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\"From Edgar Allan Poe to James Ellroy, crime writers have provided some of the most popular, controversial, acclaimed and disturbing works in American literature. 100 American Crime Writers provides critical biographies of some of the greatest and most important crime writers in American history. Both an important scholarly work and an enjoyable read accessible to a wider audience, this addition in Palgrave's Crime Files series includes discussion of the lives of key crime writers, as well as analysis of the full breadth and scope of the genre - from John Dickson Carr's Golden Age detective stories to Raymond Chandler's hardboiled Philip Marlowe novels, Ed McBain's 87th Precinct police procedurals to Megan Abbott's modern day reimagining of the femme fatale. Drawing on some of the best and most recent scholarship in the field, all of the key writers and themes of the genre are discussed in this comprehensive study of one of the most fascinating and popular of literary genres. \"-- Provided by publisher.

The addition of olanzapine to a neurokinin receptor blocker, a serotonin receptor blocker, and dexamethasone markedly improved the control of nausea and vomiting in previously untreated patients receiving highly emetogenic chemotherapy. Chemotherapy-induced nausea and vomiting are associated with a significant deterioration in quality of life and are perceived by patients as major adverse effects of cancer treatment. 1 The use of 5-hydroxytryptamine type 3 (5-HT 3 ) receptor antagonists, 2 dexamethasone, 2 and neurokinin-1 (NK 1 ) receptor antagonists 3 – 9 has significantly improved the control of this troublesome side effect. International guidelines 10 – 12 recommend combinations of these agents to prevent chemotherapy-induced nausea and vomiting in patients receiving moderately or highly emetogenic chemotherapy. Nonetheless, nausea remains a major problem for many patients. 1 , 2 Olanzapine is approved by the Food and Drug Administration (FDA) as an . . .

Head and neck squamous cell carcinoma (HNSCC) is a unique malignancy associated with two distinct risk factors: exposure to typical carcinogens and infection of human papillomavirus (HPV). HPV encodes the potent oncoproteins E6 and E7, which bypass many important oncogenic processes and result in cancer development. In contrast, HPV-negative HNSCC is developed through multiple mutations in diverse oncogenic driver genes. While the risk factors associated with HPV-positive and HPV-negative HNSCCs are discrete, HNSCC patients still show highly complex molecular signatures, immune infiltrations, and treatment responses even within the same anatomical subtypes. Here, we summarize the current understanding of biological mechanisms, treatment approaches, and clinical outcomes in comparison between HPV-positive and -negative HNSCCs.

Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC. In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs ≥1%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p<0·025 (one sided). Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned study treatment. This trial, which is closed for enrolment but continuing for follow-up, is registered with ClinicalTrials.gov, number NCT02039674. Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9–42%]; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia. Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study. Merck & Co.

Pembrolizumab plus pemetrexed–platinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo plus pemetrexed–platinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189. In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m2) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 1–5, every three cycles thereafter during year 1, and every four cycles during years 2–3. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov, number NCT02578680. Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10·5 months (range 0·2–20·4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexed–platinum group and 200 (99%) of 202 patients in the placebo plus pemetrexed–platinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexed–platinum group and 180 (90%) of 200 in the placebo plus pemetrexed–platinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·0 point [95% CI −1·3 to 3·2] increase) and placebo plus pemetrexed–platinum (−2·6 points [−5·8 to 0·5] decrease; between-group difference: 3·6 points [−0·1 to 7·2]; p=0·053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·3 points [95% CI −1·2 to 3·6] increase) than with placebo plus pemetrexed–platinum (−4·0 points [−7·7 to −0·3] decrease; between-group difference: 5·3 points [1·1 to 9·5]; p=0·014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10·2 months to not reached) with pembrolizumab plus pemetrexed–platinum, and was 7·0 months (4·8 months to not reached) with placebo plus pemetrexed–platinum (hazard ratio 0·81 [95% CI 0·60–1·09], p=0·16). The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed–platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer. Merck Sharp & Dohme.

The role of radiotherapy in metastatic renal cell carcinoma is controversial. We prospectively tested the feasibility and efficacy of radiotherapy to defer systemic therapy for patients with oligometastatic renal cell carcinoma. This single-arm, phase 2, feasibility trial was done at one centre in the USA (The MD Anderson Cancer Center, Houston, TX, USA). Patients (aged ≥18 years) with five or fewer metastatic lesions, an Eastern Cooperative Oncology Group status of 0–2, and no more than one previous systemic therapy (if this therapy was stopped at least 1 month before enrolment) without limitations on renal cell carcinoma histology were eligible for inclusion. Patients were treated with stereotactic body radiotherapy (defined as ≤5 fractions with ≥7 Gy per fraction) to all lesions and maintained off systemic therapy. When lesion location precluded safe stereotactic body radiotherapy, patients were treated with hypofractionated intensity-modulated radiotherapy regimes consisting of 60–70 Gy in ten fractions or 52·5–67·5 Gy in 15 fractions. Additional rounds of radiotherapy were allowed to treat subsequent sites of progression. Co-primary endpoints were feasibility (defined as all planned radiotherapy completed with <7 days unplanned breaks) and progression-free survival. All efficacy analyses were intention-to-treat. Safety was analysed in the as-treated population. A second cohort, with the aim of assessing the feasibility of sequential stereotactic body radiotherapy alone in patients with low-volume metastatic disease, was initiated and will be reported separately. This study is registered with ClinicalTrials.gov, NCT03575611. 30 patients (six [20%] women) were enrolled from July 13, 2018, to Sept 18, 2020. All patients had clear cell histology and had a nephrectomy before enrolment. All patients completed at least one round of radiotherapy with less than 7 days of unplanned breaks. At a median follow-up of 17·5 months (IQR 13·2–24·6), median progression-free survival was 22·7 months (95% CI 10·4–not reached; 1-year progression-free survival 64% [95% CI 48–85]). Three (10%) patients had severe adverse events: two grade 3 (back pain and muscle weakness) and one grade 4 (hyperglycaemia) adverse events were observed. There were no treatment-related deaths. Sequential radiotherapy might facilitate deferral of systemic therapy initiation and could allow sustained systemic therapy breaks for select patients with oligometastatic renal cell carcinoma. Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Institute.

Alcohol is a consistently identified risk factor for colon cancer. However, the molecular mechanism underlying its effect on normal colon crypt cells remains poorly understood. We employed RNA-sequencing to asses transcriptomic response to ethanol exposure (0.2% vol:vol) in 3D organoid lines derived from healthy colon (n = 34). Paired regression analysis identified 2,162 differentially expressed genes in response to ethanol. When stratified by colon location, a far greater number of differentially expressed genes were identified in organoids derived from the left versus right colon, many of which corresponded to cell-type specific markers. To test the hypothesis that the effects of ethanol treatment on colon organoid populations were in part due to differential cell composition, we incorporated external single cell RNA-sequencing data from normal colon biopsies to estimate cellular proportions following single cell deconvolution. We inferred cell-type-specific changes, and observed an increase in transit amplifying cells following ethanol exposure that was greater in organoids from the left than right colon, with a concomitant decrease in more differentiated cells. If this occurs in the colon following alcohol consumption, this would lead to an increased zone of cells in the lower crypt where conditions are optimal for cell division and the potential to develop mutations.

Chemoradiotherapy (CRT) for locally-advanced head and neck squamous cell carcinoma (LA-HSNCC) yields 5-year survival rates near 50% despite causing significant toxicity. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase metabolic inhibitor, reduces tumor lactate production and has been used in cancer therapy previously. The safety of adding this agent to CRT is unknown. Our randomized, placebo-controlled, double-blind phase II study added DCA to cisplatin-based CRT in patients with LA-HNSCC. The primary endpoint was safety by adverse events (AEs). Secondary endpoints compared efficacy via 3-month end-of-treatment response, 5-year progression-free and overall survival. Translational research evaluated pharmacodynamics of serum metabolite response. 45 participants (21 DCA, 24 Placebo) were enrolled from May 2011-April 2014. Higher rates of all-grade drug related fevers (43% vs 8%, p = 0.01) and decreased platelet count (67% vs 33%, p = 0.02) were seen in DCA versus placebo. However, there were no significant differences in grade 3/4 AE rates. Treatment compliance to DCA/placebo, radiation therapy, and cisplatin showed no significant difference between groups. While end-of-treatment complete response rates were significantly higher in the DCA group compared to placebo (71.4% vs 37.5%, p = 0.0362), survival outcomes were not significantly different between groups. Treatment to baseline metabolites demonstrated a significant drop in pyruvate (0.47, p < 0.005) and lactate (0.61, p < 0.005) in the DCA group. Adding DCA to cisplatin-based CRT appears safe with no detrimental effect on survival and expected metabolite changes compared to placebo. This supports further investigation into combining metabolic agents to CRT. Trial registration number: NCT01386632, Date of Registration: July 1, 2011.

Numerous demographic factors have been associated with colorectal cancer (CRC) risk. To better define biological mechanisms underlying these associations, we performed RNA sequencing of stem-cell-enriched organoids derived from the healthy colons of seven European Americans and eight African Americans. A weighted gene co-expression network analysis was performed following RNA sequencing. Module–trait relationships were determined through the association testing of each module and five CRC risk factors (age, body mass index, sex, smoking history, and race). Only modules that displayed a significantly positive correlation for gene significance and module membership were considered for further investigation. In total, 16 modules were associated with known CRC risk factors (p < 0.05). To contextualize the role of risk modules in CRC, publicly available RNA-sequencing data from TCGA-COAD were downloaded and re-analyzed. Differentially expressed genes identified between tumors and matched normal-adjacent tissue were overlaid across each module. Loci derived from CRC genome-wide association studies were additionally overlaid across modules to identify robust putative targets of risk. Among them, MYBL2 and RXRA represented strong plausible drivers through which cigarette smoking and BMI potentially modulated CRC risk, respectively. In summary, our findings highlight the potential of the colon organoid system in identifying novel CRC risk mechanisms in an ancestrally diverse and cellularly relevant population.

In this study we aimed to explore the potential biological effect of ethanol exposure on healthy colon epithelial cells using normal human colon 3D organoid \"mini-gut\" cultures. In numerous published studies ethanol use has been shown to be an environmental risk factor for colorectal cancer (CRC) development; however, the influence of ethanol exposure on normal colon epithelial cell biology remains poorly understood. We investigated the potential molecular effects of ethanol exposure in normal colon 3D organoids in a small pilot study (n = 3) using RNA-seq and ATAC-seq. We identify 1965 differentially expressed genes and 2217 differentially accessible regions of chromatin in response to ethanol treatment. Further, by cross-referencing our results with previously published analysis in colorectal cancer cell lines, we have not only validated a number of reported differentially expressed genes, but also identified several novel candidates for future investigation. In summary, our data highlights the potential importance for the use of normal colon 3D organoid models as a novel tool for the investigation of the relationship between the effects of environmental risk factors associated with colorectal cancer and the molecular mechanisms through which they confer this risk.