Search

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive hereditary cancer syndrome due to biallelic germline mutation involving one of the four DNA mismatch repair genes. Here we present a case of a young female with CMMRD, homozygous for the c.2002A>G mutation in the PMS2 gene. She developed an early stage adenocarcinoma of the colon at the age of 14. Surveillance MRI of the brain at age 18 resulted in the detection of an asymptomatic brain cancer. On resection, this was diagnosed as an anaplastic astrocytoma. Due to emerging literature suggesting benefit of immunotherapy in this patient population, she was treated with adjuvant dual immune checkpoint inhibition, avoiding radiation. The patient remains stable with no evidence of progression 20 months after resection. The patient’s clinical course, as well as the rational for considering adjuvant immunotherapy in patients with CMMRD are discussed in this report.

The PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was administered at a starting dose of 100 mg bid 2 days on/5 days off weekly with TMZ 150 mg/m2 daily for 5 days/28-days cycle. Dose escalation was according to a 3 + 3 design. Secondary objectives included assessment of vistusertib safety and toxicity profile, and preliminary efficacy. 15 patients were enrolled in the study (median age 66 (range 51–77), females 8). Vistusertib 125 mg BID in combination with TMZ 150 mg/m2 daily for 5 days was well tolerated. Vistusertib treatment-related adverse events were generally grade 1–2, with the most frequently reported being fatigue, gastrointestinal symptoms, and rash. Of 13 response evaluable patients, 1 patient (8%) had a partial response ongoing at 7.6 months of follow-up, and 5 patients had stable disease (38%) as best response (median duration 9.6 months, range 3.7-not yet reached). Six-month progression-free survival (PFS) rate was 26.6%. Combination of vistusertib with TMZ in GBM patients at first recurrence demonstrated a favorable safety profile at the tested dose levels.

Systemic therapy is an essential part of treatment for all patients with small-cell lung cancer (sclc) and for most patients with non-small-cell lung cancer (nsclc). Standards of care have evolved dramatically since 2009, especially in the setting of incurable or advanced nsclc. Part of that evolution has been the incorporation of immuno-oncology drugs, especially immune checkpoint inhibitors (icis) into multiple therapeutic scenarios. In the present review, we discuss the role of the immune system in lung cancer and the previous failures of immunotherapy for patients with lung cancer. We then provide an overview of the existing evidence for the use of icis in patients with advanced nsclc that is either treatment-naïve or pretreated, for consolidative treatment after chemoradiotherapy in stage iii nsclc, and for palliative therapy in patients with sclc. Finally, we discuss duration of treatment, special populations, and the future of immuno-oncology for patients with lung cancer. Overall, we provide an evidence-based snapshot of immuno-oncology agents in the treatment of lung cancer up to early 2019.

Lung cancer is the most common cause of cancer-related deaths worldwide with non-small cell lung cancer (NSCLC) making up most of these cases. Males have poorer overall survival compared to women following a lung cancer diagnosis. Many studies have focused on the effects of estrogen to explain higher survival rates among women, but few have looked at the effects of androgens. We describe the expression of the androgen receptor (AR) and Ki67 in lung cancer specimens in the Manitoba Tumor Bank (MTB) and correlate these factors with patient outcome. Using the MTB, we performed immunohistochemistry on lung cancer tissue to determine expression of the AR and Ki67. These were then correlated with patient outcome. Of the 136 cases, 55% were female and 55% were adenocarcinoma. AR expression was not independently associated with outcome. Ki67 was associated with a significantly higher hazard ratio for death and recurrence (HR 2.19, 95% CI 1.30-3.70; HR 1.92, 95% CI 1.07-3.46, respectively). AR expression modified the effect of Ki67 on outcome, such that when both were expressed, there was no association with recurrence or survival (HR 2.39, 95% CI 1.31-4.36 for AR- Ki67+ vs HR 1.54, 95% CI 0.44-5.37 for AR+ Ki67+). Ki67 was associated with poorer outcomes alone. AR status alone was not associated with outcome. Although the mechanism remains unclear, AR status seems to negate the association of a high Ki67 and poor outcome.

Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.

Objectives:Glioblastoma is a lethal disease in the elderly population. We aimed to evaluate disease and treatment outcomes in the oldest-old patients.Methods:Patients >80 years old with histologically confirmed glioblastoma treated between 2004 and 2009 were identified. We included patients managed with best supportive care (BSC), temozolomide (TMZ) alone, radiotherapy (RT) alone, or concomitantly with TMZ (CRT). Survival outcomes were analyzed using the Kaplan–Meier method.Results:Ultimately, 48 patients were analyzed. Median age and Eastern Cooperative Oncology Group (ECOG) Performance Status were 82 years and 2, respectively. The median Age-Adjusted Charlson Index (AAC) was 6. Gross total and subtotal resections were performed in 16.7% and 18.8% of patients, respectively. Biopsy followed by RT alone was the treatment modality for 23/48 (47.9%), while 17/48 (35.4%) received surgery followed by RT alone or CRT. A total of 8 (16.7%) were managed with BSC after biopsy. Median overall survival (OS) and progression-free survival (PFS) were 4.1 (95% confidence interval [95% CI] 3.3-4.9) and 2.7 (95% CI 1.5-3.9) months, respectively. Improved median OS was observed in those treated with surgical resection followed by RT alone or CRT (7.1 months), compared to biopsy followed by RT alone (4.2 months) or BSC (2.0 months;p=0.002). Surgical resection, age≤85, and AACp=0.032,p=0.031, andp=0.02, respectively). Cause of death was neurological progression in 56% of cases. RT was well-tolerated.Conclusions:PFS and OS outcomes remain poor in the oldest-old patients (>80 years old). Younger age, lower AAC, surgical resection, and adjuvant treatment were associated with improved OS.

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.

Objective: Paraneoplastic neurologic syndrome (pns) is a rare condition indirectly caused by an underlying malignancy. In many cases, the malignancy is occult at the time of the pns diagnosis, and the optimal diagnostic modality to detect the underlying tumour is unclear. In the present study, we aimed to assess the utility of 18F-fluorodeoxyglucose positron-emission tomography (fdg-pet) or pet integrated with computed tomography (pet/ct) in the investigation of these patients. Methods: We retrospectively analyzed data from the PET Access Program (pap) database in the province of Ontario to identify patients who underwent fdg-pet/ct imaging as part of a workup for pns. In all patients, prior conventional imaging was negative or indeterminate. To determine the diagnostic accuracy of fdg-pet/ct, data about demographics, presenting symptoms, and biochemical and radiologic workup, including fdg-pet/ct imaging results, were compared with data collected by the Ontario Cancer Registry (ocr). A systematic review of the literature and meta-analysis using our study inclusion criteria were performed for studies of fdg-pet accuracy. Results: Of 29 patients identified in the pap database, 9 had fdg-pet/ct results suspicious for malignancy. When correlated with data from the ocr, 5 fdg-pet/ct results were informative, resulting in a detection rate of 17%. Local sensitivity and specificity were 0.83 and 0.83 respectively. Two studies meeting our criteria were identified in the literature. The pooled sensitivity and specificity from the literature and local data were 0.88 and 0.90 respectively. Conclusions: When investigating for underlying malignancy in patients with suspected pns and negative conventional imaging, pet has high sensitivity and specificity.

Bone lesions from metastatic solid tumors and multiple myeloma (MM) represent an important source of morbidity in patients with incurable malignancies. Dysregulation of osteoclast and osteoblast activity caused by tumor cells in the bone microenvironment weakens the structural integrity of bone and predisposes to skeletal-related events (SREs), which can include severe bone pain, pathologic fracture, spinal cord compression and hypercalcemia. In order to reduce the risk of these complications, the supportive treatment of patients with bone lesions from advanced cancer typically includes the use of bone-modifying agents (BMAs), specifically bisphosphonates and denosumab. The choice of specific agent, dosing schedule and duration of therapy should be individualized by taking into account disease characteristics, medication side-effect profiles and patient preferences.

The epidemiology of lung cancer differs between men and women. The role of androgens in lung cancer remains unclear. This study was performed to determine if exposure to androgen pathway manipulation (APM) is associated with greater survival in male patients diagnosed with lung cancer. Using a retrospective cohort design, all men diagnosed with lung cancer from January 1, 2004 to December 31, 2010 were identified from the population-based Manitoba Cancer Registry and Manitoba Health Administrative Databases. Information from the Drug Program Information Network (DPIN) was used to determine prescriptions filled for antiandrogens, 5-alpha reductase inhibitors, and gonadotropin-releasing hormone (GnRH) agonists. Multivariable Cox proportional hazards analysis with time-varying exposure variables was used to compare survival. A total of 3018 men with lung cancer were identified between 2004 and 2010. Of these, 339 (11.5 %) were identified as having used a form of APM. The majority of patients received 5-alpha reductase inhibitors. Patients who received APM prior to the diagnosis of lung cancer had no significant difference in survival (HR 0.97, p = 0.69) compared to those who did not. Patients exposed to APM after their diagnosis were found to have a significantly better survival (HR 0.36, p = 0.0007), as were those exposed both before and after diagnosis (HR 0.53, p

The data about whether patients with a prior urothelial cancer (uca) are at increased risk of colorectal cancer (crc) are conflicting. We used a competing risks analysis to determine the risk of crc after uca. Historical cohorts were assembled by record linkage of Manitoba Cancer Registry and Manitoba Health databases. The incidence of crc for individuals with uca as their first cancer between 1987 and 2009 was compared with the incidence for randomly selected age-and sex-matched individuals without a cancer diagnosis at the index date (uca diagnosis date). Three competing outcomes (crc, another primary cancer, and death) were evaluated by competing risks proportional hazards models with adjustment for relevant confounders. The cohorts of 4591 patients with uca and 22,312 without uca were followed for a total of 179,287 person&ndash, years (py). After uca, the rate of subsequent colon cancer in uca patients was 4.5 per 1000 py compared with 3.6 per 1000 py in the non-cancer cohort. In the multivariable analysis, no overall increase in crc risk was observed for patients first diagnosed with uca (hazard ratio: 0.88, 95% confidence interval: 0.70 to 1.1, p = 0.26). Because of similar crc risk, a similar crc screening strategy should be applied for individuals with and without uca.

Until recently, systemic therapy for gastrointestinal malignancies was restricted to relatively noncancer-specific cytotoxic chemotherapy. Over the last 15 years targeted therapies have become available, most notably bevacizumab in the case of advanced colorectal cancer. Unfortunately, there are no predictive biomarkers to guide the use of this agent. In this review article, we describe the advent of "Precision Medicine" (in part, the use of patient-specific molecular markers to inform treatment) in gastrointestinal cancers: The use of monoclonal antibodies targeting epidermal growth factor receptor in advanced colorectal cancer, and human epidermal growth factor receptor 2-neu in advanced esophagogastric cancer. In both instances, biomarkers help in selecting appropriate patients for such treatment.

1597 Background: The epidemiology of lung cancer differs between men and women. There exists significant evidence suggesting estrogens influence the pathophysiology of lung cancer, however the role of androgens remains unclear. This study was performed to determine if exposure to androgen deprivation therapy (ADT) has an effect on survival in male patients (pts) diagnosed with lung cancer. Methods: Using the population-based Manitoba Cancer Registry and Manitoba Health Administrative Databases, all pts diagnosed with lung cancer from January 1, 2004 to December 31, 2010 were identified. Information from the Drug Program Information Network (DPIN) and the Aria electronic record at CancerCare Manitoba were used to determine prescriptions filled for anti-androgens, 5-alpha reductase inhibitors and GnRH agonists as a measure of exposure (defined as having filled at least 2 prescriptions and/or bilateral orchiectomy). Multivariable analysis with Cox proportional hazards analysis was used to compare survival. Results: A total of 3018 men with lung cancer were identified between 2004 and 2010. Of these, 339 (10%) were identified as having used a form of ADT. The majority of pts received 5-alpha reductase inhibitors (85%), the most common being finasteride (80% of total). Multivariable analysis revealed that patients who received ADT prior to the diagnosis of lung cancer had no statistically significant difference in survival (HR: 0.97 p=0.69) compared to those who did not. Patients exposed to ADT after their diagnosis were found to have a significantly better survival than those not exposed (HR 0.36 p=0.0007). This effect was also seen in those who received ADT before and after diagnosis (HR 0.53 p