NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis.

Natural killer (NK) cells are innate lymphoid cells, and their presence within human tumors correlates with better prognosis. However, the mechanisms by which NK cells control tumors in vivo are unclear. Here, we used reflectance confocal microscopy (RCM) imaging in humans and in mice to visualize tumor architecture in vivo. We demonstrated that signaling via the NK cell receptor NKp46 (human) and Ncr1 (mouse) induced interferon-γ (IFN-γ) secretion from intratumoral NK cells. NKp46- and Ncr1-mediated IFN-γ production led to the increased expression of the extracellular matrix protein fibronectin 1 (FN1) in the tumors, which altered primary tumor architecture and resulted in decreased metastases formation. Injection of IFN-γ into tumor-bearing mice or transgenic overexpression of Ncr1 in NK cells in mice resulted in decreased metastasis formation. Thus, we have defined a mechanism of NK cell-mediated control of metastases in vivo that may help develop NK cell-dependent cancer therapies.

Spatial Intratumoral Heterogeneity Expression of PD-L1 Antigen in Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: Immune-checkpoint inhibitors have demonstrated a significant survival benefit in metastatic and non-resectable head and neck squamous cell carcinoma (HNSCC). Patients with a combined positivity score (CPS) of 20 and higher benefit the most from therapy. Inaccurate definition of the CPS category might lead to the incorrect stratification of patients to immunotherapy. This study's main aim was to investigate programmed death-ligand 1 (PD-L1) antigen expression in HNSCC in diverse clinical situations and histological settings. MATERIALS AND METHODS: This is a prospective cohort study conducted in a tertiary referral medical center. Tissues were investigated for PD-L1 expression using the FDA-approved 22C3 immunohistochemistry assay (Dako). We analyzed potential associations between the CPS category and meaningful demographic, clinical, and outcome metrics. Furthermore, we investigated morphologically separate sites for CPS scores in whole surgical tissue specimens and matched preoperative biopsies. RESULTS: We analyzed 36 patients, of whom 26 had oral cavity SCC and 10 had laryngeal SCC. The overall, disease-specific, and progression-free survival of the HNSCC group of patients were not associated with the CPS category (p = 0.45, p = 0.31, and p = 0.88, respectively). There was a significant (18%, 95% CI 0.65-0.9) inconsistency between the CPS category determined in biopsies versus whole carcinoma analyses. We also found an uneven distribution of whole-tumor CPS attributed to spatial carcinoma invasiveness, tumor differentiation, and inflammatory cell infiltration heterogeneity. DISCUSSION AND CONCLUSIONS: Our data suggest that careful selection of tumor area for CPS analysis is important. PD-L1 antigen expression, clinically represented by CPS, may be up- or down-categorized in different clinical and pathological circumstances. The high whole-tissue CPS category scatter may clinically result in potential treatment modifications. We argue that CPS analysis requires not only adequacy (at least 100 viable tumor cells), but also correct representation of the tumor microenvironment.

PD-L1 EXPRESSION IN NORMAL ENDOCRINE TISSUES IS NOT INCREASED DESPITE HIGH INCIDENCE OF PD-1 INHIBITOR-ASSOCIATED ENDOCRINOPATHIES.

OBJECTIVE: Treatment with immune-checkpoint inhibitors often results in endocrine immune-related adverse events (irAEs), affecting the pituitary, thyroid, adrenal, and parathyroid glands and pancreas. The mechanism underlying the endocrine irAEs has not been fully elucidated, and it remains unclear why endocrine organs are so commonly affected. In the present study, we evaluated immunostaining patterns of programmed death-ligand 1 (PD-L1) in normal endocrine tissues to determine whether increased expression may explain the predilection of endocrinopathies in patients treated with programmed cell death-1 inhibitors. METHODS: Normal formalin-fixed paraffin-embedded endocrine tissues (pituitary, thyroid, adrenal, pancreas, and parathyroid) were collected from our hospital's pathology tissue archive. The tissues were assessed for membranous and cytoplasmic PD-L1 immunostaining using the Dako 22C3 pharmDx assay on an automated staining platform. RESULTS: We examined 49 endocrine tissues, including 12 thyroid, 5 pancreatic, 17 adrenal, 5 parathyroid, and 10 pituitary samples. Samples with less than 1% membranous PD-L1-positive cells were considered negative, while those with more than 1% of PD-L1 membranous staining were considered positive. Immunostaining result of immune-related cells was also evaluated, considering the cytoplasmic PD-L1-positive cells with the same cutoff of 1%. None of the endocrine tissues demonstrated PD-L1 positivity higher than 1% in the relevant cells. CONCLUSION: While our results do not suggest a role of PD-L1 expression in the pathogenesis of endocrine irAEs, they may serve as a basis for future studies further investigating the mechanisms of autoimmune, inflammatory, or malignant endocrine conditions.

[NEOADJUVANT CHEMOTHERAPY BEFORE RADICAL CYSTECTOMY - MIGHT IT BE OFFERED SELECTIVELY?]

INTRODUCTION: Neoadjuvant cisplatin-based chemotherapy prior radical cystectomy is the standard of care in patients with a muscle invasive bladder cancer. It is intended to treat micro-metastases. However, most patients do not develop metastases even without chemotherapy and are receiving this treatment in vain. In this study, we looked for pre-operative risk factors for developing metastases that can triage the patients that really need neoadjuvant therapy. METHODS: From 1998 to 2018, 285 patients underwent radical cystectomy without neoadjuvant chemotherapy. During a median follow-up of 42.5 months, 99 patients (34%) developed recurrent disease after a median duration of 12 months. The study compared 10 different preoperative parameters of patients who developed or did not develop recurrence. RESULTS: An increased risk of metastases was found in older patients (39.8% in older than 69 years vs. 33.3% in younger patients, p=0.045), in patients with a high Charlson Comorbidity index (46.2% in 5 and above vs. 28.2% when lower than 4, p=0.003), and in patients with large tumor diameter (p=0.01). No difference was found in the other variables examined including: gender, primary versus secondary tumor, tumor stage, presence of histological variant, hydronephrosis, carcinoma in situ (CIS) or sarcomatoid differentiation. CONCLUSIONS: Older age, comorbidity, and large tumor diameter predict the risk of recurrence after radical cystectomy. However, overlap between the groups precludes the use of these parameters for clinical decisions. Therefore, neoadjuvant chemotherapy treatment should currently be offered to all candidates for radical cystectomy. Hopefully, future molecular markers will be able to predict the risk of metastases.

Behavioral Health Risk Factors: the Interaction of Personal and Country Effects.

PURPOSE: This study investigated the relationship between the individual's self-assessed health status (SAHS) and health-risk factors (smoking, alcohol consumption and obesity), in 16 European countries. The associations were studied for the individual and for the country measures-and in particular, for the unexplored aspect of interaction between individual and country levels of the three risk factors. METHOD: Data for 47,114 adults, who participated in the Survey of Health Aging and Retirement Europe (SHARE), were analyzed using Multilevel Regression Analysis. The individual data were complemented by OECD data that provided country-specific risk measures: percentage of daily smokers, annual per-capita consumption of alcohol (liters), and percentage of obese individuals. RESULTS: We found that the individual's SAHS is negatively associated with smoking and with weight-risk factors and is positively associated with her/his alcohol consumption. The most pronounced associations relate to the weight variables, albeit they are attenuated in countries with higher percentages of obese individuals. Significant differences across countries were evidenced in the association between SAHS and smoking and between SAHS and alcohol consumption. CONCLUSION: Individual health levels are associated with individual risk factors and also with the behaviors in the country. Significant interactions might indicate that psychological factors are at work.

Eosinophilic Fasciitis: A Single Center Experience of Seven Patients.

BACKGROUND: Eosinophilic fasciitis (EF) is a rare disease characterized by scleroderma-like skin, inflammation of deep muscle fascia, hypergammaglobulinemia, peripheral eosinophilia, and elevated erythrocyte sedimentation rate. OBJECTIVES: To present our experience in diagnosis and treatment of seven biopsy-proven EF patients in a large tertiary medical center. METHODS: We screened all patients who were admitted to our tertiary medical center and diagnosed with EF by tissue biopsies from January 2000 to January 2016. We analyzed relevant patient files regarding diagnosis, treatment, and outcome parameters. A comprehensive framework was presented based on the results of our observations and the corresponding literature. RESULTS: We identified seven patients (six males; one child). Mean age at diagnosis was 37.4 years (range 10-67 years). Underlying autoimmune disorders were observed in three patients (42.8 %). Disease anatomical distribution was noted in lower and upper limbs (85.7% and 57.1%, respectively) as well as neck and shoulders (14.3% each). Three patients (42.8%) had a history of initial misdiagnosis. The mean time period from first clinical presentation to histopathological diagnosis was 150.3 days (range 16-602 days). Treatment included oral glucocorticoids (71.4%), pulse methylprednisolone (14.2%), and methotrexate (42.8%). Recovery from symptoms related to EF was observed in six patients. CONCLUSIONS: Diagnosis of EF is primarily based on clinical and histopathological findings. As eradication of this disease can be expedited with early treatment, it is important to increase awareness in the medical community.

Heparanase is preferentially expressed in human psoriatic lesions and induces development of psoriasiform skin inflammation in mice.

Heparanase is the sole mammalian endoglycosidase that selectively degrades heparan sulfate, the key polysaccharide associated with the cell surface and extracellular matrix of a wide range of tissues. Extensively studied for its capacity to promote cancer progression, heparanase enzyme was recently implicated as an important determinant in several inflammatory disorders as well. Applying immunohistochemical staining, we detected preferential expression of heparanase by epidermal keratinocytes in human psoriatic lesions. To investigate the role of the enzyme in the pathogenesis of psoriasis, we utilized heparanase transgenic mice in a model of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate-induced cutaneous inflammation. We report that over-expression of the enzyme promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecular/cellular characteristics. Importantly, heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT3, enhanced NF-κB signaling, elevated expression of TNF-α and increased vascularization. Taken together, our results reveal, for the first time, involvement of heparanase in the pathogenesis of psoriasis and highlight a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin. Heparanase inhibitors (currently under clinical testing in malignant diseases) could hence turn highly beneficial in psoriatic patients as well.

Induction of heparanase by HPV E6 oncogene in head and neck squamous cell carcinoma.

High-risk human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCCs) are highly invasive; however the identity of downstream effectors responsible for their aggressive phenotype remains underinvestigated. Here, we report that HPV-mediated up-regulation of heparanase enzyme can provide mechanistic explanation for augmented invasiveness of HPV-positive HNSCCs. Heparanase is the sole mammalian enzyme (endo-ß-d-glucuronidase) degrading heparan sulphate glycosaminoglycan, key polysaccharide of the extracellular matrix. Cleavage of heparan sulphate by heparanase leads to disassembly of extracellular barriers, enabling local invasion and metastatic spread of the tumour, and releases heparan sulphate-bound growth factors from the extracellular depots. Heparanase is tightly implicated in head and neck cancer progression; yet, molecular mechanisms underlying transcriptional activation of the heparanase gene in HNSCC are largely unknown. We found that HPV16 oncogene E6 is capable of inducing overexpression of heparanase in HNSCC. Notably, radiation treatment dose-dependently suppresses E6-induced heparanase expression in vitro. Our results provide the first evidence for a functional involvement of HPV in heparanase induction in head and neck tumourigenesis and, given ongoing clinical testing of several heparanase-inhibiting compounds, offer important avenue for future therapeutic exploration in HNSCC, as well as other HPV-associated malignancies (i.e. cervical carcinoma).

Extra domain-A fibronectin is necessary for the development of nasal remodeling in chronic allergen-induced rhinitis.

BACKGROUND: Extra domain A-containing fibronectin (EDA-FN) is necessary for the development of allergen-induced lower airway fibrosis. The pathogenesis of fibrosis in allergic rhinitis has not been well studied. OBJECTIVES: To determine whether EDA-fibronectin is necessary for the development of nasal remodeling in a murine model of chronic allergic rhinitis and in human allergic rhinitis. METHODS: EDA(-/-) and wild-type (WT) C57Bl/6 mice were sensitized intraperitoneally and then challenged with inhaled ovalbumin (OVA) or saline for 2 and 5 weeks. Clinical signs of rhinitis and histological analysis of nasal tissue were evaluated. Immunohistological staining for EDA-FN was performed in human tissue of inferior nasal conchae from patients with allergic rhinitis and controls. RESULTS: After 2 weeks of allergen exposure, only goblet cell hyperplasia and perivascular eosinophilia were observed. After 5 weeks, goblet cell number, thickening of the subepithelial layer, and extent and area of collagen deposition were increased in the nasal tissue of WT OVA (ovalbumin)-challenged mice as compared with saline controls (P < .0001, P < .0001, P = .018, and P = .03, respectively). Clinical signs of rhinitis were observed only in WT OVA-challenged mice. In the EDA(-/-) mice exposed to OVA, collagen deposition, collagen area, and subepithelial thickness showed no increase and were similar to saline control mice, whereas goblet cell hyperplasia was similar to WT OVA-challenged mice. EDA-FN expression was prominent in inferior conchae from patients with allergic rhinitis but was absent in control patients. CONCLUSION: EDA-containing fibronectin is necessary for the development of nasal tissue fibrotic remodeling process in both murine and human allergic rhinitis.

Tumor PD-L1 expression and molecular profiling are not associated with immune checkpoint inhibitor-induced thyroid dysfunction in advanced NSCLC patients.

Background: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), however are frequently associated with thyroid immune-related adverse events (IRAEs). We investigated the association between patient characteristics, tumor PD-L1 expression and molecular profile with the development of thyroid IRAEs in NSCLC patients. Methods: Single center, retrospective study including 107 NSCLC patients treated with PD-1/PD-L1 inhibitors from April 2016 to July 2020. All patients were euthyroid at baseline with at least two TSH measurements post-treatment initiation. The primary outcome was the difference in tumor PD-L1 expression in patients who developed any thyroid IRAEs versus those who remained euthyroid. Additional outcomes included development of overt thyroid dysfunction, the association of specific molecular alterations with thyroid IRAEs, and onset of thyroid IRAEs as a function of tumor PD-L1 expression. Results: Overall, 37 (34.6%) patients developed any thyroid dysfunction and 18 (16.8%) developed overt thyroid dysfunction. Tumor PD-L1 staining intensity was not associated with thyroid IRAEs. TP53 mutation was less likely to be associated with any thyroid dysfunction (p < 0.05) and no association was found between EGFR, ROS, ALK or KRAS mutations. There was no association between PD-L1 expression and time to develop thyroid IRAEs. Conclusion: PD-L1 expression is not associated with the development of thyroid dysfunction in advanced NSCLC patients treated with ICIs, suggesting that thyroid IRAEs are unrelated to tumor PD-L1 expression.

Varicocoele in adolescence and testicular cancer in young adulthood.

BACKGROUND: Elevated intrascrotal temperature has been suggested as a risk factor for testicular cancer, which is the most common neoplasm among young men. Varicocoele was linked to increased intrascrotal temperature, but whether it is associated with testicular cancer is unclear. OBJECTIVE: To explore the possible association between varicocoele at adolescence and the incidence of testicular cancer at adulthood. DESIGN, SETTING, AND PARTICIPANTS: This nationwide, population-based, historical cohort study includes 1,521,661 Israeli male adolescents (mean age 17.5 ± 0.4 years), who were screened for varicocoele during the years 1967-2012, as part of their medical assessment prior to compulsory military service. The mean follow-up was 18 ± 4.2 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The diagnosis of testicular cancer was ascertained from linkage of records to the the Israeli National Cancer Registry. Survival analysis was applied. RESULTS: In total, 53,210 adolescents were diagnosed with varicocoele stages 2 and 3 prior to military service. Of 1988 (0.13% of the total cohort) men who were diagnosed with testicular cancer during follow-up, 54 (0.1%) had varicocoele prior to military service, while 1934 (99.9%) did not; p = 0.213. The age at cancer diagnosis and the distribution of seminomas versus non-seminomas did not differ significantly between those with and without varicocoele in adolescence. In a multivariable analysis controlling for sociodemographic factors, varicocoele was not associated with testicular cancer; odds ratio = 0.816 (CI: 0.615-1.083). CONCLUSIONS: Varicocoele in adolescents was not found to be associated with testicular cancer in young adults. PATIENT SUMMARY: In light of the theoretical association between varicocoele and testicular cancer, we conducted this large population study. We found no association between varicocoele in young adulthood and testicular cancer later in life.

Angiogenesis in chronic rhinosinusitis with nasal polyps and in antrochoanal polyps.

OBJECTIVES AND STUDY DESIGN: Angiogenesis may be related to the pathogenesis and prognosis of chronic rhinosinusitis with nasal polyposis. This cross-sectional study, in a tertiary university hospital, evaluates angiogenesis parameters in nasal polyps, antrochoanal polyps and middle turbinates. SUBJECTS: Nasal polyps obtained from 24 consecutive patients, were compared to 10 normal middle turbinates and to 11 antrochoanal polyps. METHODS: Analyzing for the expression of the angiogenic marker CD34 by immunohistochemistry. Blood vessels count, vascular surface density and microvessel density were measured by manual and computerized methods. RESULTS: Angiogenesis was significantly higher in nasal polyps compared to control turbinates and to antrochoanal polyps (p = 0.0001 and p = 0.007, respectively). Antrochoanal polyps showed significantly more angiogenesis than normal middle turbinates (p = 0.001). Angiogenesis was not elevated in sub-groups of nasal polyposis patients considered to have worse prognosis. CONCLUSIONS: Angiogenesis probably plays a role in the pathogenesis of both nasal polyposis and antrochoanal polyps. However, the significantly higher angiogenesis found in nasal polyps compared to antrochoanal polyps may support a different mechanism of growth. The lack of difference between angiogenesis and nasal polyposis patients sub-groups, may imply that angiogenesis is not associated with the prognosis of chronic rhinosinusitis with nasal polyposis.

Asymptomatic pancreatic perivascular epithelial cell tumor (PEComa) in a male patient: report and literature review.

CONTEXT: Perivascular epithelial cell tumors (PEComas) are a family of rare mesenchymal neoplasms which share cellular, immunohistochemical and ultrastructural characteristics but are found in different visceral and soft tissue sites. PEComas of the pancreas are extremely rare neoplasms. CASE REPORT: We describe a 49-year-old male who was incidentally diagnosed with a pancreatic mass. Endoscopic ultrasound-guided biopsy suggested a PEComa. An uneventful pylorus-preserving pancreaticoduodenectomy was thus performed. The tumor was a solid well-circumscribed mass in the pancreatic head with dilatation of the main pancreatic duct. Histopathology revealed a well-circumscribed and vascularized neoplasm, measuring 32x27x30 mm, composed of epithelioid smooth muscle cells with clear cytoplasm rich in glycogen. The tumor exhibited immunoreactivity to alpha-smooth muscle actin and to melanoma-associated antigen HMB-45. CONCLUSIONS: Although rare, pancreatic PEComas should be included in the differential diagnosis of a pancreatic mass. Currently, the paucity of cases published makes it impossible to predict the behavior and prognosis of these tumors or to advocate an optimal therapy.

A novel technology for reversible fallopian tubal occlusion using a reverse thermo-responsive polymer-Preliminary results from a rabbit animal study.

OBJECTIVES: To determine if PF-88, a reverse thermo-responsive polymer designed to create a gel at body temperature and liquefy at a lower temperature (21°C) can reversibly occlude the fallopian tubes in rabbits. STUDY DESIGN: Mature female New Zealand White rabbits underwent laparotomy and placement of 22-gage catheter into the lumen of the distil uterine horns for evaluation of tubal patency by fluoroscopy using radio opaque contrast and treatment with PF-88. In the Acute Phase group (n = 5) after PF-88 treatment we immediately cooled the serosal surface of the tube with ice for 90 seconds to liquify the gel then reassessed patency. In the Survival Phase groups, animals recovered from the initial surgery and then underwent a second procedure for evaluation of tubal occlusion and reversibility at 4 (n = 3), 14 (n = 2), and 28 (n = 3) weeks after the initial procedure. We compared the histologic appearance of the treated fallopian tubes to untreated controls (n = 3). RESULTS: In the Acute Phase, we found all 10 fallopian tubes patent on initial evaluation, occluded following treatment with PF88, and patent following re-liquification by chilling. Animals in the Survival Group, all but one of the treated tubes appeared blocked at follow-up and patent following chilling. The treatment failure occurred in an animal in the 4-week group. Tubes treated with PF88 showed no histologic evidence of residual material or damage after removal of the polymer. CONCLUSION: The PF-88 reverse thermo-responsive polymer demonstrated the ability to reversibly block fallopian tubes for up to 28 weeks. IMPLICATIONS: The demonstration of reversible occlusion of the fallopian tube of rabbits using PF-88, a thermo-responsive reverse polymer, support additional studies to evaluate the potential of this polymer as a contraceptive in women.

Salivary Gland Heterotopia, a Clinical and Pathological TNM Staging Challenge - Carcinoma ex Pleomorphic Adenoma Arising in a Parotid Lymph node.

INTRODUCTION: Heterotopia is the presence of a particular tissue / tumor at a non-physiological / ectopic site. The study primary goals: To review the current data investigating heterotopic, normal appearing, and diseased salivary gland tumors, in lymph nodes. To describe the meticulous pathological investigation and multidisciplinary decision-making process of a heterotopic carcinoma ex pleomorphic adenoma arising in an intra-parotid lymph node. MATERIALS AND METHODS: A literature search in the "PubMed" database using key words "carcinoma ex pleomorphic adenoma", "parotid lymph node", "salivary gland" and "heterotopia" was conducted. We describe the thorough pathological investigation and clinical decision-making process, focusing TNM staging system limitations. RESULTS: A few case reports presented either normal appearing salivary tissue, benign tumors or low and high-grade salivary malignancies arising in lymph nodes. We present the investigation, controversies and treatment decision process of a 46-year-old man with CXPA in intra-parotid lymph node. CONCLUSIONS: The staging scheme does not distinguish between nodal spread and primary tumor arising in a lymph node. Multidisciplinary input regarding prognosis and follow-up plans, may consider heterotopia differently from the usual pattern of nodal spread.

Trimodal therapy in T2-4aN0M0 bladder cancer--How to select the best candidate?

The reported results of trimodal treatment (TMT) in muscle-invasive bladder cancer vary widely. We attempted to characterize the profile of ideal candidates for this approach. Between 2000 and 2019, 105 patients (median age 78 years) with T2-4aN0M0 bladder cancer were treated with TMT and analyzed retrospectively. Mean radiotherapy dose was 62 Gy (SD 8.4). Ten pretreatment prognostic parameters were evaluated including tumor diameter on pre-TURBT CT. Multivariate analyses was performed and combination of parameters was studied. After a median follow-up of 29 months, 53 patients (50.5%) developed recurrence and 70 patients (67.7%) died. Death was disease-specific in 46 patients (65.7%). Tumor diameter was the most significant prognostic parameter with p < 0.0001 for overall, disease-specific and recurrence-free survivals. For every 1 cm increase in tumor diameter, the risk of disease-specific mortality increased by 1.57. Age, cisplatin eligibility and the Charlson Comorbidity Index were significant predictors of overall survival but not of disease-specific or recurrence-free survival. Patients who were cisplatin-eligible with a tumor diameter ≤3 cm had a 5-year disease-specific survival rate of 79.2% as opposed to 33.9% in patients without one of these features (p < 0.001). When tumor diameter exceeded 5 cm (irrelevant of all other parameters), 5-year disease-specific survival rate was only 28.2%. Patient profiles can accurately predict response to TMT. In cisplatin-eligible patients with a tumor diameter ≤3 cm, TMT provides an excellent disease-specific survival rate. In patients with a tumor diameter >5 cm TMT renders unacceptably poor treatment outcomes.

Predicting and affecting response to cancer therapy based on pathway-level biomarkers.

Identifying robust, patient-specific, and predictive biomarkers presents a major obstacle in precision oncology. To optimize patient-specific therapeutic strategies, here we couple pathway knowledge with large-scale drug sensitivity, RNAi, and CRISPR-Cas9 screening data from 460 cell lines. Pathway activity levels are found to be strong predictive biomarkers for the essentiality of 15 proteins, including the essentiality of MAD2L1 in breast cancer patients with high BRCA-pathway activity. We also find strong predictive biomarkers for the sensitivity to 31 compounds, including BCL2 and microtubule inhibitors (MTIs). Lastly, we show that Bcl-xL inhibition can modulate the activity of a predictive biomarker pathway and re-sensitize lung cancer cells and tumors to MTI therapy. Overall, our results support the use of pathways in helping to achieve the goal of precision medicine by uncovering dozens of predictive biomarkers.