologist Productivity.

PURPOSE: To study factors that have an impact on the conduct of high-quality goals of care (GoC) discussions and productivity of oncologists among four different practice settings in patients with advanced cancer. METHODS: Solid-tumor oncologists from community, academic, municipal, and rural hospitals were randomly assigned to receive a coaching model of communication skills to help them facilitate a GoC discussion with newly diagnosed patients with advanced cancer who had a less-than-2-year prognosis. Patients were surveyed after the first restaging visit regarding the quality of the GoC discussion on a scale of 0 to 10 (0, worst; 10, best) with a score of 8 or better indicating a high-quality GoC discussion. Productivity was measured by work revenue value units (wRVUs) per hour for the day each oncologist saw the study patient after imaging. RESULTS: The four sites differed significantly in the socioeconomic patient populations they served and in the characteristics of the oncologists who cared for the patients. Overall median productivity across the four sites was 3.6 wRVU/hour, with the highest observed in the community hospital (4.3 wRVU/hour) and the lowest in the rural setting (2.9 wRVU/hour; P < .001). There was no significant difference in productivity observed when high-quality GOC discussion occurred versus when it did not (3.6 v 3.7 wRVU/hour; P = .86). CONCLUSION: Despite differences in patient populations and oncologists' characteristics between the four practice settings, the conduct of high-quality GoC discussions did not affect productivity.

Conducting Goals-of-Care Discussions Takes Less Time Than Imagined.

PURPOSE: To describe the length of encounter during visits where goals-of-care (GoC) discussions were expected to take place. METHODS: Oncologists from community, academic, municipal, and rural hospitals were randomly assigned to receive a coaching model of communication skills to facilitate GoC discussions with patients with newly diagnosed advanced solid-tumor cancer with a prognosis of < 2 years. Patients were surveyed after the first restaging visit regarding the quality of the GoC discussion on a scale of 0-10 (0 = worst; 10 = best), with ≥ 8 indicating a high-quality GoC discussion. Visits were audiotaped, and total encounter time was measured. RESULTS: The median face-to-face time oncologists spent during a GoC discussion was 15 minutes (range, 10-20 minutes). Among the different hospital types, there was no significant difference in encounter time. There was no difference in the length of the encounter whether a high-quality GoC discussion took place or not (15 v 14 minutes; P = .9). If there was imaging evidence of cancer progression, the median encounter time was 18 minutes compared with 13 minutes for no progression (P = .03). In a multivariate model, oncologist productivity, patient age, and Medicare coverage affected duration of the encounter. CONCLUSION: Oncologists can complete high-quality GoC discussions in 15 minutes. These data refute the common misperception that discussing such matters with patients with advanced cancer requires significant time.

Effects of a Communication Intervention Randomized Controlled Trial to Enable Goals-of-Care Discussions.

PURPOSE: Patients with advanced cancer often have a poor understanding of cancer incurability, which correlates with more aggressive treatment near the end of life (EOL). We sought to determine whether training oncologists to elicit patient values for goals-of-care (GoC) discussions will increase and improve these discussions. We explored its impact on use of aggressive care at EOL. METHODS: We enrolled and used block randomization to assign 92% of solid tumor oncologists to 2-hour communication skills training and four coaching sessions. We surveyed 265 patient with newly diagnosed advanced cancer with < 2-year life expectancy at baseline and 6 months. We assessed prevalence and quality of GoC communication, change in communication skills, and use of aggressive care in the last month of life. RESULTS: Intervention (INT) oncologists' (n = 11) skill to elicit patient values increased (27%-55%), while usual care (UC) oncologists' (n = 11) skill did not (9%-0%; P = .01). Forty-eight percent (n = 74) INT v 51% (n = 56) UC patients reported a GoC discussion (P = .61). There was no difference in the prevalence or quality of GoC communication between groups (global odds ratio, 0.84; 95% CI, 0.57 to 1.23). Within 6 months, there was no difference in deaths (18 INT v 16 UC; P = .51), mean hospitalizations (0.47 INT v 0.42 UC; P = .63), intensive care unit admissions (5% INT v 9% UC; P = .65), or chemotherapy (26% INT v 16% UC; P = .39). CONCLUSION: Use of a coaching model focused on teaching oncologists to elicit patient values improved that skill but did not increase prevalence or quality of GoC discussions among patients with advanced cancer. There was no impact on high care utilization at EOL.

Genistein combined with FOLFOX or FOLFOX-Bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study.

BACKGROUND: Epidemiologic and preclinical data suggest isoflavones have anticancer activity in colorectal malignancy prevention and treatment. This is the first clinical trial assessing safety and tolerability of Genistein in combination with chemotherapy in metastatic colorectal cancer. METHODS: Patients who had histologically confirmed metastatic colorectal cancer and had not received previous treatment were eligible to enroll. Subjects were treated with FOLFOX or FOLFOX-Bevacizumab as per the investigator choice. Genistein was administered orally for 7 days every 2 weeks, beginning 4 days prior to chemotherapy and continuing through days 1-3 of infusional chemotherapy. Primary endpoint was safety and secondary endpoints included cycle 6 response rate, best overall response rate (BOR), and median progression-free survival (PFS). RESULTS: Thirteen patients received chemotherapy with Genistein in this trial. The most common adverse events related to Genistein alone were mild and included headaches, nausea, and hot flashes. One subject was observed to have grade 3 hypertension. No increase in chemotherapy-related adverse events was observed when Genistein was added. BOR and median PFS were 61.5% and 11.5 months, respectively. CONCLUSION: We observed that adding Genistein to FOLFOX or FOLFOX-Bevacizumab was safe and tolerable. Efficacy results are notable and warrant verification in larger clinical trials. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov Identifier: NCT01985763.

ME-143 Is Superior to Genistein in Suppression of WNT Signaling in Colon Cancer Cells.

BACKGROUND: This study tested the effect of the soy isoflavones genistein and ME-143, and two chemotherapeutic agents, 5-fluorouracil (5FU) and oxaliplatin, on WNT signaling. MATERIALS AND METHODS: Colon cancer cell lines RKO (hereditary nonpolyposis colorectal cancer type) and DLD1 (most common colorectal cancer type driven by a mutation in WNT pathway) were utilized. WNT throughput was measured using a ß-catenin-responsive SuperTopFlash luciferase assay. A stabilized ß-catenin construct was employed to test ß-catenin involvement in the mechanism of drug activity. RESULTS: ME-143 was a more than 10-fold potent inhibitor of DLD1 proliferation than genistein at 3.125 µM. Genistein alone did not inhibit WNT signaling in either cell line. In RKO cells, oxaliplatin and its combination with 5FU significantly inhibited WNT throughput. Neither 5FU, oxaliplatin nor their combination inhibited WNT signaling in DLD1 cells. In both the RKO and DLD1 cell lines, ME-143 significantly reduced WNT throughput by 65-75%. The introduction of stabilized ß-catenin attenuated the ME-143-dependent inhibition of the WNT/ß-catenin pathway. CONCLUSION: ME-143 alone and in combination with 5FU and oxaliplatin effectively inhibits the WNT/ß-catenin pathway in colorectal cancer cells of diverse genetic background. ß-Catenin is directly involved in the mechanism of inhibition, and clinical studies are warranted.

Impact of inpatient radiation on length of stay and health care costs.

BACKGROUND: Health care costs are rising. Identifying areas for health care utilization savings may reduce costs. OBJECTIVE: To identify oncology patients receiving inpatient radiotherapy with the purpose of measuring length of stay (LoS) and hospital charges. METHODS: During July 2013 the oncology service physicians at Mount Sinai Medical Center in New York City were surveyed daily to identify patients receiving inpatient radiation. Actual LoS, acuity LoS were determined from the chart review. Expected LoS was calculated using the University Healthsystem Consortium database. Charges associated with actual LoS, acuity LoS, and expected LoS were then reported. Actual and expected LoS were compared for inpatient radiotherapy and nonradiotherapy groups. RESULTS: 7 patients were identified as having remained in the hospital to receive radiation treatment. In that cohort, the average actual LoS and charges per patient were 40.1 and $48,724, compared with acuity LoS and charges of 25.6 days and $34,089 and expected LoS and charges of 7.7 days and $10,028. Mean LoS and charges attributed to radiation alone amounted to 11 days and $12,514. The mean actual LoS of oncology patients admitted during the same time period who did not receive radiation was 6.7 days, compared with 40.1 days for patients who received radiation (𝑃 < .0001). LIMITATIONS: Inability to access actual reimbursement data prevented exact cost calculations, small sample size, and single-institution focus. CONCLUSIONS: Delivery of radiation therapy during inpatient hospitalization extends LoS and contributes to higher health care costs. Methods to facilitate the delivery of outpatient radiotherapy may result in cost savings.

An Unusual Course of Metastatic Gastroesophageal Cancer.

We are reporting on a case of a 41-year-old woman who presented with metastatic gastroesophageal junction cancer and who achieved prolonged survival with a multimodal treatment approach. After initially experiencing robust response to chemotherapy, she was treated for distant recurrence with palliative radiation to the gastrohepatic and supraclavicular lymph nodes and subsequently, given her unusual near-complete response, with reirradiation to the abdomen with curative intent for residual disease. The case presented is unique due to the patient's atypical treatment course, including technically difficult reirradiation to the abdomen, and the resulting prolonged survival despite metastatic presentation.

Sickle cell trait: is there an increased VTE risk in pregnancy and the postpartum?

UNLABELLED: Blacks are purported to have a higher venous thromboembolism (VTE) risk than whites. We hypothesized that this might be due, in part, to the greater presence of sickle cell trait (SCT) among blacks. We investigated whether the presence of SCT resulted in a higher VTE incidence in a population predisposed to VTE, the pregnant/postpartum women. METHODS: Using a mirrored clinical database that prospectively gathered in- and out-patient information for the years 1998-2008, we collected demographic data, including hemoglobin electrophoreses, on all pregnant/postpartum non-Hispanic women who delivered at a large, diverse, urban hospital. We identified those women who developed VTE either while pregnant or postpartum during those 11 years. Charts initially identified as potential VTE cases were subjected to review to ensure accuracy of VTE coding. RESULTS: Of 12,429 women, 679 non-Hispanic SCT black women, 5,465 non-Hispanic Hemoglobin AA (women with HbA as the only hemoglobin present on electrophoresis, with normal amounts of the minor hemoglobins) black women and 1,162 non-Hispanic HbAA white women were included in the analysis. SCT prevalence was high (11.1%) within this black population as compared to 8.3% in the general non-white population. Proportions with VTE were similar for black SCT and black HbAA groups: 0.44% for the SCT group, 0.49% for non-Hispanic black HbAA women. Black HbAA women had a non-significantly higher proportion of VTE than white HbAA women 0.49% vs 0.26% (RR 1.9, 95%CI:0.6,6.3, p = 0.28). Women with VTE were older than those without VTE (32.2 vs. 27.6 years, p = 0.0002) and the majority of VTE occurred postpartum in all groups, and significantly in the HbAA groups. There was no increase in the incidence of pulmonary emboli in the SCT group. CONCLUSION: In the largest analysis to date, we could not detect a meaningful difference in peripartum VTE incidence between women with and without sickle cell trait.

Sweet's syndrome in a patient with metastatic melanoma after ipilimumab therapy.

Sweet's syndrome, a neutrophilic dermatosis, is a known paraneoplastic complication occurring with various malignancies. It has been infrequently reported in association with melanoma. Ipilimumab is an antibody against an inhibitory cytotoxic T-lymphocyte-associated antigen 4 receptor on T cells. It is associated with a range of immune-related toxicities. Sweet's syndrome in association with ipilimumab has been reported only briefly in the literature. However, neutrophilic infiltration has been seen in biopsies of patients with ipilimumab-associated enterocolitis. We report, in detail, the case of a woman with metastatic melanoma undergoing ipilimumab therapy. After the second cycle of immunotherapy, the patient presented with high-grade fever followed by a rash on her hands. No infectious etiology was elucidated after an extensive workup. Pathologic examination of the skin biopsy from the hands confirmed neutrophilic dermatosis. The patient was treated with systemic steroids achieving complete remission of the skin lesions. Physicians should be aware of Sweet's syndrome as a possible cutaneous side effect of ipilimumab therapy and be familiar with its management.