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Phenotypic alterations in the lung epithelium have been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but the precise mechanisms orchestrating this persistent inflammatory process remain unknown because of the complexity of lung parenchymal and mesenchymal architecture. To identify cell type-specific mechanisms and cell-cell interactions among the multiple lung resident cell types and inflammatory cells that contribute to COPD progression, we profiled 57,918 cells from lungs of patients with COPD, smokers without COPD, and never-smokers using single-cell RNA sequencing technology. We predicted pseudotime of cell differentiation and cell-to-cell interaction networks in COPD. Although epithelial components in never-smokers were relatively uniform, smoker groups represent extensive heterogeneity in epithelial cells, particularly in alveolar type 2 (AT2) clusters. Among AT2 cells, which are generally regarded as alveolar progenitors, we identified a unique subset that increased in patients with COPD and specifically expressed a series of chemokines including CXCL1 and CXCL8. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred significantly increased intercellular networks of inflammatory AT2 cells. Our results identify previously unidentified cell subsets and provide an insight into the biological and clinical characteristics of COPD pathogenesis.

Figure legends for suppremental Figure 1 to 5.

Multivariate analysis of clinicopathological factors and infiltrating immune cells

Neoplastic cancer cells and cancer stroma (including infiltrating immune cells) determine the biology and prognosis of cancer. Various types of adaptive and innate immune cells are known to infiltrate the cancer stroma. However, the patterns and spatial distribution of immune cell infiltration as well as its association with tumor histology remain poorly understood. To address these issues, we comprehensively analyzed the infiltrating immune cells present in lung adenocarcinoma. The principal types of both adaptive and innate infiltrating immune cells were immunohistochemically evaluated in the predominant histologic components of 111 lung adenocarcinomas. The same analysis was also carried out on 143 samples of histologic subtypes making up more than 20% of tumors. As a result, plasma cells and B cells with interfollicular distribution were almost exclusively observed in invasive histologic subtypes, while an increased number of mast cells were observed in noninvasive histologic subtypes. Cluster analysis revealed four distinct immunosubtypes (CD8, mast cell, macrophage/dendritic cell, and plasma cell subtypes) based on the infiltrating immune cell profiles. These immunosubtypes correlated with histologic subtypes, and univariate and multivariate analyses identified the plasma cell subtype as an independent negative prognostic factor. These plasma cells may be one of the major producers of the immunosuppressive cytokine IL35 in cancer stroma. Cancer Immunol Res; 4(3); 234–47. ©2016 AACR.

Figure S1. Infiltration of immune cells and grades of histological subtypes. Figure S2. Infiltration of interfollicular plasma cells and Kaplan-Meier curves for DFS. Figure S3. Infiltration of interfollicular mast cells and Kaplan-Meier curves for DFS. Figure S4. Plasma cell/CD8 ratio and Kaplan-Meier curves for DFS. Figure S5. Immunohistochemical staining for immunoglobulins and PD-L1.

Supplementary Table S1. Mutation signature analysis. Supplementary Table S2. Baseline characteristics of the transdifferentiated SCLC patients included in this study. Supplementary Table S3. Intensity of EGFR and Ki67 staining in lung cancer tissues obtained from the indicated patients. Supplementary Table S4. Baseline characteristics of the primary SCLC patients included in this study. Supplementary Table S5. Genetic alterations of the indicated lung cancer cell lines. Supplementary Figure S1. FGF9 immunohistochemistry staining in lung cancer cell lines. Supplementary Figure S2. List of the mutated genes before and after transdifferentiation. Supplementary Figure S3. Gene ontology term analysis in the context of upregulated (A) and downregulated (B) genes. Supplementary Figure S4. Computed tomography images of the patients (Case2-4) during the course of gefitinib therapy. Supplementary Figure S5. EGFR, Ki67 and FGFR1 immunohistochemistry staining of tissues from Cases #5 and #6. Supplementary Figure S6. mRNA expression levels of FGF family genes in lung cancer cell lines. Supplementary Figure S7. Expression of FGF9 and FGF2 in human NSCLC and SCLC cells. Supplementary Figure S8. Functional evaluations of FGF9 in human SCLC cell lines. Supplementary Figure S9. Tumor volumes after MLE12-EGFR transplantation. Supplementary Figure S10. Expression levels of Fgfr family genes in MLE12-FGF9 cells in vitro and in vivo. Supplementary Figure S11. Characteristics of lung adenocarcinoma cell lines. Supplementary Figure S12. In vivo evaluations of FGF9 in H2087 and H2110 cells.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9–FGFR axis as a therapeutic target for transdifferentiated SCLC.Significance:This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.

The functions of isoprothiolane (IPT), which is a fungicide against rice blast, in carotenoid accumulation were examined in satsuma mandarin fruit (Citrus unshiu Marc). Whole trees were treated with IPT at 25 days before harvest. Concentrations of gibberellic acid-1 (GA1) and GA4 in the flavedo of IPT-treated trees were significantly decreased at 5 days after treatment (DAT) compared to the untreated control. The expressions of CitGA20ox1 in IPT-treated flavedo were lower than those in the untreated controls at 5 and 25 DAT. The CitGA3ox expressions in IPT-treated flavedo were lower than those in the untreated control at 5 DAT. ABA concentrations in IPT-treated flavedo were significantly higher than those in the untreated control at 25 DAT. The concentrations of b-cryptoxanthin in IPT-treated flavedo were higher than those in the untreated control at 25 DAT. The chlorophyll concentrations of IPT-treated flavedo were lower than those in the untreated control at 5 and 20 DAT. These results suggest that IPT advances b-cryptoxanthin accumulation through the regulation of endogenous GA1 and GA4 based on the inhibition of CitGA20ox1 and CitGA3ox expressions. It is possible that IPT can be utilized to improve coloration in other citrus fruit.

Background Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms with malignant potential. No effective treatment other than surgical resection has been established for lung metastases of PEComas. We describe a patient who underwent complete surgical resection via bilateral lobectomy involving a two-step procedure for lung metastases 8 years after undergoing radical surgery for a colonic PEComa. Case presentation A 53-year-old woman underwent partial colectomy for a PEComa in the transverse colon 8 years ago. She presented with an abnormal chest shadow during a health examination. Chest computed tomography (CT) revealed a solid nodule 2 cm in diameter located centrally in the right lower lobe and a solid nodule 3 cm in diameter located centrally in the left upper lobe. Positron emission tomography revealed 18F-fluorodeoxyglucose uptake in these nodules. These nodules were suspected to be metastatic tumors of the colonic PEComa and were considered for complete surgical resection. Segmentectomy could not be performed because of the anatomical location of the tumors straddling the segments; therefore, bilateral lobectomy was required for complete surgical resection. Therefore, we performed two-step lobectomy safely with the expectation of pulmonary function recovery. Microscopically, the tumors were diagnosed as lung metastases of the PEComa. One year after the last surgery, no recurrence was detected, and the patient’s pulmonary function improved. Conclusions This case indicates that even if multiple lung metastases of a PEComa require bilateral lobectomy, complete resection with a two-step surgery may be considered.

This study evaluated the feasibility of performing non-intubated video-assisted thoracoscopic surgery (VATS) with local anesthesia for parapneumonic effusion and empyema resistant to conservative treatment.We retrospectively reviewed 80 patients who underwent surgery for parapneumonic effusions and empyema between 2015 and 2021. Patients were divided into those who received non-intubated local anesthesia and general anesthesia during surgery. Patient demographics, characteristics, laboratory findings, treatment progress, and treatment outcomes were compared. The primary outcomes were duration of postoperative drainage, postoperative complication rate, and postoperative mortality rate within 30 days.Among patients who received local (n = 21) and general anesthesia (n = 59), there was a significant difference in age (median 79.0 years [interquartile range (IQR) 77.0-80.0] vs. 68.0 years [IQR 54.5-77.5]; p 0.001), preoperative performance status (3.0 [IQR 2.0-4.0] vs. 2.0 [IQR 1.0-3.0]; p 0.001), and operative time (69 min [IQR 50-128] vs. 150 min [IQR 107-198]; p 0.001) but not in preoperative white blood cell count (12,100/μL [IQR 8,400-18000] vs. 12,220/μL [IQR 8,950-16,724]; p = 0.840), C-reactive protein (15.2 mg/dL [8.8-21.3] vs. 17.9 mg/dL [IQR 9.5-23.6]; p = 0.623), postoperative drainage period (11 days [IQR 7-14] vs. 9 days [7-13]; p = 0.216), postoperative hospital stay (22 days [IQR 16-53] vs. 18 days [IQR 12-26]; p = 0.094), reoperation rate (9.5% vs. 15.3%; p = 0.775), postoperative complication rate (19.0% vs. 18.6%; p = 0.132), or postoperative 30-day mortality rate (4.8% vs. 0%; p = 0.587).VATS using local anesthesia is feasible for patients with treatment-resistant parapneumonic effusion and empyema with poor general condition.

OBJECTIVES We retrospectively analysed the surgical prognosis of patients with pathological stage I non-small-cell lung cancer (NSCLC) who after complete resection underwent low-dose computed tomography (LDCT) or conventional CT as postoperative surveillance. METHODS We investigated 416 patients who underwent lobectomy or segmentectomy between January 2013 and December 2016. We compared the prognosis between the LDCT and conventional CT groups using the propensity score-matched analysis. RESULTS The median follow-up period was 57 months. Cancer recurrence occurred in 47 patients (11.3%). In the entire cohort (n = 416), recurrence-free survival (RFS) and overall survival (OS) were better in the LDCT group (P = 0.001 and 0.002, respectively). Both intrathoracic recurrence and distant metastasis were higher in the conventional group (P = 0.015 and 0.009, respectively). However, there was no statistical difference in the factors leading to recurrence detection (routine radiological examination, symptoms and elevated tumour markers: all P > 0.05). Both groups were matched using a ratio of 1:1. The area under the receiver operating characteristic curve was 0.788. A total of 226 patients were successfully matched. After matching, there was no statistical difference between the 2 groups for RFS and OS (P = 0.263 and 0.226). There were also no statistical differences in recurrence rate, the factors leading to recurrence detection or recurrence site (all P > 0.05). CONCLUSIONS After using propensity score matched, RFS and OS did not differ significantly between LDCT and conventional CT groups. Retrospective comparisons suggest no disadvantages of using LDCT for postoperative surveillance of pathological stage I NSCLC. Further validation will be needed in the future.

In this study, we analyzed prognostic radiological tools and surgical outcomes for radiologically pure solid adenocarcinomas (AD) and squamous cell carcinoma (SQ) in clinical stage IA. We retrospectively investigated 130 patients who underwent surgical resections. We assessed the predictive risk factors for recurrence and pathological lymph node metastasis (LNM). There was no statistical difference in recurrence free survival (RFS) or cancer-specific survival (CSS) between AD and SQ groups (p = 0.642 and p = 0.403, respectively). In the whole cohort, tumor size on lung window and mediastinal settings, and tumor disappearance ratio using high-resolution computed tomography (HRCT) were not prognostic parameters (p = 0.127, 0.066, and 0.082, respectively). The maximal standardized uptake value (SUVmax) using positron emission tomography-CT was associated with recurrence (p = 0.016). According to the receiver operating characteristic curve, the cut-off value of SUVmax for recurrence was 4.6 (p = 0.016). The quantitative continuous variables using any radiological tools were not associated with LNM. However, tumor diameter on mediastinal setting ≥8 mm with SUVmax ≥2.4 could be a risk factor for LNM. Pure solid AD and SQ were equivalent for the RFS and CSS. SUVmax was useful to predict recurrence. The tumor diameter on a mediastinal setting and SUVmax were useful in predicting pathological LNM.

OBJECTIVES Postoperative pulmonary function is difficult to predict accurately, because it changes from the time of the operation and is also affected by various factors. The objective of this study was to assess the accuracy of predicted postoperative forced expiratory volume in 1 s (FEV1) at different postoperative times after lobectomy. METHODS This retrospective study enrolled 104 patients who underwent lobectomy by video-assisted thoracic surgery. Pulmonary function tests were performed preoperatively and postoperatively at 3, 6 and 12 months. We investigated time-dependent changes in FEV1. In addition, the ratio of measured to predicted postoperative FEV1 calculated by the subsegmental method was evaluated to identify the factors associated with variations in postoperative FEV1. RESULTS Compared with the predicted postoperative FEV1, the measured postoperative FEV1 was 8% higher at 3 months, 11% higher at 6 months and 13% higher at 12 months. The measured postoperative FEV1 significantly increased from 3 to 6 months (P = 0.002) and from 6 to 12 months (P = 0.015) after lobectomy resected lobe, smoking history and body mass index were significant factors associated with the ratio of measured to predicted postoperative FEV1 at 12 months (P CONCLUSIONS Postoperative FEV1 increased up to 12 months after lobectomy by video-assisted thoracic surgery. The predicted postoperative pulmonary function was underestimated after 3 months, particularly after lower lobectomy.

Although the value of video-assisted thoracic surgery for acute pyothorax is becoming widely recognized, the optimal timing of surgery has not been established. Therefore, we aimed to determine the optimal timing of video-assisted thoracic surgery in acute pyothorax. We retrospectively reviewed 38 consecutive video-assisted thoracic surgeries performed for acute pyothorax between January 2013 and December 2017 at our institution. Data were analyzed using the independent samples t test and Mann–Whitney U test. A receiver-operating characteristic curve was used to identify the optimal time for intervention. The average time from disease onset to surgery was 17.9 days, and the average preoperative drainage period was 8.3 days. The operation was completed in all patients with video-assisted thoracic surgery curettage and drainage under general anesthesia; single lung ventilation was administered, and one or two thoracic drains were placed. The average postoperative drainage period was 10.8 days. Intraoperative complications were observed in two cases; no perioperative death occurred. Additional surgery was performed in four cases because of poor treatment response. There was no recurrence of pyothorax over a mean postoperative follow-up period of 42.5 months. A receiver-operating characteristic curve showed that the cut-off time from disease onset to surgery was 21.0 days; complication rates were 14.3% and 25.0% for patients operated on before and after 21 days, respectively. Thoracoscopic surgery for acute pyothorax is safe and curative, and should be performed within 21 days of disease onset to avoid postoperative complications.

To elucidate the clinical, pathologic, and prognostic impacts of epidermal growth factor receptor (EGFR) mutation and mutation subtypes in early-stage lung cancer, the study investigators conducted a retrospective analysis of the Japanese Joint Committee of Lung Cancer Registry database (a nationwide database for patients with surgically resected lung cancer; n = 18,973).Of 13,951 patients classified as having nonsquamous non-small cell lung cancer in the database, 5780 patients (41.0%) had been tested for an EGFR mutation and were included in this study.An EGFR mutation was detected in 2410 patients (41.7%), and the presence of an EGFR mutation was significantly correlated with clinicopathologic factors such as the presence of ground-glass opacity (P.001) and better prognosis. Analysis of initial recurrence sites identified significantly higher frequencies of brain and adrenal gland metastases in patients with and without an EGFR mutation, respectively. Of 2410 patients with EGFR mutations, 983 (40.8%) had an exon 19 deletion (Exon 19 Del), 1170 (48.5%) had an L858R mutation, and 257 (10.7%) had other EGFR mutations. A higher smoking rate was found in patients with other EGFR mutations (P = .02). In the comparison of Exon 19 Del and L858R, we found that Exon 19 Del correlated with younger age (P.001), a higher rate of pure solid tumors (P.001), advanced pathologic stage (trend P.001), and poorer recurrence-free survival (P = .001).In addition to the clinicopathologic and prognostic impacts of EGFR mutation status, tumors with Exon 19 Del have a more aggressive phenotype and patients have a poorer prognosis than with L858R in early-stage lung cancers.

OBJECTIVES Radiologically invasive non-small-cell lung cancer, defined as consolidation size to maximum tumour diameter ratio of over 0.5, is associated with pathological invasiveness and worse prognosis. However, there are no real-world, nationwide database studies on limited resections that consider radiological invasiveness. This study aimed to investigate the prognostic validity of limited resection, such as segmentectomy and wedge resection, in cStage IA (TNM 8th edition) radiologically invasive lung cancer. METHODS We conducted a retrospective analysis of patients who underwent complete resection according to the Japanese Joint Committee of Lung Cancer Registry Database. The relationship between surgical procedures and prognosis was examined using stratification by cT factor and radiological invasiveness. RESULTS Among the 5,692 patients enrolled, lobectomy, segmentectomy and wedge resection were performed in 4,323 (80.0%), 657 (11.5%) and 712 (12.5%) patients, respectively. Multivariable analysis with or without propensity score matching indicated that older age, poor performance status and wedge resection were significantly associated with worse prognosis and that patients who underwent segmentectomy showed an equivalent prognosis to those who underwent lobectomy. Subset analyses revealed that segmentectomy showed an equivalent prognosis to lobectomy in patients with cT1b or less, but not in those with cT1c, especially for non-pure radiological invasive cT1c; 5-year overall survival rates were 91.4% vs 90.4% in cT1b with non-pure radiological invasiveness and 80.0% vs 83.8% in cT1b with pure radiological invasiveness, respectively. CONCLUSIONS Segmentectomy can be an alternative to lobectomy in patients with radiologically invasive lung cancer with cT1b or less but not in those with cT1c.

OBJECTIVES Weight assessment is an easy-to-understand method of health checkup. The present study investigated the association between weight loss (WL) after lung cancer (LC) surgery and short–mid-term prognosis. METHODS The data of patients who underwent radical lobectomy for primary LC were assessed between December 2017 and June 2021. Percentage weight gain or loss was determined at 3, 6 and 12 months postoperatively based on preoperative weight. The timing of decreased weight was divided into 0–3, 3–6 and 6–12 months. We also evaluated the relationship between severe WL (SWL) and prognosis. RESULTS We reviewed 269 patients, of whom 187 (69.5%) showed WL within 1 year after surgery. The interquartile range for maximal WL was 2.0–8.2% (median 4.0%). Furthermore, we defined SWL as WL ≥8%. Twenty-five patients (9.3%) died: 9 from primary LC and 16 from non-LC causes. Cancer recurrences occurred in 45 patients (16.7%). WL occurred from 6 to 12 months postoperatively was associated with poor overall survival and recurrence-free survival (P CONCLUSIONS WL from 6 to 12 months postoperatively and SWL were associated with poor prognosis. Ongoing nutritional management is important to prevent life-threatening WL in patients with predictive factors.

In patients with clinical stage I non-small cell lung cancer (NSCLC), the prediction of occult lymph node metastasis (LNM) based on a combination of morphology using high-resolution computed tomography (HRCT) and metabolism using positron emission tomography (PET)-CT is unknown. The present study evaluated the use of predictive radiological tools, chest CT and PET-CT, for occult LNM in patients with clinical stage I NSCLC. The records of patients who underwent lobectomy between July 2014 and November 2021 were retrospectively reviewed. The differences in clinicopathological parameters, including CT and PET, between the LNM and non-LNM groups were assessed. Pure solid tumor was defined as a consolidation-to-tumor ratio of 1. The optimal cut-off value for predictive radiological tools for LNM was assessed according to the area under the receiver operating characteristic (ROC) curve. The present study included 288 patients, of whom 39 (13.5%) had LNM; of these 38 (97.4%) were pure solid type. Larger consolidation size (CS), higher maximal standardized uptake (SUVmax) value and histological type were statistically associated with LNM (all P0.05). The optimal cutoff values of CS and SUVmax for predicting LNM were 19 mm and 5.5 respectively, as assessed using the area under the ROC curve. The combination of CS ≥19 mm and SUVmax ≥5.5 demonstrated a markedly higher odds ratio (9.184; 95% CI, 4.345-19.407) than each parameter individually. The minimum values of CS and SUVmax associated with LNM were 10 mm and 0.8 respectively. Pure solid formation and CS as morphology and SUVmax as metabolism were useful tools that complemented each other in predicting LNM. The combined method of evaluating SUVmax and CS may identify eligibility for LN dissection. However, considering the minimum values of CS and SUVmax in LNM, it cannot affirm the omission of LN dissection for cases that do not meet the combined criteria using HRCT and PET-CT.

The aim of this study was to evaluate the impact of the preoperative body mass index (BMI) on the postoperative outcomes in patients with completely resected non-small cell lung cancer (NSCLC).The data of patients with NSCLC in whom R0 resection was achieved were extracted from the database of NSCLC samples accumulated by the Japanese Joint Committee of Lung Cancer Registry in the year 2010, and the surgical outcomes including postoperative morbidity, mortality and the prognosis, were evaluated.Among 18,978 registered lung cancer cases, 16,509 patients (9996 men and 6513 women) were extracted. The median of age was 69 years old, and the histologic types included adenocarcinoma (n = 12,029), squamous cell carcinoma (n = 3286), large-cell carcinoma (n = 488) and others. The patients were divided into three groups according to their BMI: normal (BMI 18.5 to25), underweight (BMI 18.5) and overweight (BMI ≥ 25). Multivariate logistic regression analyses of factors associated with postoperative morbidity and mortality showed no significant differences among the three groups. In comparison to the normal group, the overall survival (OS) of the underweight group was significantly worse (p 0.001) while that of the overweight group was marginally better (p = 0.075). A multivariate analysis of factors associated with OS showed that in addition to the age, sex and clinical stage, the preoperative BMI (underweight group vs. normal group: hazard ratio [HR] 1.417 [95% confidence interval {CI}: 1.278-1.572, p 0.001], overweight group vs. normal group: HR 0.883 [95% CI: 0.806-0.967, p = 0.007]) was an independent prognostic factor. A multivariate analysis for the disease-free survival (DFS) also showed the preoperative BMI to be an independent significant prognostic factor.The preoperative BMI is an independent prognostic factor in patients with completely resected NSCLC. A low preoperative BMI was associated with significantly poor survival in Japan.

This study aims to assess the feasibility and impact on long-term pulmonary function of chest drain removal on the operation day following thoracoscopic right upper lobectomy for clinical stage I non-small cell lung cancer. We retrospectively evaluated the data of 116 patients between May 2013 and March 2019. We evaluated the correlations of clinical parameters of chest drain removal and medium- and long-term pulmonary function by comparing removal on operation day (R group) and retainment (D group). The R group comprised 64 patients, and the D group had 52 patients. Fifty patients (96.2%) in the D group had chest drain removed within 3 postoperative days. Since February 2016, chest drain removal on operation day was performed in 64 of 74 patients (86.5%) according to our chest drain removal protocol. Removal of chest drains on operation day was associated with shorter postoperative hospitalization (p

We aimed to analyze the feasibility and risk factors associated with early mobilization (EM) within 4 h after thoracoscopic lobectomy and segmentectomy. This study retrospectively evaluated 214 consecutive patients who underwent thoracoscopic anatomical pulmonary resection using our EM protocol between October 2017 and February 2019. We compared the correlations of the patients’ characteristics including the total number of drugs and perioperative parameters such as air leak, and orthostatic hypotension (OH) between the EM (E group) and failed EM (F group) groups. Second, we evaluated risk factors for OH, which often causes critical complications. A total of 198 patients (92.5%: E group) completed the EM protocol, whereas 16 patients did not (7.5%: F group). The primary causes of failure were severe pain, air leak, postoperative nausea and vomiting, and OH (n = 1, 3, 8, and 4). Upon univariate analysis, air leakage, OH, and non-hypertension were identified as risk factors for failed EM (all p